C8.Infections and antimicrobial therapy

At some point in their life, everybody is likely to suffer an infection that will require treatment with

antimicrobial agents. However, such an infection is unlikely to prove serious unless there is some

underlying chronic condition, a complication, or a highly resistant pathogen is implicated. Only

65 years ago death from acute infection was common and antimicrobial chemotherapy was still in its infancy.

Antimicrobial chemotherapy began with the introduction of the sulphonamides in the 1930s,

and this was followed by penicillin in the 1940s. The original benzylpenicillin had an enormous

impact on the early therapeutics of infection, but now has only limited applications. This illustrates

the important principle that the therapeutics of infectious disease must be developed continually

in order to remain effective. Compare this situation with that of diabetes, in which the major

therapy (insulin) was introduced in the 1920s and remains largely unchanged up to the present.

The disease itself has neither changed nor ‘adapted’ to the treatment. By contrast, the staphylo-

coccal organism against which benzylpenicillin was originally so dramatically effective is now

almost universally resistant to antimicrobials.

It must be emphasized that recommended antimicrobials and doses change from time to time and depend on the location of patients. Current local guidance must be consulted before making any therapeutic recommendations.

Introduction

antimicrobial therapy

Before   considering   individual   agents,   we

review a simple classification system for microor-

The  constantly  changing  pattern  of  microbial

sensitivity has been a prime factor contributing to

the proliferation of antimicrobial agents. Most of

this chapter addresses the treatment of bacterial

infections but similar principles apply to the treat-

ment of fungal and viral infections. We use the

term  antimicrobials  when  describing  chemo-

therapeutic agents generally, and antibacterial,

antifungal and antiviral for those used specific-

ally to treat corresponding infections. The term

‘antibiotic’ was originally applied only to those

agents derived from living organisms, usually

fungal   or   bacterial.   However,   many   anti-

microbials are now manufactured synthetically

or semi-synthetically, e.g. chloramphenicol and

the more recent penicillins, so ‘antibiotic’ is now

synonymous with ‘antimicrobial’. Similarly, the

unqualified term ‘chemotherapy’ is now usually

applied to the treatment of neoplastic disease,

discussed in Chapter 10.

Although there is a very wide range of anti-

bacterials available, patients may commonly be

prescribed agents from among the penicillin,

cephalosporin, macrolide, tetracycline or quin-

olone groups. However, in some situations (e.g. a

lower urinary-tract bacterial infection) the most

likely pathogen is known to be Escherichia coli,

an organism against which only some of these

agents are effective. The prescriber then has to

choose the most appropriate antimicrobial for

treating that infection in their particular patient,

guided by advice from the pathologist or the

results of laboratory tests.

This chapter first describes the various groups

of antimicrobial agents, and then discusses the

principles of selection by considering the various

steps in the decision-making process that should

be  taken  when  diagnosing  and  treating  an

infected patient. The final part of the chapter

will consider the application of these principles

in the treatment of some important infections.

Although   the   treatment   of   HIV/AIDS   is   a

speciality,  the  principles  of  its  treatment  are

discussed,   together   with   some   AIDS-related

infections.

The chapter also discusses antibiotic-

associated colitis.

ganisms and define the concepts of minimum inhibitory and microbicidal concentrations.

Classification of microorganisms

Table  8.1  presents  some  aspects  of  bacterial

classification.  Bacteria  may  be  described  as

Gram-positive  or  Gram-negative,  depending

on whether the bacterial cell wall retains the

Gram stain used for microscopy, and by their

shape, i.e. bacillus (rod), coccus (spherical) or

spiral.  Aerobic  organisms  only  grow  in  the

presence  of  oxygen  and  anaerobic  species

require  the  absence  of  oxygen  for  growth.

Facultative organisms are able to grow with or

without  oxygen,  reflecting  a  more  adaptable

metabolism.

Thus  Escherichia  coli  is  described  as  a  fac-

ultatively anaerobic, Gram-negative rod. Refine-

ments of classification include whether a stain

cannot be removed by acid, i.e. they are acid-

fast, e.g. Mycobacterium spp. If an organism is

found in the human GIT, the name used often

indicates  this,  e.g.  the  species  Enterococcus

faecalis. Some of these descriptions may help

predict likely sensitivities to antibacterials. In

general, it is more difficult for antibacterials to

penetrate the cell wall of Gram-negative bacteria

than Gram-positive ones.

Antibacterials that are predominantly effective

against a restricted range of either Gram-positive

or (less commonly) Gram-negative bacteria are

said to possess a narrow spectrum of activity,

whereas those that are effective against several

types of organism are termed broad-spectrum.

Anaerobes  may  be  either  Gram-positive,  e.g.

the clostridia, or Gram-negative, e.g. Bacteroides

spp.,  and  usually  require  special  groups  of

agents. The antimicrobials used to treat other

classes of microorganism, such as viruses, fungi

or protozoa, are largely narrow-spectrum agents,

though some newer antifungal agents, e.g. caspo-

fungin and voriconazole, are active against a range

of fungi. Antiviral agents usually have a fairly

restricted spectrum, e.g. aciclovir is effective only against herpes viruses.

Table 8.2 gives an approximate guide to the sensitivity of some bacterial pathogens to the

antimicrobials in common use.

Minimum inhibitory and microbicidal (bactericidal) concentrations

For  an  antimicrobial  agent  to  be  effective  in

treating a particular infection it must be able to

inhibit the growth of the causative organism or

to kill it. The minimum inhibitory concentra-

tion (MIC) is the minimum concentration of an

antimicrobial that is capable of inhibiting the

growth  of  an  organism  and  the  minimum

bactericidal concentration (MBC) is the lowest

concentration that will kill it. Because of statis-

tical   uncertainties   in   counting   very   low

numbers of survivors, it is common to deter-

mine  the  concentration  of  an  antimicrobial

agent that kills 50% of a population, i.e. the

MBC50. If the MIC or MBC for an organism is

higher than the concentration of an antimicro-

bial that can reasonably be achieved clinically,

that  organism  is  described  as  being  resistant.

Thus, an antimicrobial agent will possess a spec-

trum of activity, those organisms inhibited at

low  MIC  being  termed  sensitive  and  those

inhibited only at a clinically unattainable MIC

being resistant.

However, the distinction between MIC and

MBC is often clinically irrelevant, because inhi-

bition may be perfectly satisfactory if immune

mechanisms (Chapter 2) are able to eliminate

the  inhibited  organisms.  Table 8.2  gives  the

approximate sensitivities of a range of Gram-

positive and Gram-negative pathogens to the

common antibacterial agents. However, many

factors other than intrinsic sensitivity or resis-

tance are involved, e.g. acquisition of resistance

factors  and  the  emergence  of  new  mutants.

Further, if a sufficiently high, non-toxic dose of,

for example, a penicillin is used, many organ-

isms that are normally considered to be resistant

will be inhibited. With some diseases, e.g. bac-

terial endocarditis, it is essential to use bacteri-

cidal  agents,  to  penetrate  the  vegetations  in

which the organisms are protected (p. 564), so

that the organisms are killed, not merely inhib-

ited, in order to prevent relapse. In such cases

the MBC is more relevant.

Classification and properties of antimicrobials

Antimicrobials may be classified by their chem-

ical structure, mode of action or spectrum of

activity.

Chemical structure

For  many  purposes,  the  classification  of  an

antimicrobial by its chemical structure (Figure

8.1) may be the most convenient because the

group, having similar basic structures, will cause

similar adverse reactions, e.g. allergic reactions

with penicillins or ototoxicity and nephrotoxi-

city with aminoglycosides. This type of classifi-

cation depends on the chemical nucleus of the

original (parent) drug. Different side chains are

attached to this basic nucleus to form the various

members  of  the  group,  which  often  possess

properties different from those of the parent

compound.   Such   derivatives   may   have   an

extended  spectrum  of  activity,  the  ability  to

overcome    normally    resistant    organisms,

improved   bioavailability,   resistance   to   acid

inactivation in the stomach or fewer adverse

effects.

Mode of action

The modes of action of antimicrobials (Table 8.3)

are  of  little  practical  therapeutic  relevance,

though  it  may  determine  the  spectrum  of

activity. However, there is one aspect in which the distinction between bacteriostatic  agents

and bactericidal ones may be important. Thus

tetracyclines, sulphonamides and low doses of

erythromycin are bacteriostatic agents. The peni-

cillins and most other antibacterials are bacteri-

cidal and it is this group that must be used if it is

necessary to eliminate organisms completely to

avoid persistent problems, e.g. in bacterial endo-

carditis (p. 564). This distinction may sometimes

be a concentration effect (see above). Further-

more, host defence mechanisms play an impor-

tant  part  in  eliminating  the  effects  of  an

infection (e.g.   pus),   even   with   bactericidal

agents.

The ability to use antimicrobials effectively to

cure human disease relies on selective toxicity,

i.e. structural or metabolic differences between

the microbial and host (human) cells. Because

penicillins  specifically  inhibit  a  step  in  the

formation of bacterial cell walls, which are not

present in mammalian cells, they are virtually

non-toxic to animals. The aminoglycosides (e.g.

gentamicin)  interfere  with  bacterial  ribosomal

activity  and,  fortunately,  bacterial  ribosomes

differ from human ones sufficiently to enable

relatively   selective   action.   However,   these

antimicrobials may still be toxic to man, due to

their action as allergens in low concentration

or  causing  other  toxicities  when  present  in

sufficiently high concentration.

Activity spectrum

The problem faced by prescribers is to decide

which of many antimicrobials will be the most

effective against the organism responsible. In the

absence of sensitivity testing and identification

this decision must be based on a knowledge of

the spectrums of activity of available antimicro-

bials (Table 8.2)  and  local  knowledge  of  the

most  likely  infective  agent  in  a  particular

patient: this is empirical treatment, sometimes

described as treating ‘blind’ or on a ‘best guess’

basis (see p. 538). Monotherapy with the single

most  effective  narrow-spectrum  agent  is  the

usual aim.

Penicillins

Chemical structure

The penicillins possess a beta-lactam group as

part of the parent nucleus (6-amino-penicillanic

acid;  Figure 8.1).  The  cephalosporins,  mono-

bactams and carbapenems are also beta-lactam

antibacterials, although the parent nuclei differ

somewhat  in  each  case.  The  substitution  of

different side chains on the parent nucleus has

produced compounds with an extended spec-

trum of activity,  the  ability  to  overcome  the

resistance   of   some   bacteria   to   the   parent

compound and improved bioavailability.

Spectrum of activity

The  original  benzylpenicillin  (penicillin  G)  was

active only against Gram-positive organisms (e.g.

Staphylococcus aureus) and Gram-negative cocci

(e.g.  Neisseria  meningitidis  and  N.  gonorrhoea).

Despite resistance problems, this drug remains

the  most  effective  agent  for  the  treatment  of

streptococcal infection in the UK and strepto-

coccal resistance is rarely a problem, except for

Enterococcus faecalis. Benzylpenicillin also remains

the first-line treatment for both Neisseria meningi-

tidis (the  meningococcus)  and  N.  gonorrhoea

(the gonococcus), both Gram-negative species,

although acquired resistance is limiting its use as

a sole agent for the latter. All other Gram-negative

organisms are inherently resistant.

Beta-lactamase-resistant penicillins

Staphylococcus aureus, one of the most important

wound  pathogens,  was  initially  satisfactorily

treated  with  benzylpenicillin.  However,  90%  of

Staph. aureus isolates now produce the enzyme

beta-lactamase (penicillinase), which splits the

beta-lactam  nucleus  and  renders  the  anti-

microbial ineffective. Indeed, most beta-lactam

antibacterials may be inactivated by staphylo-

coccal  beta-lactamase.  Penicillins  have  been

developed  that  are  beta-lactamase  resistant;

notably methicillin and flucloxacillin. Methicillin is

not used clinically now, but resistance to it is used

as  a  marker  for  methicillin-resistant  Staph.

aureus (MRSA; see below). Flucloxacillin is now

the most widely prescribed penicillin in Staph.

aureus infections, because it is resistant to peni-

cillinase and has superior oral bioavailability.

However, as a result of gaining beta-lactamase

stability, the spectrum of this group is narrowed.

Even though flucloxacillin retains activity against

streptococci, its MIC against these organisms is

greater than that of benzylpenicillin.

Flucloxacillin is therefore restricted to the treat-

ment of suspected or confirmed Staph. aureus

infections, all of which are assumed to be resistant

to benzylpenicillin. If more than this single species

is suspected in a particular infection, another

Penicillins          519

antibacterial  must  be  added.  Alternatively,  a beta-lactamase inhibitor, e.g. clavulanic acid or tazobactam, may be used with a broad-spectrum penicillin, e.g. amoxicillin plus clavulanic acid (as co-amoxiclav  in  the  UK)  and  piperacillin  plus tazobactam (marketed as Tazocin).

Broad-spectrum penicillins

Ampicillin was the first broad-spectrum penicillin

developed  and  extended  the  Gram-negative

range of penicillins to include Haemophilus and

Escherichia  coli  species.  However,  a  common

observation is that as the spectrum of activity of

an  antimicrobial  is  extended  into  the  Gram-

negative  range,  its  usefulness  against  Gram-

positive  organisms  diminishes.  Unfortunately,

many  strains  of  Gram-negative  organisms  are

now resistant to ampicillin, its activity against

many other Gram-negative organisms is unim-

pressive and it is completely ineffective against

Pseudomonas spp. Amoxicillin, a prodrug of ampi-

cillin, has better bioavailability (see below), but a

similar activity spectrum, and is widely used.

Carbenicillin  was  the  first  antipseudomonal

penicillin, but this has now been superseded by

the ureidopenicillins, e.g. piperacillin and ticar-

cillin, which are available only for IV use. There

is little to choose between these. Although the

ureidopenicillins are also active against Gram-

positive  organisms,  the  older  penicillins  are

usually used against these infections because

they are often effective at lower concentrations,

are cheaper, and may be administered orally.

As well as being used for the empirical treat-

ment of septicaemia, the ureidopenicillins are also  used  prophylactically  in  certain  surgical procedures or in immunocompromised patients. However,  they  are  beta-lactamase  susceptible and so are available only as co-formulations with beta-lactamase  inhibitors,  e.g.  tazobactam  or clavulanic  acid.  Ticarcillin  and  piperacillin  are available only in combination with clavulanic acid and tazobactam, respectively.

The data in Table 8.2 may be taken to imply

that most infections could be adequately treated

with a ureidopenicillin, and that there could be little  reason  to  prescribe  any  other  type  of penicillin. However, drug penetration to the site of infection, cost, ease of administration, resis-

tance of certain strains, toxicity and other factors may affect antimicrobial choice in addition to activity spectrum (Figure 8.2).

Bioavailability and formulation

A particular problem of benzylpenicillin is that it

can only be administered parenterally because

it is inactivated by gastric acid. The substitution

of  a  phenoxymethyl  group  for  benzyl,  giving

phenoxymethylpenicillin  (penicillin  V),  confers

improved acid stability and absorption, but it is

less active. Oral bioavailability is improved still

further by synthesizing a derivative, e.g. amoxi-

cillin, a prodrug of ampicillin. It is acid-stable, well

absorbed orally and absorption is not affected by

the presence of food, making for simpler dosing,

the blood levels achieved orally being similar

to those following IM injection of ampicillin. It

is used widely in clinical practice and is the

preferred aminopenicillin, except for the treat-

ment  of  shigellosis (p. 569).  However,  it  is

penicillinase-sensitive and so is often used in

combination  with  the  penicillinase  inhibitor,

clavulanic acid.

It is sometimes advantageous to administer a

single high dose of penicillin intramuscularly,

using the depot product procaine benzylpenicillin

(unlicensed, available through the named patient

mechanism in the UK), but this is only slowly

absorbed and is now used only to treat syphilis, to

avoid  the  need  for  repeated  injections  of

benzylpenicillin and the consequent likelihood of

patients dropping out from treatment. For other

purposes,  alternative  antimicrobials  are  now

available.

Because benzylpenicillin is a polar compound,

it is distributed widely in the tissues in body

water.   However,   it   does   not   pass   the

blood-brain  barrier  in  significant  amounts

unless very high doses are used, the patient has

renal failure or the meninges are inflamed (see

meningitis, p. 548). It is excreted rapidly in the

urine, mostly as the unchanged compound, and

the  effect  of  severe  renal  failure  may  be

dramatic, e.g. the elimination half-life of amox-

antimicrobial therapy

icillin is increased from 0.9-2.3 h to 5-20 h, and for  benzylpenicillin  the  normal  t1/2 of 0.5 h  is increased to 10 h.

Side-effects

The penicillins have a very wide therapeutic

index, i.e. blood levels far higher than those

required for treatment need to be attained before dose-related side-effects occur.

A disadvantage that broad-spectrum penicillins

share  with  many  other  broad-spectrum  oral

antibacterials is the tendency to cause diarrhoea,

owing to the suppression of sensitive species in

the  gut  flora.  Consequently,  resistant  species

become dominant, because they no longer have

to  compete  for  nutrients  with  the  very  large

numbers of sensitive organisms. This effect is

particularly true of the less well-absorbed, broad-

spectrum antimicrobials (e.g. ampicillin), whereas

the  closely-related,  well-absorbed  amoxicillin

tends to cause far less diarrhoea.

The main problem associated with penicillins

is a hypersensitivity reaction. This results from

their action as haptens (see Chapter 2), and

hypersensitivity developed to one member of

the group may preclude the use of all other

related compounds. The further a compound is

from the basic penicillin structure, the less the

chances of a cross-reaction. An individual who is

hypersensitive to a penicillin has about a 10%

chance of reacting similarly to a cephalosporin

or carbapenem (Figure 8.1), but the chances of

developing  a  cross-reaction  to  a  monobactam

(e.g. aztreonam) are reduced. However, there are

reports that patients with an allergy to ceftazidime

react  also  to  the  monobactam  aztreonam,

probably due to a common side-chain moiety.

The hypersensitivity reactions experienced are

very variable. The most serious form is acute

anaphylaxis (see  Chapter 2),  but  a  delayed

pruritic  rash  is  much  more  common.  Other

reactions include urticarial rash (Chapter 13),

fever and organ damage. Although a patient

presenting with a mild reaction need not neces-

sarily  develop  a  life-threatening  reaction  on

subsequent   treatment,   penicillins   are   not

prescribed if there is any previous history of

allergy  to  them  or  the  patient  claims  to  be

‘allergic’. A careful history of such allergy should

be taken, as patients may confuse true allergy

with non-allergic side-effects such as diarrhoea,

although relying on patients’ recall and under-

standing  of  an  incident  is  very  unreliable.

However, if hypersensitivity is a possibility it is

safer to choose a different class of antibacterial

completely, such as a macrolide (e.g. erythromycin),

rather than risk a major hypersensitive reaction.

We have noted that penetration into the CNS

is normally poor. However, very high doses may

produce a concentration sufficient to cause a rare

encephalopathy, which may be fatal. This hazard

is clearly greater in a patient with renal failure or

severe renal impairment. Because of this poten-

tial side-effect, penicillins should not normally

be given intrathecally.

From a therapeutic standpoint, an important advantage  of  the  structural  classification  of antimicrobials is to be able to predict and avoid the hypersensitivities or other adverse reactions associated with a particular group.

There  is  concern  over  the  occurrence  of cholestatic jaundice associated with the use of flucloxacillin. This reaction is rare, reversible and more likely in older patients, but may occur up to several weeks after treatment has ceased. The UK’s CSM advises that:

•  Flucloxacillin should not be used if there is a

            patient history of hepatic damage associated

with it.

•  Flucloxacillin should be used with caution in

            patients with a history of hepatic impairment.

•  Careful   enquiry   should   be   made   about

hypersensitivity   reactions   to   beta-lactam antibacterials.

Amoxicillin  also  carries  a  risk  of  cholestatic jaundice and this is about six times greater if it is combined with clavulanic acid (as co-amoxiclav in the UK), because clavulanic acid reduces the renal  clearance  of  amoxicillin  and  so  higher concentrations are produced.

Another problem with high doses of peni-

cillins is the increased load of potassium or

sodium, according to which salt is used, and

should be avoided in patients with renal impai-

ment, e.g. the elderly who are likely to be taking

diuretics.   The   interaction   with   potassium-

sparing  diuretics  is  particularly  hazardous.  A

Cephalosporins 521

further group of patients particularly susceptible

to electrolyte disturbances is those with myas-

thenia  gravis,  an  autoimmune  condition  in

which  antibodies  are  developed  against  the

acetylcholine    receptor    protein.    Antigen-

antibody complexes are deposited in neuromus-

cular junctions, causing destruction of synaptic

acetylcholine receptors, resulting in weakness

and fatigability of the respiratory, ocular, eyelid

and proximal limb muscles. Large increases in

electrolyte concentration may precipitate a crisis

requiring respiratory support.

Therapeutic role of penicillins

Benzylpenicillin  and  flucloxacillin  are  generally used for cellulitis, an infection of the loose SC tissue, and in combination with gentamicin for endocarditis (p. 564).

Amoxicillin is used for simple, i.e. uncompli-

cated,   urinary-tract   infection (p. 576)   and

community-acquired   pneumonia.   It   is   also

used prophylactically for dental procedures in

patients  who  have  had  rheumatic  fever (see

Chapters 4 and 12), because these patients are at

risk of endocarditis from organisms liberated

into the blood from the mouth.

Phenoxymethylpenicillin  or  amoxicillin,  being

orally  active,  are  used  for  prophylaxis  post-

splenectomy because these patients are at high

risk of infections by encapsulated bacteria, e.g.

Strep. pneumoniae, Haemophilus spp. and Neisseria

spp.

Newer broad-spectrum agents, e.g. piperacillin and  ticarcillin,  are  used  with  beta-lactamase inhibitors for the initial empirical therapy of

serious hospital-acquired chest and abdominal infections, in which a wide range of organisms are usually implicated.

Cephalosporins

Chemical structure and mode of action

This  is  the  antimicrobial  group  most  closely

related structurally to the penicillins, because

they all possess a beta-lactam ring (Figure 8.1). As  with  the  penicillins,  substitutions  on  the parent nucleus, 7-amino-cephalosporinic acid, produce agents with differing pharmacokinetic profiles,   spectrums   of   activity   and   adverse effects. Cephalosporins are conventionally clas-

sified in terms of ‘generations’, three to date, each new generation producing members with improved Gram-negative activity.

Spectrum of activity

Orally active cephalosporins

The      ‘first-generation’           cephalosporins,

cefadroxil,  cefalexin  and  cefradine,  and  the

‘second-generation’,  cefaclor  is  orally  active

and  have  a  similar  spectrum  of  activity  to

ampicillin  (Table  8.2),  but  these  have  been largely   supplanted   by   the   newer   agents. Cefuroxime  axetil  is  another  second-generation drug  that  is  available  in  an  oral  formulation, but is absorbed poorly. It has the same antibac-

terial spectrum and indications as cefaclor, but is less susceptible than earlier cephalosporins to inactivation by beta-lactamases.

As a further complication to this somewhat

awkward classification system, there are now

‘third-generation’   oral   cephalosporins,   e.g.

cefixime, which have improved Gram-negative

activity   compared   with          ‘second-generation’

agents. However, unlike the ‘third-generation’

parenteral  agents  they  are  ineffective  against

pseudomonads.  They  have  long  durations  of

action and can be given once or twice daily.

Cefixime is long-acting and can be given once or twice daily.

Although cephalosporins are more stable to

staphylococcal beta-lactamase than benzylpeni-

cillin, they are not completely unaffected by the

enzyme, so flucloxacillin is a more rational choice

for  treating  staphylococcal  infection.  Gram-

negative organisms also inactivate many of the

first- and second-generation cephalosporins by

the production of beta-lactamases. Thus, the first-

generation cephalosporins, especially cefradine,

have limited use.

antimicrobial therapy

Parenteral cephalosporins

Cefpirome  has  greater  activity  against  pseudo-

monads and the greatest beta-lactamase stability of  the  third-generation  cephalosporins.  It  is licensed in the UK for treating lower respiratory tract, urinary-tract and skin infections, bacter-

aemia and septicaemia, especially in infections in neutropenic patients (see Chapter 2).

The parenteral third-generation agents, cefo-

taxime,  cefpirome,  cefpodoxime,  ceftazidime  and

ceftriaxone   are   more   active   than   second-

generation cephalosporins against some Gram-

negative   bacteria,   including   pseudomonads.

However, as often happens, they are less active

against Gram-positive organisms, notably Staph.

aureus. Their broad spectrum of activity may

encourage superinfection by fungi and resistant

bacteria.

The main application of ceftriaxone is in the

management of severe infections, e.g. bacterial

meningitis (see p. 548), septicaemia and bacterial

endocarditis (see  p. 564).   Its  long  half-life

allows for convenient once-daily dosing and use

in  Outpatient  Antimicrobial  Therapy (OPAT)

schemes in which patients are discharged from

hospital and either attend daily clinics to receive

IV antimicrobials, or have them administered at

home. This is a recent innovation in the UK.

Typical patient groups include those requiring

6 weeks’ IV therapy for MRSA osteomyelitis and those needing prolonged therapy for deep-tissue or implant-associated infections.

Therapeutic role

This is much debated, because the spectrum of

action  of  cephalosporins  can  be  covered  by

various  penicillins  and  other  cheaper  anti-

bacterials. The use of IV cephalosporins as first-

line  agents  is  often  determined  by  the  local

antimicrobial  policy,  where  recommendations

for  antimicrobial  prescribing  in  a  particular

area  are  made  by  the  local  hospital  micro-

biology  department.  Thus  a  hospital  might

employ ceftazidime as first-line therapy for severe

Pseudomonas  infection,  often  in  combination

with an aminoglycoside, in preference to an

aminoglycoside-ureidopenicillin   combination.

This is because of the risk of Clostridium difficile-

associated diarrhoea (antibiotic-associated colitis,

AAC;  p.  570)  with  ceftazidime,  its  propensity

to select for extended-spectrum beta-lactamase

(ESBL) producers, and because of a preference to

avoid aminoglycosides, owing to their potential

toxicity (p. 524). Additionally, many hospitals

now find it necessary to include carbapenems

in  their  treatment  protocols  because  of  the

increased prevalence of ESBL producers.

The    first-    and    second-generation    oral

cephalosporins remain useful for urinary-tract

infections unresponsive to other antibacterials,

especially in pregnancy, and for respiratory tract,

middle ear, paranasal and frontal sinus, skin and

soft tissue infections. However, antimicrobials

are not recommended for the first-line treatment

of otitis media, because many of these infec-

tions are viral and clear without antimicrobial

intervention. An antimicrobial is indicated if the

infection does not settle in 3 days or if there are

complications. The agents usually used to treat

infected otitis externa are those not used sytem-

ically, e.g. neomycin  and  clioquinol, but these

should not be used for more than about 7 days

because prolonged treatment may cause local

sensitivity reactions and predispose to resistant

fungal infections.

First-line  uses  of  agents  such  as  cefuroxime

may  include  acute  pancreatitis,  prophylaxis

before  surgery  (e.g.  appendectomy),  treatment

of   severe   community-acquired   pneumonia

requiring  hospital  admission,  and  pyrexia  of

unknown origin (PUO; p. 539). Cefradine and

cefalexin are more suitable for dental use, largely

for  their  activity  against  the  Streptococcus  viri-

dans  group.  However,  if  resistant  bacteria  are

known to be present, prophylaxis and therapy

must  be  guided  by  the  results  of  laboratory

tests, as usual. Other possible applications for

first-line  use  include  exacerbations  of  COPD

(see Chapter 5) if H. influenzae is suspected, and

PUO. However, a carbapenem is often preferred

in acute pancreatitis.

Ceftriaxone is used for the late symptoms of

Lyme disease, caused by a tick-borne spirochaete

Borrelia burgdorferi, which is widespread in rural

wooded areas of Europe and North America.

Although   the   initial   symptoms   are   mild

(arthralgia,  skin  rash,  fever,  etc.)  this  is  an

Aminoglycosides           523

increasingly  important  disease,  because  some

weeks to months later patients often develop

arthritis  and  severe,  persistent  cardiovascular

and neurological problems. Ceftriaxone  is also

used in some types of endocarditis (p. 564), the

empirical treatment of meningitis (p. 551) and

brain  abscesses,  and  in  OPAT  schemes (see

above).

Cefadroxil and the oral prodrug of cefuroxime, cefuroxime axetil, have poor oral bioavailability, but are useful in the treatment of H. influenzae chest infections that are resistant to ampicillin. However, it is doubtful whether they should be used as first-line agents in the community on

grounds of cost and the danger of development of cephalosporin resistance.

Side-effects

Although the very early cephalosporins, cefalotin

and cefaloridine, caused significant renal damage,

this does not occur with later members of the

group.

Hypersensitivity  reactions  similar  to  those with  the  penicillins  are  encountered  and

cross-reactions may occur.

Diarrhoea, and sometimes AAC (p. 570) can occur, together with nausea and vomiting and malaise.   Blood   disorders,   e.g.   haemolytic anaemia and leucopenia, may also arise. The

indiscriminate use of third-generation cephalo-

sporins is thought to promote the spread of

ESBL-producing organisms (see above).

Aminoglycosides

Chemical structure and mode of action

Streptomycin,  first  isolated  from  the  fungus

Streptomyces griseus in 1944, revolutionized the

treatment  of  TB.  However,  this  has  been

supplanted by newer antimicrobials (p. 574).

The class name describes the chemical struc-

ture of this group; they are glycosidally linked aminosugars.

The   most   widely   used   are   gentamicin,

tobramycin  and  amikacin,  which  are  members

of  the  kanamycin  group,  although  kanamycin

itself is no longer used in theUK. Despite the

availability of numerous derivatives, the prop-

erties  of  the  kanamycin  group  vary  little.

The  other  aminoglycosides  have  few  clinical

applications.

The aminoglycosides act by interfering with bacterial protein synthesis via actions on bac-

terial  messenger  and  transfer  RNAs (mRNA, tRNA). Miscoding causes incorrect amino acid insertion into peptide chains, causing loss of the protein  activity  and  suppressing  cell  growth, eventually causing cell death.

Spectrum of activity

Gentamicin is the aminoglycoside of choice in

theUK. The other clinically useful members of

the kanamycin group (tobramycin, amikacin and

netilmicin) have very similar activity against a

wide  variety  of  Gram-negative  bacteria  (Table

8.2),  particularly  pseudomonads,  and  there  is

little  to  choose  between  them.  Amikacin  is

claimed to have greater stability to inactivating

enzymes produced by Pseudomonas spp. and is

active against some Gram-negative species with

acquired gentamicin resistance. All aminoglyco-

sides are active against Proteus spp., but anaer-

obic bacteria are resistant. Gentamicin is useful

for  treating staphylococcal infections but has

only moderate activity against streptococci. It

is   synergistic   with   penicillin   against   these

organisms, e.g. Enterococcus faecalis, possibly by

increasing   cell   permeability   to   penicillin.

Gentamicin  is the basis of treatment for most

types of endocarditis (p. 564).

Other  aminoglycosides  have  more  specific

uses.  Spectinomycin  is  highly  effective  against

gonococci but is inactive against other organ-

isms, so it is only used for the treatment of

penicillin-resistant  gonorrhoea.  Streptomycin  is

rarely used in theUKbecause of problems with

toxicity and resistance and because it can only

be administered intramuscularly. However, it is

used occasionally as a second/third-line agent

for resistant TB (p. 574) and for some cases of

enterococcal endocarditis. It is also used as an

adjunct to doxycycline for brucellosis, a rather

unpleasant localized (two-thirds of patients) or

antimicrobial therapy

systemic (one-third) infection that may persist for a year. It is usually contracted by drinking unpasteurized cows’ or goats’ milk and is rare in theUKbecause it has been eliminated almost completely from cattle there.

Gentamicin is used as single low-dose prophy-

laxis before changing urinary catheters, when an

infection has been confirmed, and in larger doses

as part of the therapy of severe Gram-negative

infections.

Amikacin is sometimes used in place of genta-

micin  when resistance to the latter has been

demonstrated, and as a second-line agent for

treating multi-drug-resistant TB (MDR-TB).

Tobramycin is used as a nebulized formulation in the management of cystic fibrosis.

Neomycin  is  too  toxic  for  parenteral  use. Given orally, it retains its antibacterial activity in the gut lumen and has been used to reduce

the  gut  flora  before  gastrointestinal  surgery. Although  it  is  often  used  as  an  antiseptic  in topical corticosteroid preparations, e.g. in some skin creams and eye drops, it is liable to cause skin and conjunctival sensitization.

Pharmacokinetics

The aminoglycosides are highly polar, not signifi-

cantly absorbed orally, and are largely excreted unchanged via the kidney. Good renal function is an important factor in their safe use. They are usually administered parenterally unless intended for topical use (e.g. in eye drops), and are generally well distributed in the tissues after parenteral

administration,  but  penetrate  the  CSF  poorly unless the meninges are inflamed.

Toxicity

The aminoglycosides are among the most toxic

antimicrobials.  Nephrotoxicity  is  a  rare,  but

serious,   problem   if   used   in   patients   with

previous renal impairment, but ototoxicity is

more common and may cause hearing impair-

ment or even deafness. These effects are related

to plasma levels, although it has been suggested

that  some  ototoxicity  may  occur  even  with

careful control of gentamicin  dosage if this is

given for longer courses than usual. Courses are

preferably no longer than 7 days. Other rare

side-effects  include  hypersensitivity  reactions

and  neuromuscular  blockade.  For  the  latter

reason they must be avoided in myasthenia

gravis (see above).

When aminoglycosides are used, especially in

high  doses  for  serious  infections,  initial  and

maintenance  doses  are  calculated  from  the

patient’s weight and serum creatinine level or

determined using a nomogram, to ensure appro-

priate blood levels and adequate renal clearance.

Adjustments are then made, based on the results

of therapeutic drug monitoring to determine

plasma  peak  and  trough  levels.  As  toxicity

appears to be associated with sustained trough

levels rather than the peak level attained imme-

diately   post-dose,   once-daily   dosing   of   an

aminoglycoside is now the treatment mode of

choice in most situations.

The activity of these drugs is concentration-

dependent and they exhibit a long post-dose

antimicrobial   action,   retarding   regrowth   of

organisms despite the absence of significant drug

levels,   because   regrowth   requires   extensive

anabolic synthesis. Therefore a single daily dose

of  gentamicin  would  be  expected  to  produce

blood levels adequate to treat Pseudomonas infec-

tions  and  accumulation  is  avoided,  allowing

trough levels to fall below the 2 mg/L known to

be associated with both ototoxicity and nephro-

toxicity. In practice, the target trough level is

1 mg/L and regular plasma level drug moni-

toring  is  still  prudent.  Once-daily  dosing  is unsuitable in endocarditis, where regular smaller doses are required to produce maximal synergy with penicillin therapy.

Other antibacterial agents

The  penicillins,  cephalosporins  and  amino-

glycosides are the most widely used groups of

antibacterials, and provide the first-line agents for

the treatment of many infections. The groups

discussed  next  are  older  agents  whose  use  is

diminishing (e.g. sulphonamides), recent intro-

ductions  whose  full  potential  has  yet  to  be

realized (e.g. new beta-lactams), or groups repre-

Other antibacterial agents          525

sented by only a few related agents in clinical use (e.g. the macrolides).

Newer beta-lactam antimicrobials

Two relatively new classes, the carbapenems and monobactams, have widened the choice.

Imipenem is a very broad-spectrum carbapenem

that is active against most Gram-negative organ-

isms,  including  Pseudomonas,  and  has  useful

activity against a range of Gram-positive bacteria

and anaerobes. Metabolism of imipenem by renal

dihydropeptidases tended to shorten the half-life

of the antimicrobial considerably, but this prob-

lem  has  been  overcome  by  co-administration

with cilastatin, an alpha-dihydropeptidase inhib-

itor  that  prevents  inactivation  in  the  kidney.

However,  this  combination  has  been  largely

superseded by meropenem, which has a similar

spectrum of activity, and does not require the

co-administration of cilastatin, because it is not

metabolized  similarly.  Further,  imipenem  has

significant potential to cause convulsions if over-

dosed with respect to renal function. Meropenem

has less seizure potential and so lessens this risk

in renal failure.

Ertapenem is a new carbapenem that has the advantage  of  once-daily  administration,  but does  not  cover  Pseudomonas  infections.  This limits its utility as an empirical agent, but may be  advantageous  in  the  hospital  setting  due to  the  potential  reduction  of  selection  for

carbapenem-resistant pseudomonads.

Faropenem, which is active orally, is not avail-

able in theUK, but is used inJapanand the

USAfor the treatment of upper respiratory tract

infections.

Aztreonam is the only monobactam in general

use in theUK. It is active only against aerobic

Gram-negative organisms, notably Ps. aeruginosa,

and must be given parenterally. Its clinical utility

is limited by its narrow spectrum of activity, but

it is used in drug trials as a comparator agent.

Macrolides

The  most  important  member  of  this  group

is   erythromycin.   Other   macrolides,   such   as

clindamycin and lincomycin, are now less used in theUKowing to their associated incidence of AAC (pp. 570 and Chapter 3). Clarithromycin and azithromycin are recent additions with superior bioavailability   to   erythromycin,   and   reduced potential to cause nausea and vomiting, the

chief adverse effects of the latter.

Erythromycin  is  bacteriostatic  at  the  serum

levels achieved with usual oral doses, but the

higher levels achieved with IV use are bacteri-

cidal.   It   interferes   with   bacterial   protein

synthesis by inhibiting the transfer of amino

acids  from  tRNA  to  growing  peptide  chains.

Erythromycin  is   particularly   effective   against

Gram-positive organisms (Table 8.2) and is a very

useful alternative for patients who are hypersen-

sitive to penicillins, or believed to be so, but

resistance is now common. It has limited appli-

cation in the treatment of Gram-negative infec-

tions  because  cell  wall  penetration  is  poor,

although some Haemophilus strains are sensitive.

Activity is particularly good against bacteria that

do not have a cell wall, e.g. mycoplasmas, and it

is the agent of choice for treating Legionella

pneumonia, but high doses must be used, e.g.

4 g/day. Gastrointestinal upset is reported to be less of a problem with low doses, e.g. 1 g/day, and with clarithromycin and azithromycin.

Clarithromycin, is          more    active    than

erythromycin and is given twice daily, or once

daily   as   an   extended-release   formulation,

although the latter is not suitable for use in renal

impairment. A further important advantage of

both clarithromycin and azithromycin is enhanced

activity   against   Haemophilus  spp.   A   major

distinction between these two agents is that

while azithromycin has superior tissue penetration

it achieves poorer sustained blood levels than

clarithromycin, so the latter is preferred to treat

septicaemia. Due to its long tissue half-life clar-

ithromycin can be given only once daily for tissue

infections and so is preferred for conditions such

as impetigo and carbuncles.

The main indications for azithromycin are to

treat Lyme disease (p. 523), as a convenient

single-dose   therapy   for   treating   Chlamydia

trachomatis, the commonest cause of blindness

worldwide, and for the prophylaxis of endo-

carditis (unlicensed application, see p. 564 and

Chapter 4) in children. Chlamydias are the most

antimicrobial therapy

common cause of sexually transmitted infection

and these are inreasing, especially in women,

and Chl. trachomatis is present in about 40% of

these.

Telithromycin,   a   ketolide   derivative   of

erythromycin,  has  a  similar  activity  spectrum

and  is  especially  useful  for  treating  sinusitis,

community-acquired pneumonia, exacerbations

of COPD (see Chapter 5), and pharyngitis and

tonsillitis   caused   by   resistant   streptococci.

However, it has been reported recently to cause

an   increased   rate   of   hepatic   side-effects,

including cholestatic jaundice, so it should not

be  used  in  patients  with  hepatic  or  renal

impairment.  It  may  also  prolong  the  QT

interval (see Chapter 4) and is contra-indicated

if there is a personal or family history of QT

prolongation.

Chloramphenicol

This synthetic, bacteriostatic agent has a very broad spectrum of activity. The mode of action is by inhibition of bacterial protein synthesis,

competing with mRNA for bacterial ribosomal binding.  It  also  inhibits  peptidyl  transferase, thus preventing the addition of amino acids to growing peptide chains.

Major  drawbacks  to  its  use  include  bone

marrow toxicity and the development of resis-

tance.  Being  among  the  cheapest  of  broad-

spectrum agents, chloramphenicol has been used

extensively  and  often  inappropriately  in  the

Third World for treating many types of infection.

Consequently, this very useful agent has become

virtually ineffective in the treatment of various

serious endemic infections, e.g. typhoid fever, in

some countries.

The incidence of aplastic anaemia associated

with  chloramphenicol  has  led  to  the  general

recommendation that it should only be used

systemically for life-threatening infections resis-

tant to other agents. Plasma level monitoring is

required  for  neonates,  who  metabolize  and

excrete it poorly, so it is best avoided in this

patient group. Monitoring is also desirable for

children under 4, in the elderly and in patients

with hepatic impairment. Peak concentration,

1 h after IV use, should not exceed 25 mg/L and trough concentrations determined immediately pre-dose should not exceed 15 mg/L.

Owing  to  the  development  of  many  safer

broad-spectrum antibacterials, the only principal

systemic indication for chloramphenicol  is the

treatment of meningitis caused by H. influenzae,

when cephalosporins cannot be used owing to

severe drug allergies. In this case, the risks of brain

damage or death from the infection outweigh the

risks from the drug.

Chloramphenicol still has valuable topical use

in the treatment of eye infections, e.g. severe

conjunctivitis, because it penetrates well into

optic tissues. There have been occasional reports

of aplastic anaemia, possibly associated with the

small doses used in eye preparations, and this

has  led  some  physicians  to  advise  against  its

use for bacterial conjunctivitis. However, there is

little direct evidence of a causal relationship and

the incidence of such reactions seems no greater

than  that  observed  for  aplastic  anaemia  in

the  general  population,  so  the  eye  drops  are

now available OTC from pharmacies without

prescription. Although ear drops, formulated in

propylene glycol, are available there is a high

incidence of sensitivity reactions to the vehicle

and  are  regarded  as  less  suitable  for  general

prescribing. Moreover, the OTC prescribing of

ear drops for the treatment of moderate to severe

ear pain, usually due to otitis media, is highly

undesirable (p. 531) because of lack of efficacy,

the risk of hearing loss, or even meningitis, and

the risk of missing a diagnosis of meningitis.

Instead, ear drops of ciprofloxacin and ofloxacin

are  available  on  a  named-patient  basis  for

treating  chronic  otitis  media  associated  with

perforation of the ear drum (unlicensed indica-

tion)  and  avoid  the  use  of  the  potentially

ototoxic aminoglycosides or polymyxins.

Tetracyclines

Like  chloramphenicol,  and  introduced  at  the

same time, the tetracyclines are broad-spectrum

bacteriostatic   agents   that   inhibit   bacterial

protein synthesis. Their Gram-negative activity

is   unimpressive   because   many   organisms,

including  Pseudomonas  and  Proteus  spp.,  are

intrinsically resistant, and resistance has emerged

Other antibacterial agents          527

with Haemophilus. Even in Gram-positive infec-

tions,  acquired  resistance  has  led  to  reduced

usage.

The group contains a number of closely related compounds, all of which have a very similar

spectrum  of  activity  but  different  pharmaco-

kinetic   profiles.   Oxytetracycline   has   largely replaced tetracycline  for oral use owing to its superior bioavailability.

The long half-life of doxycycline allows once-

daily dosage and minocycline, another long-acting agent, requires twice-daily dosing. The latter has an extended spectrum, being active against N. meningitidis, but it causes dizziness and vertigo and has been superseded by rifampicin (see below) for prophylaxis in meningitis contacts.

Their  low  toxicity  has  made  this  group  a

popular choice for the treatment of chest infec-

tions in the community. Interestingly, it has

been claimed by some that the fall in popularity

of  the  tetracyclines,  due  to  resistance,  has

produced a decline in certain resistant strains of

bacteria.

These agents are used principally for gonor-

rheal  and  chlamydial  infections,  which  often

occur  together  in  sexually  transmitted  disease

and for treatment of other chlamydial infections,

e.g. trachoma, urethritis, salpingitis (infection of

the Fallopian tubes, possibly causing infertility

in  women)  and  psittacosis.  Tetracyclines  (and

rifampicin) are also used to treat brucellosis, an

infection contracted from infected cows, sheep

and goats (p. 524), and Lyme disease (p. 523).

Tetracyclines are still widely used for the treat-

ment of acne, when they are given orally at low dosage for courses lasting many months, and are also applied topically. Topical application is also used for infections of the skin or eyes.

Doxycycline and minocycline are the only tetra-

cyclines that can be administered safely in renal

impairment.  However,  caution  is  required  in

patients with hepatic impairment. Doxycycline is

also used for malaria prophylaxis in high-risk

areas.

Because  they  cause  irreversible  staining  of

teeth in children and possibly dental hypoplasia

(by  complexing  with  calcium  in  developing

teeth and bone), they are contra-indicated in

pregnancy and in children under 12 years of age.

These drugs are chelating agents, reacting with

salts  of  calcium  in  supplements  and  milk, aluminium  and  magnesium  in  antacids,  and iron and zinc. This results in decreased absorp-

tion if taken with food, so they should be taken on an empty stomach.

Sulphonamides and trimethoprim

Sulphonamides   were   the   earliest   synthetic

antibacterials to be used, but have been largely

replaced  by  more  effective  agents.  They  are

bacteriostatic, being competitive inhibitors of p-

aminobenzoic  acid  uptake  in  bacterial  folate

synthesis (see  Figure 11.4).  Because  humans

cannot synthesize folate and require it to be

supplied preformed in their diet, sulphonamides

are not toxic to humans by this mechanism.

Determining true MICs for sulphonamides is difficult because their action is markedly affected by p-aminobenzoic acid in the culture media used.   Because   many   previously   susceptible strains are now resistant it is difficult to be sure of their true spectrum of activity.

Sulphonamides have been used in the treat-

ment of a variety of infections, and both Gram-

negative and Gram-positive organisms may be

sensitive, so the theoretical spectrum is quite

broad. Their slow onset of action, high incidence

of side-effects (e.g. renal and hepatic damage,

hypersensitivity   and   blood   dyscrasias)   and

pattern of resistance have greatly limited their

use. Until recently, the only widely used member

of the group was sulfamethoxazole, usually in

combination   with   another   folate   synthesis

inhibitor trimethoprim (as co-trimoxazole in the

UK; Table 8.2). Synergism occurs between these

two agents that act at different points in the

folate synthetic pathway, but in clinical practice

trimethoprim alone is equally effective in most

situations.

Recent  fears  over  the  incidence  of  bone

marrow suppression have further limited the

indications for co-trimoxazole. The most impor-

tant remaining indication is the prevention and

treatment of Pneumocystis jiroveci (formerly Pn.

carinii) pneumonia in HIV-positive patients and

in   those   who   are   immunosuppressed,   e.g.

following organ transplantation. The UK CSM

advises   that   co-trimoxazole  should   now   be

antimicrobial therapy

considered only for treating acute exacerbations

of COPD (see Chapter 5) and sensitive urinary-

tract infections (p. 576), and then only when

there are good reasons to prefer it. It should also

be  used  for  treating  the  protozoal  infection,

toxoplasmosis, which is acquired from cats, and

nocardiosis.

Nocardia  is  branching  bacterium,  and  infec-

tions  are  acquired  by  walking  barefoot  on infected soil, producing a local lesion known as a mycetoma,  or  by  inhalation.  The  pulmonary disease is seen in immunocompromised individ-

uals, causing fever, cough and haemoptysis. If immunosuppression is severe, this becomes a widespread systemic infection.

Nitroimidazoles

The principal agent in this group is metronida-

zole,  originally  employed  successfully  in  the

treatment of trichomoniasis, and now a widely

used antiprotozoal agent, e.g. for amoebiasis and

giardiasis (see Chapter 3). It is also effective and

used frequently in the treatment and prophy-

laxis of anaerobic bacterial infections, caused by

either Bacteroides fragilis or clostridia, especially

following gut surgery or similar ‘dirty’ surgery.

Metronidazole is also used to treat mouth infec-

tions,  e.g.  acute  ulcerative  gingivitis,  a  gum

infection caused by spirochaetes or other mouth

commensals  if  oral  hygiene  is  poor.  Further

common uses are the eradication of H. pylori

from  the  stomach (see  Chapter 3)  and  the

treatment of rosacea (see Chapter 13).

Resistance to metronidazole is uncommon. Its

use  is  limited  by  gastrointestinal  disturbance

and the occurrence of a ‘disulfiram-like’ reaction

in  patients  drinking  alcohol,  a  consequence

of the inhibition of acetaldehyde hydrogenase.

The  resultant  accumulation  of  acetaldehyde

causes    flushing,    orthostatic    hypotension,

causing  faints,  central  nervous  effects,  e.g.

dizziness,  headache and epileptiform seizures,

and peripheral neuropathy.

Disulfiram   is   used   as   an   adjunct   to

psychotherapy  in  the  treatment  of  alcohol

dependence,  but  is  of  doubtful  value  because

heavy  drinkers  usually  prefer  to  give  up  the

disulfiram. Further, the reaction is triggered by

contact  with  the  very  small  amounts  of

alcohol used in some medicines, even that used in some mouthwashes.

The newer compound tinidazole is used simi-

larly  to  metronidazole.  Its  longer  duration  of

action means that it can be given less frequently.

Quinolones

The prototype of the class, nalidixic acid, has the disadvantage of low activity, poor tissue concen-

tration and the rapid development of acquired resistance, and so is now rarely used.

The    more    recently    introduced    fluoro-

quinolones have wider therapeutic applications.

Ciprofloxacin, the first to enter clinical use, is

active against Gram-negative and, to a lesser

extent,  Gram-positive  organisms (Table 8.2).

Important  exceptions  include  the  anaerobic

species Bacteroides fragilis and Cl. difficile, some

pseudomonads, Ent. faecalis and Strep. pneumo-

niae. Its main indication is therefore in the treat-

ment of aerobic Gram-negative infections. Its

principal advantage over other antimicrobials is

that it is the only orally active antipseudomonal

agent.

Ciprofloxacin is used with other antimicrobials as   a   first-line   treatment   for   pulmonary   or gastrointestinal  anthrax,  but  definitive  treat-

ment depends on laboratory data.

The   newer      ‘third-generation’   quinolones, levofloxacin  and  ofloxacin,  which  is  a  racemic mixture  of  the  S-isomer  levofloxacin  and  the R-isomer,   have   increased   activity   against Gram-positive organisms, e.g. Strep. pneumoniae, and may be administered once daily.

Norfloxacin is given twice daily, but is licensed

only for urinary-tract infections and prostatitis.

Quinolones act by interfering with bacterial

DNA gyrase, responsible for the supercoiling of

DNA. The resultant aberrant DNA cannot fit the

bacterial cytoplasmic space, resulting in rapid cell

death. This mode of action has the advantage of

preventing  plasmid  formation  and  therefore

plasmid-mediated resistance, although resistance

can still develop by chromosomal mutation.

Levofloxacin,  moxifloxacin  and  ofloxacin  are

recent additions to this group, with the impor-

tant advantage of greater activity against Gram-

Other antibacterial agents          529

positive   pathogens.   However,   ciprofloxacin, levofloxacin and ofloxacin are not active against MRSA and are contra-indicated if this organism is suspected.

Moxifloxacin is used as a second-line agent for treating  community-acquired  pneumonia  and sinusitis, and as a reserve agent for acute exacer-

bations of COPD (see Chapter 5), if all other

treatments have failed or are contra-indicated: because this group comprises an older popula-

tion the risk of side-effects is increased. It has some activity against anaerobes.

Side-effects

Almost any body system may be involved. All

quinolones  are  liable  to  cause  a  range  of

gastrointestinal disorders, but AAC (p. 570) is

rare. CNS effects include headache, dizziness and

sleep  disturbance.  Although  convulsions  are

uncommon, quinolones should not be used in

patients with epilepsy (see Chapter 6) or those

who have a reduced seizure threshold. Taking

NSAIDs  at  the  same  time  may  increase  the

seizure risk. The risk of neurological impairment

is increased by alcohol and this is one group of

antimicrobials   for   which   the   appropriate

response to the question “Can I drink with this?”

is a firm “No”.

Pruritis  and  rashes  may  occur  (see  Chapter 13),  but  the  latter  are  rarely  serious.  Patients should avoid excessive exposure to sunlight and if photosensitization occurs the drug should be discontinued:  this  also  applies  if  psychiatric, neurological or hypersensitivity reactions occur, including severe rash.

The occasional occurrence of tendon damage

and rupture within 48 h of use has led the UK

CSM to issue specific advice. Previous tendon

inflammation  with  any  of  this  group  is  an

absolute  contra-indication  to  quinolone  treat-

ment. The risk of tendon damage is increased

by the concomitant use of corticosteroids and

elderly patients are more prone to tendonitis.

If  tendonitis  is  suspected  the  drug  must  be

discontinued immediately.

They should be used with caution in preg-

nancy, during breastfeeding and in young chil-

dren or adolescents, because of possible damage to weight-bearing joints.

Moxifloxacin is not suitable for use in hepatic

impairment or with other drugs that prolong the

QT interval or if there is a history of IHD,

electrolyte disturbances or heart failure with a

reduced left ventricular injection fraction (see

Chapter 4).

Levofloxacin appears to be less likely to cause problem side-effects than other quinolones.

Rifamycins

The chief member of this group, rifampicin, will

be considered in greater detail in the treatment

of  TB  in  combination  with  other  antibac-

terials (p. 574). It is also active against M. leprae

(causing leprosy), staphylococci, various myco-

plasmas,   meningococci   and   Legionella   pneu-

mophila, although its wider application has been

limited  by  fears  of  M.  tuberculosis  resistance.

However,  it  is  used  prophylactically  in  close

contacts of meningococcal meningitis and, in

combination with other drugs, e.g. fusidic acid,

for the treatment of serious infections due to

rifamycin-sensitive MRSA. It is also used to treat

brucellosis,  but  this  disease  is  rare  in  the  UK

because  it  has  been  virtually eliminated from

cattle.

Rifabutin has similar properties. It is also used for the treatment of non-tubercular disease due to other mycobacteria and for the prophylaxis of M. avium-intracellulare complex in immuno-

compromised  subjects,  e.g.  in  HIV/AIDS  and post-transplant patients.

The rifamycins have numerous side-effects, e.g.

gastrointestinal  symptoms,  including  AAC  (p.

570), headache, drowsiness, influenza-like symp-

toms,  shortness  of  breath,  thrombophlebitis,

collapse  and  shock,  haemolytic  anaemia (see

Chapter 11), acute renal failure (see Chapter 14),

jaundice,  oedema,  thrombocytopenic  purpura

(see  Chapter 11)  and  exfoliative  dermatitis.

They  are  hepatotoxic,  so  liver  function  tests

should be done before commencing treatment

and regularly during treatment, especially in the

first 2 months (see TB; p. 574). Jaundice is a

contra-indication to the use of rifamycins.

They induce liver enzymes, with potentially

serious consequences (Chapter 3). The effective-

ness  of  many  drugs  will  be  reduced  when

antimicrobial therapy

rifamycin treatment commences and will return

to normal  when  treatment  ceases, but will be

enhanced if doses have been increased recently.

The plasma levels of essential drugs, e.g., corti-

costeroids, phenytoin, sulphonylureas (in type 2

diabetes  mellitus),  and  oral  contraceptives,

should  be  monitored.  Other  end-points,  e.g.

clotting  function  with  anticoagulants,  should

also be determined.

Vancomycin and teicoplanin

These  glycopeptides,  which  inhibit  cell  wall

synthesis,  have  a  bactericidal  action  against

aerobic and anaerobic Gram-positive bacteria.

They are ineffective in Gram-negative infections.

Vancomycin is not significantly absorbed from

the gut, but is given orally every 6 h for up to

10 days  to  treat  AAC  with  Cl.  difficile  over-

growth. It is given by IV infusion for the treat-

ment of endocarditis (see Chapter 4 and p. 564)

caused by Gram-positive cocci, though there are

persistent reports of resistant enterococci (e.g.

Ent.  faecalis  and  Strep.  viridans).  It  has  been

particularly useful systemically as a treatment for

MRSA infection and has been used for treating

peritonitis in peritoneal dialysis patients (see

Chapter 14). For this latter purpose, it has been

added to the dialysis fluid, but this is an unli-

censed route. Because of its long half-life it can

be given 12-hourly.

Because  resistance  has  been  reported  it

should be reserved for treating serious, resistant

infections and used under laboratory guidance.

Although relatively expensive and somewhat nephrotoxic there is often little alternative when treating MRSA (but see below).

Teicoplanin is similar to vancomycin and is also

indicated  for  the  treatment  of  MRSA,  with

similar precautions. Advantages are its long half-

life, allowing once-daily dosing, and that it can

be given by IM injection, though this is painful.

Linezolid

This is the first of a new class of antimicrobials, the

oxazolidinones, which inhibit protein synthesis by preventing the association of mRNAs with ribo-

somes. It is effective against MRSA and other Gram-positive bacteria, including vancomycin-

resistant enterococci (VRE), but is ineffective against Gram-negative species.

The   chief   problems   with   this   agent   are

reversible myelosuppression and neurotoxicity.

It has excellent tissue penetration, but resistance

can develop readily, especially if doses below

those recommended are used and if treatment is

prolonged.

Thus this is another reserve antimicrobial for treating infections resistant to other drugs or if other agents are not tolerated.

Sodium fusidate

This is the only antibacterial of steroid structure in clinical use. It is a narrow-spectrum agent, the only indication being the treatment of staphylo-

coccal infection. It is used in conjunction with either penicillin or erythromycin because resistance is likely to occur if used alone.

It is used in staphylococcal endocarditis (p.

564) and because it is concentrated in bone,

combinations with sodium fusidate are often used in   osteomyelitis,   a   difficult-to-treat,   usually staphylococcal, bone infection.

Sodium  fusidate  is  also  used  topically  for

staphylococcal skin infections and the ocular

preparation has gained in popularity for the

treatment of conjunctivitis, as an alternative to

chloramphenicol with its potential adverse effects

on bone marrow.

It is cleared hepatically and renally, so clear-

ance may be delayed in hepatic and gallbladder disease and biliary obstruction. Renal impair-

ment may be accompanied by jaundice. Because of these associations, hepatic monitoring should be used if treatment is prolonged.

Peptide antimicrobials: polymyxins

Only two members of this group of decapeptide

antimicrobials are used currently, polymyxin B

and the related compound colistin (polymyxin

E). They act by binding to Gram-negative cell membranes, altering their permeability.

Other antibacterial agents          531

Being  highly  polar,  they  are  not  absorbed

orally. Reports from 30-40 years ago recorded

serious neurotoxicity and nephrotoxicity when

given parenterally. Thus they have been used

only topically until recently, e.g. in the eradica-

tion of nasal carriage of MRSA prior to surgery,

and in eye drops. They are active against many

Gram-negative organisms, including Ps. aerugi-

nosa and colistin is sometimes used orally, usually

with nystatin, for reducing the normal gut flora

in immunosuppressed patients. However, resis-

tant Gram-negative species occur, e.g. strains of

Ps. aeruginosa, so they are not recommended for

treating  gastrointestinal  infections.  Colistin  is

also used as a nebulized inhalation to treat Ps.

aeruginosa lung colonization in cystic fibrosis.

Multidrug-resistant Gram-negative organisms,

e.g. Acinetobacter baumannii, K. pneumoniae and

Ps. aeruginosa, are increasingly causing problems

in the intensive care units of large hospitals.

Some strains are now sensitive only to colistin

and polymyxin B, thus forcing the use of agents

that had previously been abandoned owing to

their toxicity. Accordingly, the utility and tox-

icity of these agents are being reappraised for

use  against  multidrug-resistant  Gram-negative

organisms (see References and further reading).

They are not used in ear drops because of the

risk of serious ototoxicity. Members of this group

have been used topically, often in combination,

to treat infected wounds and in eye drops, and

are  included  in  some  OTC  topical  products.

However, the use of any topical antimicrobial for

wounds is to be discouraged owing to problems

with acquired resistance, healing and skin sensi-

tization:  it  would  be  a  seriously  retrograde

outcome if the potential value of the polymyxins

as rescue drugs in serious Gram-negative infec-

tions were to be lost as a consequence of their

trivial use.

Streptogramin antimicrobials

There are only two members of this group, quin-

upristin and dalfopristin, which are always used

together in a fixed combination. Their sole appli-

cations are in the treatment of serious Gram-

positive  infections  that  are  resistant  to  other

antimicrobials and in patients in whom other treatments cannot be used. They are not active against Ent. faecalis and should be used with other antimicrobials  for  mixed  infections  involving Gram-negative bacteria.

Newer antibacterial agents

Tigecycline is now licensed in the UK for treating

complex bacterial skin infections, e.g. impetigo

and erysipelas, and complex skin and soft tissue

infections (cSSTIs),   e.g.   cellulitis   and   intra-

abdominal infections (peritonitis). It is a very

broad-spectrum   agent,   active   against   Gram-

positive organisms, including MRSA and VRE,

and most Gram-negatives, but excluding Proteus

and Pseudomonas species.

Daptomycin  is licensed in the USA, also for

treating cSSTIs, but is active only against Gram-

positive organisms, including MRSA and VRE. It

has a novel mechanism of action, involving

Ca2÷-mediated   membrane   disruption.   It   is

rapidly bactericidal in vitro  and can be given

once daily.

Oritavancin  and  dalbovancin  are  extended

half-life   glycopeptides,   designed   to   permit

dosing once weekly. They are not yet licensed

in the UK.

Antifungal agents

Fungal infections require quite separate agents

from those effective against bacteria. Included

here are agents active against true filamentous

fungi, e.g. Aspergillus spp., and those used for

treating yeast infections, e.g. Candida albicans.

Candida  infections,  e.g.  oropharyngeal  and vaginal thrush, are common and troublesome, and two principal groups of agents are used in their treatment: the polyene antimicrobials and the imidazoles.

Another common fungal infection in humans is tinea, caused by the filamentous fungi known collectively as dermatophytes. Tinea may affect various areas of the body surface, causing the skin   infections   known   as   ringworm   and athlete’s foot. Fungal infections of the skin and, especially, nails are usually difficult to eradicate, so therapy is often prolonged.

antimicrobial therapy

More serious systemic fungal infections, e.g.

pulmonary  aspergillosis,  or  those  caused  by

Cryptococcus  and  Pneumocystis  spp.  are  usually

opportunistic  infections  in  immunocompro-

mised  patients,  in  whom  they  may  be  life-

threatening.  Cryptococcosis  is  treated  with

prolonged  IV  infusion  of  amphotericin  plus

fluconazole (see  below)  and  is  followed  by

fluconazole PO for 8 weeks. Pneumocystis pneu-

monia requires parenteral therapy with high-

dose co-trimoxazole. IV pentamidine isetionate is

used in patients with severe disease who cannot

tolerate co-trimoxazole, but this may cause severe

hypotension during the infusion or immediately

afterwards.   Mild   to   moderate   infections   in

patients  who  cannot  tolerate  co-trimoxazole

can  be  treated  PO  with  atovaquone,  or  the

antileprotic  agent  dapsone  plus  trimethoprim

(unlicensed indication). A combination of clin-

damycin and the antimalarial primaquine is also

used (unlicensed indication), but is rather toxic.

A 21-day course of a corticosteroid is used in HIV-positive patients with moderate to severe disease, started at the same time as the anti-

pneumocystis medication. The latter should be continued  for  several  days  after  the  cortico-

steroid is withdrawn and continued until all

infection has been cleared. Some patients will need long-term prophylaxis.

Because Pneumocystis infection is so common

in HIV/AIDS patients, antimicrobial prophylaxis

with oral co-trimoxazole or inhaled pentamidine

isetionate  is   used   widely.   However,   inhaled

pentamidine  does  not  protect  against  extra-

pulmonary disease. Dapsone can also be used.

Atovaquone is used occasionally, but this is an

unlicensed indication.

Imidazoles

Clotrimazole,  miconazole  and  niridazole  are  all

used topically in the treatment of vaginal thrush.

Miconazole gel is a useful alternative to nystatin

for the treatment of oropharyngeal thrush. The

newer imidazoles are well absorbed. The first of

the  orally  active  agents  was  ketoconazole,  but

this is associated with severe, even fatal, hepa-

totoxicity if administered at high doses or in long courses so it should be reserved for serious systemic infections.

Newer, less toxic agents, e.g. fluconazole, are available and are useful for the treatment of

candidiasis. However, resistant candidiasis, e.g. caused  by  Candida  glabrata  and  C.  krusei,  is a  recurring  problem  in  sexually  transmitted disease clinics. Fluconazole is used parenterally for these and other invasive fungal infections, but resistance is common.

Parenteral  voriconazole  may  be  used  for

fluconazole-resistant and life-threatening fungal

infections.

very many side-effects, including blurred vision,

photophobia  and  altered  visual  perception,

which  affects 30%  of  patients,  but  usually

disappears  with  continued  treatment.  The  IV

formulation  is  unsuitable  for  patients  with  a

creatinine  clearance      30 mL/min,  owing  to

the   accumulation   of   a   carrier   molecule

(sulphobutylether  beta  cyclodextrin  sodium).

Careful  monitoring  is  essential,  e.g.  hepatic,

renal,  respiratory  and  cardiac  function  both

before  and  during  treatment  and,  similarly,

blood counts and serum electrolytes. The drug

has  many  interactions,  notably  with  anti-HIV

and immunosuppressant agents. Voriconazole is

active  against  Candida  and  Aspergillus  species

and is often the agent of choice for confirmed

pulmonary aspergillosis. Because it is available

in an oral formulation it can be used to switch

patients  from  IV  administration,  thus  permit-

ting  the  discharge  from  hospital  of  patients

being treated for serious fungal infection once

the initial hazard is passed.

Itraconazole  has  a  similar  activity  spectrum

to voriconazole and is available as oral and IV

infusion  formulations.  The  oral  liquid  form

has  a  much  higher  bioavailability  than  the

capsules. However, even when the oral liquid

is used for the prophylaxis of fungal infection

in   neutropenic   patients           (see   Chapter   2),

serum  levels  should  be  monitored  to  ensure

adequate  protection.  Parenteral  itraconazole  is

less  toxic  than  voriconazole,  but  may  cause

rare,  life-threatening  hepatotoxicity.  Patients

should therefore be warned to report immedi-

ately any fatigue, anorexia, nausea, abdominal

pain,  or  dark  urine,  due  to  cholestasis (see

Chapter 3).

Antifungal agents           533

Polyenes

Examples of these are amphotericin and nystatin,

which damage the fungal cell membrane to cause

cytoplasmic leakage. They are not absorbed orally

and may be administered as lozenges or mouth-

washes for treating oropharyngeal thrush. For

vaginal  thrush,  nystatin  is  administered  as  a

pessary,  but  has  largely  been  replaced  by  the

imidazoles.

Amphotericin is administered parenterally for

serious systemic fungal or yeast infections, but

may cause severe renal damage, even at low doses,

and   also   severe   neurological   side-effects,

including deafness and convulsions. Skin rashes

may necessitate stopping treatment. Anaphylaxis

(see Chapter 2) is fortunately rare, but the CSM

recommends giving a test dose before any IV

use, the patient being supervised for 30 min

afterwards.

Liposomal formulations are somewhat more effective and less toxic than the original sodium deoxycholate  complex  for  IV  use.  However, nephrotoxicity may still be a problem. They

are  very  expensive  compared  to  the  sodium deoxycholate complex.

Other antifungals

Fungal infections of the scalp and nails respond

well to oral griseofulvin, which accumulates in

those tissues, although this may need to be

administered continuously for up to 6 months,

possibly 12 months for infection of the toenails.

Shorter courses of treatment and better cure rates

are achieved by using more modern agents such

as  terbinafine,  but  they  have  greater  toxicity.

Tinea  pedis (athlete’s  foot)  may  respond  to

topical antifungals such as tolnaftate or an unde-

canoate, but is now often treated with topical

imidazoles.

Ketoconazole is used as a shampoo to control dandruff, which is associated with the yeast Pity-

rosporum ovale, which also occurs in a hyphal form, known as Malassezia furfur.

In  the  treatment  of  systemic  candidiasis,

amphotericin may be used in combination with

flucytosine, an antimetabolite of cytosine that has

no   action   on   the   true   filamentous   fungi.

Flucytosine may cause serious blood and hepatic disorders, so careful monitoring is required.

Caspofungin is the first of a new class of anti-

fungal agents, the echinocandins, which inter-

fere with fungal cell wall synthesis through their

action against 1,3-beta-D-glycan synthase. These

agents appear to be less toxic than amphotericin

and may be used to treat invasive candidiasis

and aspergillosis. Caspofungin is also used for the

empiric treatment of suspected fungal infections

in neutropenic patients. However, it may cause

hepatic damage and blood dyscrasias.

Antiviral agents

The search for useful antiviral drugs has intensi-

fied since the emergence of HIV/AIDS. Because

the life cycles of viruses are intimately associated

with those of their host cells, it is difficult to find

agents that selectively inhibit virus replication

without damaging human cells. However, there

are certain events in the synthesis of viral DNA

and RNA that differ from those of the host, and

these have been exploited with the nucleoside

group of antivirals. These act either by inhibiting

DNA or RNA polymerases or by incorporation

into nucleic acid to form ‘nonsense’ nucleotide

sequences.

Influenza and HIV/AIDS are dealt with on pp. 553-554 and 557, respectively.

Herpesvirus infections

These DNA viruses have the ability to migrate up

sensory nerve axons and integrate with nerve

cell  nuclei  in  the  regional  nerve  ganglia  as

proviruses. Their persistence in the nerve cells is

due to the production of a microRNA from the

only viral gene that is active during herpesvirus

latency. This promotes the degradation of host

cell messenger RNAs that code for molecules

involved in apoptosis and thus keeps the nerve

cell alive.

Although the primary infection may be minor,

a subsequent trigger event, such as high sun

exposure, major physical stress or immunosup-

pression, may activate the provirus, which then

tracks back down the nerve axon to produce skin

antimicrobial therapy

lesions. Reactivation may occur from the trigem-

inal ganglion in most people who have had

herpes labialis (‘cold sore’), sometimes causing

painful neuralgia as the provirus is activated.

Chickenpox is similar, but reactivation of the

varicella-zoster   virus   causes   shingles            (see

Chapter 7).

One of the first nucleoside antivirals, idoxuri-

dine, is now rarely used and has been supplanted

by aciclovir and its congeners. Table 8.4 lists the

antiviral  drugs  currently  in  use  in  the  UK,

including their applications, except those used

to treat AIDS.

Human cytomegalovirus (CMV) infection is a complication   in   severely   immunosuppressed patients, including those with AIDS, and has

been  successfully  treated  with  ganciclovir,  a nucleoside analogue.

These   antiviral   treatments   are   similar   in concept to the use of the purine and pyrimidine antimetabolites used in cancer chemotherapy

(see Chapter 10).

Interferons  are  the  body’s  own  natural

antiviral agents (see Chapter 2), and recombinant

genetic   engineering   techniques   have   now

produced them in commercially useful quanti-

ties. In addition to their antiviral properties, some

interferons have cytomodulating and cytotoxic

effects.  Interferons  alpha  and  beta  can  be

produced by most cells in response to a variety of

stimuli, e.g. viruses, dsRNA, ILs 1 and 2, and

TNFa. Interferon gamma is produced only by T

cells and natural killer cells (see Chapter 2). Those

used in medicine are non-glycosylated proteins

with a molecular weight about 19.5 kDa.

The interferons have several modes of action,

e.g.:

•  Block mRNA synthesis.

•  Activation of enzymes that:

-  Degrade viral RNA.

-  Inhibit mRNA translation.

-  Block tRNA function.

•  Block protein glycosylation that confers final

            protein functionality.

•  Block:

-  Viral protein maturation.

-  Release of mature virions from host cell.

Interferon gamma-1b is licensed to reduce the

frequency of infections in chronic granuloma- tous disease, in which the intracellular bacteri-

cidal mechanisms of neutrophils and monocytes are impaired (see Chapter 2).

Interferon alfa (IFN alfa) is used to treat chronic

hepatitis B (only 50% response; see Chapter 3)

and  for  chronic  hepatitis  C,  preferably  as  a

combination of peginterferon-alfa with ribavirin.

Early use in acute hepatitis C may reduce the risk

of chronic infection. IFN alfa is also used as an

antineoplastc agent in some lymphomas and

solid tumours.

Interferon beta-1b is used in relapsing, remitting multiple  sclerosis  and  possibly  for  secondary progressive multiple sclerosis.

Despite  their  biological  origin  as  antiviral agents,  the  interferons  have  numerous  side-

effects, but are proving useful in the management of viral hepatitis B and C.

Therapeutic decisions in antimicrobial therapy

Simply possessing a knowledge of the organism involved and spectrum of activity of various

antimicrobials  is  usually  insufficient  to  treat suspected infections effectively. The full thera-

peutic decision-making process is summarized in the flow diagram (Figure 8.2).

General clinical features of infection

The first decision to be made is whether the symp-

toms are in fact caused by microbial infection.

Local infection

Any tissue injury, including infection of mucous

membranes (e.g. sore throat) or the skin surface

(e.g. impetigo), causes inflammation (Chapter

2). However, localized inflammation can have

origins   other   than   infection,   e.g.   contact

dermatitis may often be restricted to a particular

area of skin. Non-infective inflammation can be

complicated  by  the  presence  of  a  secondary

(opportunistic) infection invading the damaged

issue  and  increasing  the  inflammation.  Pus

formation usually indicates the presence of a

localized   bacterial   infection   and   is   most

commonly associated with staphylococcal infec-

tions. However, provided that the infection does

not penetrate the dermis or traverse mucous

membranes and is not caused by MRSA, patients

are unlikely to suffer much harm if they are

otherwise healthy.

Systemic infection

Physicians need to be particularly vigilant for

the signs of progressive or systemic infection. An

initially localized infection may invade deeper

tissues, sometimes progressing to become more

generalized  and  even  life-threatening.  When

bacteria  penetrate  the  dermis  or  SC  layers,

resulting   in   cellulitis,   there   is   widespread

inflammation. The pathogen, usually a strepto-

coccus, may then enter the blood directly or via

the lymphatic system. The subsequent systemic

antimicrobial therapy

spread via the blood can be very rapid and severe

septicaemia may cause septic shock (Chapter 2),

e.g. in meningococcal and streptococcal infec-

tions and listeriosis. In the absence of effective

antimicrobial  therapy,  hypothermia  and  life-

threatening hypotension may ensue. In hospital

patients, most cases of septicaemia are associ-

ated  with  breaches  of  skin  and  mucosal

integrity, e.g. by catheters and other implanted

devices  and  traumatic  or  surgical  wounds.

Similar,   though   less   dramatic,   long-term

complications such as endocarditis, rheumatic

fever and glomerulonephritis (see Chapters 4,

12 and  14)  may  follow a streptococcal sore

throat.

The early signs of a systemic infection tend to

be non-specific: lethargy, tiredness, chills and

muscular  and  joint  aches  are  common.  The

cardinal  sign  of  systemic  infection  is  fever

(pyrexia;  raised  body  temperature).  However,

this does not always indicate the presence of

living  organisms  in  the  bloodstream  because

endotoxins (pyrogens)   derived   from   Gram-

negative bacteria, and WBCs that have ingested

them, may be responsible. The biological advan-

tage to the host of an increase in body temper-

ature  in  response  to  infection  is  obscure.

Possibly a slight rise in temperature may be less

favourable  to  the  growth  of  the  invading

organism,  or  it  may  stimulate  host  defence

mechanisms  more  than  it  does  microbial

activity.

Many non-microbial systemic inflammatory

diseases, e.g. RA (Chapter 12), may also cause

fever. Body temperature can also be raised by

tumour  growth,  as  a  presenting,  non-specific

symptom, and following severe trauma. Medi-

cines may also be implicated, as ‘drug fever’ can

give   rise   to   influenza-like   symptoms,   e.g.

rifampicin,   penicillins,   phenytoin  and   carba-

mazepine. All these possibilities must be consid-

ered   before   infection   is   diagnosed   and

antimicrobials are prescribed.

Some signs of systemic infection can be deter-

mined from blood samples. The ESR and CRP

(Chapter 2) will be raised, but this will also occur

with any systemic inflammatory process. The

neutrophil count has a greater diagnostic value,

and may be extremely high in bacterial infec-

tion. However, there may be neutropenia in

severe bacterial infection, e.g. typhoid fever, and

in viral infection. In addition, the occurrence of

WBCs in normally sterile body fluids, e.g. urine

or CSF, may indicate the presence of pathogens.

Finally, if a particular organ becomes inflamed it  may  eventually  malfunction.  Almost  any organ can become infected, from parts of the GIT (e.g. the appendix) to vital organs such as the heart, kidney, brain or liver. In severe cases, and in the absence of effective treatment, organ failure may lead to death.

Laboratory culture and sensitivity testing

In  hospital,  the  identity  of  any  suspected

infecting  organism  and  its  sensitivity  to  a

representative range of antimicrobials, are usually

determined routinely. Swabs will be taken from

infected wounds, and a wide range of body fluids

is sampled. Samples are then inspected micro-

scopically and cultured in appropriate media and

the organism is provisionally identified. Small

filter  paper  discs  impregnated  with  different

antimicrobials are placed on an agar plate inocu-

lated with the organism, and its sensitivities are

determined by observing areas of growth inhibi-

tion. Wherever possible, culturing and sensitivity

testing are performed before antibacterial treat-

ment  is  initiated.  Sampling  before  empirical

treatment (see below) is started is the minimum

requirement, because the presence of antibac-

terials in the sample, or the effect of treatment

on the organism, may inhibit the test culture

sufficiently  to  give  negative  or  inconclusive

results. Sometimes, the laboratory will carry out

detailed identification and typing, to direct treat-

ment  and  to  support  epidemiological  moni-

toring,  e.g.  to  trace  the  origin  of  a  food

poisoning outbreak or MRSA infection.

Limitations of culturing and sensitivity testing

Not  all  sites  of  infection  are  amenable  to

culturing and sensitivity testing. Areas that are

heavily colonized with commensals, such as the

skin, GIT and the superficial genitourinary tract,

often   yield   unhelpful,   false-positive   results

because a large variety of organisms will invari-

ably be cultured, including organisms that may

antimicrobial therapy

be potentially pathogenic but are unrelated to

the  current  infection.  E.  coli  is  a  ubiquitous enteric commensal, but only certain toxigenic or enteropathogenic  strains  are  responsible  for gastrointestinal upsets.

Similarly,  identification  of  Staph.  epidermidis

in  a  wound  swab  does  not  necessarily  mean

that antibacterial therapy should be given. It is

only when the patient’s immunity is compro-

mised, or a particularly heavy infection leads to

cellulitis  or  septicaemia,  that  treatment  is

required. In some gastrointestinal and genito-

urinary  infections,  the  use  of  antibacterials,

especially  broad-spectrum  ones,  can  permit

over-growth  and  infection  by  resistant  but

normally non-pathogenic organisms.

Because  all  laboratory  culture  media  and

methods are artificial, they cannot provide the

ideal  conditions  appropriate  for  fastidious  or

damaged microorganisms and may give false-

negative results. Thus failure to grow pathogens

should not be taken as evidence of their absence

in samples. Other techniques may be required if

a patient’s condition clearly points to infection,

e.g. serology for the detection of Chlamydia and

spirochaetes. Staining and microscopic examina-

tion of sputum for acid-fast bacilli is an example

of  this  in  diagnosing  TB,  and  permits  the

commencement of treatment long before culture

can give positive evidence.

New techniques of DNA multiplication by the

polymerase chain reaction are now available for

microbial identification and, being automated,

can give rapid results. This is being done already

for TB and should also be capable of predicting

antimicrobial sensitivity, but the process is still

relatively expensive and so is not used routinely.

However, these techniques are bound to grow in

popularity  as  the  genomes  of  pathogens  are

determined,  because  they  are  sensitive  and

specific, can be automated and are applicable

even after antimicrobials have been used.

Treating in the absence of sensitivity tests (empirical treatment)

Culturing and sensitivity testing can take days

(e.g. in meningitis) or even weeks (e.g. in TB, p.

574), and treatment may have to be started on

an empirical (‘blind’, ‘best guess’) basis. This is

usually based on knowledge of the epidemiology

of the disease, the site of infection, and local

experience. Table 8.5 lists some organisms most

commonly associated with different infections.

However, organisms other than those described

may be responsible: for example, E. coli causes

95% of urinary-tract infections, but other Gram-

negative organisms, such as Klebsiella aerogenes,

Ps. aeruginosa or Proteus spp. have been impli-

cated,  especially  in  hospital-acquired (noso-

comial) infections. After deciding on the most

likely organism, local knowledge of the spectrum

of activity will determine the choice of antimi-

crobial, although strain resistance may confound

even the most astute choice. These empirical

decisions are later modified when the results of

laboratory tests become available.

Pyrexia (fever) of unknown origin (PUO,

FUO)

This may be defined as a temperature    38°C

persisting for 2-3 weeks without a clear diag-

decisions in antimicrobial therapy           539

nosis being made, despite a range of carefully targeted examinations being done.

Provided that possible non-infectious causes

have been excluded, a more detailed history

needs to be taken. This will include information

on travel, occupation, animal contact, leisure

activities (especially water sports), recreational

drug use, tattooing or body piercing, blood trans-

fusions, sexual activity and medication usage. A

wider  range  of  blood  tests,  examination  of

biopsy material (including washings or scrap-

ings) and additional imaging may be needed.

There needs to be a systematic examination of all

body systems.

While these investigations are proceeding only

general supportive measures should be taken, i.e.

no antimicrobial agents or corticosteroids, etc.

that might obscure the signs of infection should

be  used  unless  the  condition  compromises

patient safety. Blood tests, etc. may need to be

repeated regularly.

Despite all this, no definitive diagnosis can be

made in a small proportion of patients. Such

patients may feel unwell for several months, until

the  condition  finally  resolves,  often  without specific treatment.

Antimicrobial resistance

The high incidence of bacterial resistance makes

culture and sensitivity testing essential, espe-

cially in hospital. There is a lesser problem in the

community because severe infections are less

frequent and the true scale of the problem is

unknown. Knowledge of local patterns of resis-

tance is therefore important, especially when

treating empirically.

Mechanisms of resistance

An organism may protect itself from antimicrobial

attack in a number of ways (Table 8.6), enzyme

degradation of the antimicrobial being the most

important. Extracellular beta-lactamases tend to

be produced by Gram-positive organisms, whereas

intracellular  lactamases  may  be  found  in  the

periplasmic space of Gram-negative organisms.

Prevention of access to the target due to decreased

penetration is more likely to be found in Gram-

negative organisms and binding of antimicro-

bials  in  the  periplasmic  space  is  a  particular

problem   for   beta-lactam   antimicrobials.   A

further mechanism is efflux resistance, in which

an antimicrobial is actively expelled from the

bacteria.

Resistance develops primarily by selection from

a small population of genetically resistant strains

in the general infective pool under the selective

pressure  imposed  by  the  antibacterial,  so  the

‘fittest’ (i.e. resistant) organisms survive. Mutation

antimicrobial therapy

during treatment, with a genetic change confer-

ring resistance, is rare except with some highly

mutable pathogens, e.g. influenza A virus (p. 554).

Plasmid transfer, whereby one or multiple resis-

tance genes are transferred together from one

bacterium  to  another,  plays  a  key  role  in

spreading resistance rapidly throughout a micro-

bial population. This may even occur between

unrelated species. Less commonly, DNA can be

transferred by two further mechanisms: trans-

duction by bacteriophages and transformation

by uptake of soluble DNA.

Patterns and causes of resistance

The  development  of  resistance  by  previously sensitive organisms has been a problem ever since the introduction of the sulphonamides in the

1930s. A number of factors are involved in this phenomenon, with the resistance of organisms responsible for nosocomial (hospital-acquired) infections playing a central role.

The emergence of resistance in the community

and  hospitals  are  closely  inter-related.  Recent

problems with resistance in the community by

organisms such as streptococci and staphylococci

may have contributed to the level of resistance of

these bacteria in nosocomial infections, or vice

versa. Also, the use of antimicrobials in animal

feeds  is  believed  to  have  contributed  to  the

prevalence of antimicrobial resistance, and the

prohibition of using clinically useful antimicro-

bials in animal husbandry is usual in developed

countries.

Of particular concern in the UK is the emer-

gence  of  penicillin-resistant  pneumococci  in

community-acquired pneumonia. In this case, it

has been suggested that the problem can largely

be overcome by administering higher than usual

doses.

Although 80% of antimicrobials are prescribed

in the community, hospitals and nursing and

residential homes are regarded as the major reser-

voir of resistant organisms. The reasons behind

this  are  not  fully  understood,  although  the

broadest-spectrum agents are used most heavily

in these settings, with their populationss of at-

risk patients. Both appropriate and inappropriate

antimicrobial  use  can  drive  the  emergence  of

resistance, so reduction of inappropriate use is a

priority.

The spread of resistance within hospitals and,

increasingly, residential care units is of prime

concern and may be associated with a lack of

adequate  isolation  facilities.  Simple  infection

control procedures, e.g. hand washing, scrupu-

lous ward cleaning, mask wearing and the steril-

ization   of   uniforms,   should   be   rigorously

enforced. Barrier nursing can be used either to

protect a vulnerable patient from ward infection

or to protect patients on a ward from an infected

patient. In the 1990s doctors in Holland reduced

the incidence of MRSA infections by a rigorous

‘search and destroy’ process that involved identi-

fication of MRSA carriers on admission and their

isolation in single rooms. However, this would

now be much more difficult in the UK, because

of greater pressure on beds and the higher inci-

dence of MRSA infection.

Immunocompromised  patients,  e.g.  those

with  febrile  neutropenia  following  cytotoxic

chemotherapy  or  high  doses  of  steroids,  the

frail  and  elderly,  cancer  patients  and  AIDS

sufferers, will often require intensive empirical

cover  with  very  broad-spectrum  agents.  Addi-

tionally,  sub-therapeutic  antibacterial  concen-

trations  can  occur  in  the  immediate  patient

environment due to the indiscriminate use of

topical   antimicrobials   and   sub-therapeutic

dosing.

Resistant organisms cause particular problems in intensive therapy units, where antimicrobial use is high, with many staff in direct patient

contact,  and  where  patients  have  impaired resistance to infection.

Patterns of resistance vary on the national and

the international scale. For instance, the inci-

decisions in antimicrobial therapy           541

dence of beta-lactamase-producing H. influenzae

is far lower in the UK (about 6%) than in the USA

( 30%). High-level penicillin resistance is preva-

lent in about 10% of Strep. pneumoniae isolates in

the USA, and lower level resistance in a further

40%. This compares with figures of between 10

and 40% and up to 70% respectively in main-

land Europe. In the UK, high-level penicillin

resistance is found currently in less than 5% of

pneumococci. Local changes in the resistance of

E. coli to trimethoprim and ampicillin have been observed within the UK.

Patients  receiving  multiple  or  prolonged

courses of treatment are more likely to experience

a resistant infection subsequently. Resistance can

also develop within an individual either quite

rapidly or some time after commencing treat-

ment, usually by transfer of resistance factors

between  conjugating  bacteria.  Microbial  resis-

tance  in  an  individual  patient  is  a  particular

problem in intensive care and burns units where

staphylococcal,  coliform,  pseudomonad  and

Haemophilus infections are often implicated. As

well as resistant organisms occurring in an indi-

vidual they can be transferred between patients,

unwittingly, by health workers.

Resistance usually starts to be reported quite

soon after the introduction of a new antibacterial

into clinical use. Thus resistance to ciprofloxacin

was observed only a year after its introduction,

and even the newest antimicrobials (e.g. linezolid)

have  been  the  subject  of  clinical  reports  of

resistance.

Certain organisms tend to cause more prob-

lems than others. Ps. aeruginosa has a particularly

high tendency to develop resistance, and there

have been reports of isolates that are resistant to

both   ciprofloxacin  and   the   ureidopenicillins.

Another   group   of   Gram-negative   organisms

causing concern is Klebsiella  spp., particularly

because of their propensity to carry genes coding

for extended spectrum beta-lactamases (ESBLs).

The latter can hydrolyse most penicillins and

cephalosporins, may be mediated by plasmid or

chromosomal genes and are selected for by the

use of the third-generation cephalosporins and

clavulanate. Such resistant organisms are causing

increasing  concern  because  of  their  greater

frequency of occurrence in urinary-tract infec-

tions in the community. These infections require hospital treatment, because only parenteral anti-

microbials are effective, e.g. carbapenems and aminoglycosides.

After  a  period  during  which  staphylococcal

resistance  appeared  to  stabilize,  Staph.  aureus

has re-emerged in the form of MRSA, posing a

major problem. Once these occur in a hospital

ward  the  most  stringent  infection  control

measures are required. Community-onset MRSA

(C-MRSA), where a patient presents with MRSA

infection without traditional risk factors being

present (e.g.  prior  hospital  in-patient  treat-

ment), is increasingly present in the USA and a

number of cases have been reported in the UK.

There  have  been 11 cases  of  nosocomial

infection  recently (end 2006)  by  a  virulent,

highly toxigenic strain of MRSA that produces

Panton-Valentine  leucocidin (PVL),  infections

which may be fatal within 24 h of symptoms

occurring. Disturbing features of PVL ÷ MRSA

infection are:

•  The speed of attack, placing a premium on rapid

            diagnosis and correct empirical treatment.

•  It will infect young, previously healthy indi-

viduals, unlike most other strains of MRSA

that affect immunosuppressed and debilitated

people.

•  PVL÷ MRSA is present in the community and

            there have been five deaths from community-

acquired infection in the UK over a 2-year period.  Despite  their  pathogenicity,  these strains tend to differ from those acquired in hospital because they are still susceptible to many antibacterials.

However, most MRSA strains are not ‘super-

bugs’:  many  strains  are  weak  pathogens,  but

cause  problems  because  they  infect  patients

who are already seriously ill or are exposed to

surgical  wound  infections  from  major  pro-

cedures.  Further, despite media attention, there

is not a current epidemic of MRSA in the UK,

and  TB  is  a  far  greater  international  problem

(see below).

Overcoming resistance

Methods of counteracting the problem are either

to find new antimicrobials to which resistant

organisms are sensitive, or to use compounds

antimicrobial therapy

capable of neutralizing any enzymes produced by  the  bacteria  that  inactivate  antimicrobial agents, e.g. clavulanic acid  and tazobactam  for penicillinases.

However, it is less costly to prevent resistance

occurring in the first place, by controlling the

way in which these agents are used - particularly

in the hospital - through the introduction of

antimicrobial policies. Because breakdown of

infection control in one hospital unit inevitably

affects the whole, there needs to be a multidisci-

plinary infection control team (IFT) under the

direction of a senior staff member, with adequate

laboratory  and  secretarial  support  and  direct

access to the chief executive. The latter carries

overall  responsibility  for  the  performance  of

infection  control  procedures  in  the  hospital.

There is a UK Nosocomial Infection National

Surveillance  Scheme  to  assist  hospitals  and

ensure quality.

Part of infection control measures involves

periodical   change   of   the   antimicrobials   in

common use for particular organisms or pro-

cedures,  preventing  inappropriate  prescribing

and ensuring the prescribing of full courses at

adequate  doses.  Full  courses  are  particularly

important to individuals, as they will prevent

either the re-emergence of an infection with

potentially  resistant  organisms,  which  might

follow incomplete kill, or superinfection with

another pathogen. A further method is to use

combinations of antimicrobials. This is an essen-

tial element in the treatment of TB and endo-

carditis (pp. 574 and 564), where it is essential to

kill the organism involved, but there are few

other applications.

Infection control is integral to clinical gover-

nance and is part of the responsibilities of all

staff members, including cleaners, maintenance

engineers, caterers, pharmacists, nurses, doctors

and managers.

Combination therapy

Apart from attempting to circumvent resistance,

there are a few other instances when combina-

tions of antimicrobials might be indicated. These

include:

•  To achieve synergy, e.g. the concurrent use

            of  an  aminoglycoside  and  a  ureidopeni-

cillin  in  the  treatment  of  pseudomonad

infection.

•  In   life-threatening   infections  (e.g.   septi-

caemia), where urgent empirical treatment is

essential, a combination may be used until sensitivity testing has been performed.

•  When the immune system is compromised, as

in the chemotherapy of leukaemia, where very

broad prophylactic cover is required using a

combination of both antibacterial and anti-

fungal agents. This also applies in the early

stages of bone marrow transplantation, until

the implanted tissue has acquired adequate

function. Similarly, in HIV/AIDS, the immune

system is severely compromised because of the

destruction of CD4÷ TH  cells and combina-

tions of antiretroviral drugs are always used

(p. 558 Table 8.11).

The problems of TB treatment are dealt with below (p. 574).

Penetration to the site of infection

Even if the pathogen is sensitive to an antimicro-

bial agent, the drug must reach the site of infec-

tion in order to be effective. Factors that impair the achievement of adequate local antibacterial concentrations include:

•  Perfusion problems. •  Internal barriers.

•  Route of elimination.

Perfusion problems

Any  systemically  administered  drug  must  be

transported in the blood to the desired site of

action before it can have an effect. Thus, well-

perfused tissues will be the most accessible to

systemic antimicrobials. The alveoli of the lung

are  particularly  well  perfused,  because  they

receive the whole of the cardiac output. Thus, if

they  become  infected (pneumonia,  p. 559)

appropriate  antibacterial  therapy  is  almost

invariably successful if the patient is otherwise

healthy.  Conversely,  an  infection  within  the

poorly    perfused    pleural    cavity       (e.g.    in

decisions in antimicrobial therapy           543

pleural empyema), may require longer courses of treatment and higher doses.

The treatment of wound infections can be

made particularly difficult when the peripheral circulation  is  impaired.  This  is  important  in diabetics (see Chapter 9), in whom atheroscle-

rotic arterial damage and microangiopathy slow wound healing and impair the penetration of

antimicrobials. The elderly also tend to have a poor  peripheral  circulation,  predisposing  to pressure  sores  and  venous  ulcers  and  such lesions  are  very  difficult  to  treat  should  they become infected (see Chapter 2).

Connective tissue infection is similarly prob-

lematical,  e.g.  staphylococcal  bone  infections

(osteomyelitis) can be very difficult to treat if

the  organism  becomes  sequestered  in  bone

following orthopaedic surgery or a compound

fracture. A combination of antibacterials is then

needed,  e.g.  sodium  fusidate  plus  flucloxacillin

and/or gentamicin.

Internal barriers

In several circumstances infections may occur in body sites that are not easily accessible to antimi-

crobials. In others, the infection itself will create a barrier to penetration.

If  large  amounts  of  infected  sputum  are

produced   in   pulmonary   infections,   as   in

bronchiectasis  and  cystic  fibrosis,  the  mucus

protects the organisms and prevents ready access

by antimicrobials, necessitating frequent high-

dose treatment. Although it has been claimed

that  amoxicillin  is  better  than  ampicillin  in

treating chest infections owing to a superior

penetration into sputum, the difference is prob-

ably of minor clinical significance, provided that

adequate blood levels of ampicillin are attained.

Similarly,  when  the  infection  results  in  the

formation of large quantities of pus, as in a

staphylococcal boil or abscess, the bacterial coag-

ulase enzyme causes a fibrin clot to be formed

around the lesion that inhibits penetration of

the antibacterial. Surgical drainage must then

precede antimicrobial therapy. A cyst, which is

not   surrounded   by   a   fibrin   clot,   is   more

amenable to antibacterial treatment.

Penetration of the CNS by antimicrobials is

also extremely variable due to the blood-brain barrier that usually prevents the penetration of

hydrophilic  molecules.  Fortunately,  IV  benzyl-

penicillin, cephalosporins and other antimicro-

bials attain therapeutic concentrations in the CSF

and cure bacterial meningitis (p. 548) because

meningeal  inflammation  opens  the  tight  cell

junctions of the blood vessels’ endothelium that

form the barrier and so permits antimicrobial

penetration.

Route of elimination

This is of particular importance when dealing with urinary-tract infections (p. 576). Nitrofuran-

toin is excreted unchanged in the urine in concen-

trations that exceed the MIC for likely urinary pathogens, even though the plasma concentra-

tion is inadequate to treat a systemic infection. This is fortunate because adequate antimicrobial plasma  levels  would  cause  unacceptable  side-

effects.  In  contrast,  penicillins  achieve  both adequate urine and plasma levels.

With biliary tract infections it is essential that

a sufficient amount of the unchanged antimi-

crobial  is  eliminated  by  biliary  excretion  to

obtain therapeutic levels. This occurs with peni-

cillins and cephalosporins, which consequently

may be effective in the treatment of infective

cholecystitis.

Indications for antimicrobial therapy

Before antimicrobials are prescribed it is impor-

tant to consider whether this is the most appro-

priate  therapy:  there  may  be  very  positive

indications  for  their  use  or  they  may  be  of

limited value. Thus, most viral infections, espe-

cially of the respiratory system, do not respond

to currently available antiviral therapies. The

major exceptions to this are the herpesvirus and

cytomegalovirus infections that can be cured

with aciclovir  and ganciclovir, respectively (see

above), and HIV/AIDS, which can be treated, but

not cured.

Even if the organism is sensitive, treatment

may still not be worthwhile if the infection is

self-limiting, e.g. herpes labialis, mild strepto-

coccal throat infection or mild staphylococcal

antimicrobial therapy

skin  infection.  In  an  otherwise  healthy  indi-

vidual  such  infections  will  be  overcome  by

host  defences  within  5 days.  Salmonellosis  of

the  GIT (p. 567)  does  not  respond  well  to

antimicrobial treatment and some agents may

actually prolong the carrier state, i.e. the time

during  which  the  organism  will  be  found  in

the stools.

In summary, injudicious use of antimicrobials increases the risk of resistance developing, and may also cause serious toxicity.

Severe and systemic infection

Many systemic infections require prompt empir-

ical treatment owing to the danger of spread to

vital organs or the development of septicaemia

and, in extreme cases, septicaemic shock. Clin-

ical judgement of severity is important and the

physician needs to consider several factors:

•  Degree of pyrexia and other signs associated

            with fever, e.g. fits in young children, rigors

and malaise.

•  Likely time course of the infection. •  Patient’s immune status.

The choice of an empirical agent is determined

by what is known of the probable aetiology of

the infection. However, this must be kept under

review,  e.g.  Vibrio  valnificans,  a  warm-water

species  usually  found  in  the  waters  around

Mexico has now been detected in the Baltic sea,

a result of global warming. This could become a

novel cause of serious wound infections and

cellulitis in Europe.

Impaired resistance to infection is associated

with a number of diseases. Major inherited disor-

ders of the immune system (e.g. hypogamma-

globulinaemia, impaired phagocyte activity and

deficiency of complement components) predis-

pose to infection, but most are rare. A more

common problem occurs in leukaemia, where

the WBCs, although produced in large numbers,

are ineffectual in combating infections. Also, the

use of cytotoxic agents for treating neoplasms

often causes myelosuppression and so compro-

mises the immune system. Leukaemic patients

are thus particularly prone to infection by a

variety of organisms, some of which are oppor-

tunistic. Even commensals normally resident in

the  gut  may  cause  opportunistic  infections

under   these   conditions,   and   any   infection

occurring  in  these  patients  must  be  treated

aggressively.

Immunosuppressive  therapy  is  given  to

prevent  rejection  following  an  organ  trans-

plant,  so  antimicrobial  therapy  and  barrier

nursing  are  employed  prophylactically  until

the  danger of early organ rejection has passed.

Immunosuppression   to   treat   autoimmune

diseases also renders patients more susceptible

to infections.

Immunodeficiency associated with disease is

now a worldwide problem owing to HIV/AIDS

infections,  in  which  destruction  of  CD4÷  TH

cells (see Chapter 2) exposes the patient to a

variety of unusual infections. One of the most

common and serious of these is pneumocystis

pneumonia,  which  is  treated  with  high-dose

co-trimoxazole.  Nebulized  pentamidine  may  be

administered  prophylactically  for  this.  TB  is

common  in  HIV  patients  and  about  50%  of

these  are  believed  to  be  infected  with  TB  in

southern  Africa.  HIV  patients  are  also  unable

to  deal  immunologically  with  human  herpes-

virus (HHV)  infections  and  these  cause  neo-

plasms  and  serious  infections,  e.g.  HHV6,  a

common commensal, may cause severe pneu-

monia  and  HHV8  is  associated  with  Kaposi’s

sarcoma.

Elderly debilitated patients are also at risk, and

prompt treatment may be indicated for even a

mild infection in such cases. This occasionally

raises ethical problems, because the prognosis

may be extremely poor owing to other medical

conditions, and treating such an infection may

prolong a life of greatly reduced quality.

Prophylaxis

Antimicrobial prophylaxis is contentious. Inap-

propriate  prophylaxis  may  not  only  lead  to

increased populations of resistant organisms but

also adds significantly to drug costs. However,

prophylaxis against infection may sometimes be

appropriate.

In  some  surgical  procedures  prophylaxis  is

essential, particularly in ‘dirty’ surgery involving

decisions in antimicrobial therapy           545

the GIT or lower abdomen, when the antimicro-

bials used must protect against opportunistic

infection  by  gastrointestinal  commensals.  A

combination   of   a   cephalosporin,   to   cover

coliforms,   and   metronidazole   for   anaerobic

bacteria, is usual. The aim is to prevent such

organisms from causing a systemic infection if

they should reach the patient’s bloodstream and

to prevent sepsis along suture lines. The practice

of   oral   pre-surgical   gut ‘sterilization’   using

neomycin, or a non-absorbed sulphonamide, is

now rarely used: antimicrobials are preferably

given intravenously just before surgery and for

one or two doses afterwards, although there is

evidence that single-dose prophylaxis prior to

surgery is usually adequate. Antimicrobials are

similarly used after major orthopaedic surgery,

e.g. total hip replacement. A further example is

in dental surgery, where those with a history of

heart valve disease or endocarditis (p. 564) may

require prophylaxis before any procedures are

carried out, however minor.

Prophylaxis may sometimes be required over

longer periods. Those with sickle-cell anaemia

(Chapter 11) can suffer an extremely painful,

and   sometimes   fatal,   sickling   crisis,   which

predisposes   to   infection   with   Salmonella

(osteomyelitis)  and  Strep.  pneumoniae (pneu-

monia or meningitis). Because streptococci are

so   common,   continuous   low-dose   penicillin

prophylaxis  is  often  prescribed.  Splenectomy

greatly increases the risk of infection by encap-

sulated organisms, e.g. Haemophilus and Neisseria

spp.   and   Strep.   pneumoniae,   and   long-term

penicillin prophylaxis is prescribed. Vaccinations

are also given.

Cystic   fibrosis   patients   may   also   require

continuous,  lifelong  prophylaxis  in  order  to

prevent the chest infections that are a major

feature   of   this   disease.   Ps.   aeruginosa   is

commonly implicated and frequent courses of

parenteral or inhaled aminoglycosides are often

prescribed.

Finally, prophylaxis is often indicated when there has been contact with certain virulent

infections,    e.g.    meningococcal    meningitis (p. 548).  Close  contacts  require  only  short courses of rifampicin or ciprofloxacin (unlicensed applications) in such cases.

Side-effects

Hypersensitivity is a major contra-indication to

using  a  particular  antimicrobial.  This  is  well

recognized with the penicillins, but can occur

with any agent. Close questioning is necessary to

ascertain the status of claimed hypersensitivity

reactions because patients sometimes confuse

these reactions with minor adverse effects such

as gastric disturbance, reporting that they are

‘allergic’ to a particular antimicrobial. Taken at

face value this may preclude the use of an other-

wise useful drug because prescribers will always

avoid the possibility of a major allergic reaction,

however unlikely it seems to be from the history.

If no suitable alternative is available, and the

treatment is essential, or when an antimicrobial

is given intravenously for the first time, it is

common practice to prepare for the possibility

of an anaphylactic reaction by having injections

of  adrenaline,  hydrocortisone  and an antihista-

mine readily available. Penicillin desensitization,

whereby  the  patient  is  exposed  to  gradually

increasing concentrations of penicillin, is rarely

employed as it is a perilous procedure, potentially

causing anaphylaxis, and it is usually possible to

choose an alternative antibacterial.

Some  serious  adverse  effects,  such  as  the

nephrotoxicity and ototoxicity associated with

aminoglycoside  therapy,  are  dose-related (see

above),  as  is  encephalopathy  with  excessive

doses of penicillins. Other adverse effects may be

antimicrobial therapy

more difficult to predict and may not resolve on discontinuation  of  treatment,  e.g.  the  bone marrow toxicity associated with chloramphenicol. Table 8.7 summarizes some of the most common adverse reactions to antimicrobials. Apart from these there are various rare idiosyncratic and

unpredictable   reactions,   such   as   the   lupus syndrome with isoniazid  and blood dyscrasias with  cephalosporins.  Gastrointestinal  adverse effects are discussed in Chapter 3.

Interactions

Consideration should also be given to potential

interactions between antimicrobials and other

drugs, although these are uncommon. The use of

gentamicin and a loop diuretic has been reported

to increase the incidence of ototoxicity. Similarly,

the  combination  of  a  cephalosporin  and  a

loop  diuretic  may  increase  nephrotoxicity,

although this is a problem only with the early,

first-generation cephalosporins, e.g. cefradine.

There  is  a  theoretical  interaction  between

bactericidal  and  bacteriostatic  agents  because

bactericidal agents depend on microbial repro-

duction or active metabolism for their effect, so

activity may be reduced by agents that inhibit

cell division. However, such combinations are

rarely necessary. When they are used together,

e.g. in the treatment of an atypical chest infec-

tion   with   amoxicillin  and   erythromycin,   the

combination  does  not  seem  to  present  any problems.

The potential of certain antimicrobials to affect

the activity of liver enzymes is well recognized.

The  rifamycins  are  hepatic  enzyme  inducers

(Chapter 3),  which  results  in  low  concentra-

tions of many drugs. This may be very important

if adequate blood levels are critical for the activity

of essential drugs, and patients taking oral contra-

ceptives,  anticonvulsants,  oral  hypoglycaemic

agents or theophylline should be warned that they

will  be  less  effective.  Failure  of  contraception

has been reported after women had taken short

courses  of  rifampicin  for  prophylaxis  against

meningococcal infection.

The converse, enzyme inhibition, has been

reported with erythromycin and quinolone anti-

microbials. This causes increased blood levels

of, e.g. theophylline, causing convulsions, and

warfarin, causing bleeding. These effects make it

difficult to maintain proper control of plasma

levels of affected drugs, because the levels will

rise  or  fall  during  therapy  with  an  enzyme

inhibitor or inducer, and then change again

when that treatment ceases (see also Chapters 2

and 3; Table 3.34).

Dose and frequency

These parameters are often determined on the

usual age and weight basis, and with due regard

to renal and liver function. Precise dose calibra-

tion is not particularly important with the beta-

lactams, because they have a wide therapeutic

range.  However,  they  have  a  concentration-

dependent  killing  profile,  so  blood  levels  of

these should be maintained above the MIC for

most of the interval between doses. However,

close  monitoring  is  essential  for  more  toxic

agents, e.g. gentamicin. Antimicrobials such as

the aminoglycosides and quinolones exhibit a

concentration-independent microbicidal profile,

so it is necessary to exceed the MIC for only a

short time to kill the organism.

The aminoglycosides are eliminated via the

kidneys, and gentamicin clearance correlates well

with glomerular filtration rate, as estimated from

the  plasma  creatinine  level.  However,  with

longer courses of gentamicin treatment it is neces-

decisions in antimicrobial therapy           547

sary to monitor plasma levels directly because the volume of distribution can vary markedly

between individuals. Also the toxic effects, espe-

cially ototoxicity, are more likely if trough levels are too high. Once-daily administration may be appropriate (see p. 524, gentamicin).

Antimicrobials eliminated by hepatic metabo-

lism can accumulate in liver failure, but this is

difficult to predict or calculate. It is probably

best  to  avoid  giving  antimicrobials  such  as

erythromycin and rifampicin if liver dysfunction is

suspected. If these are essential, plasma level

monitoring should be used, at least initially,

until the extent of the liver problem is defined.

The frequency of administration is important, not least because of the level of non-compliance associated with this group of drugs. Patients tend to stop in the middle of a course if the regimen proves too irksome or if they feel better, as they often do after 24-48 h of antimicrobial therapy. Therefore, the fewer doses that are taken each day the greater the likely compliance.

The half-lives of the penicillins and many

cephalosporins are only a few hours. Ideally,

doses should be timed to the half-life of the

drug, but this would be impractical in most cases

of penicillin therapy. Therefore, with these less

toxic  antimicrobials,  doses  are  chosen  that

achieve plasma levels several times greater than

the MIC. In this way the frequency of adminis-

tration can then be reduced, as the plasma level

will still exceed the MIC before each subsequent

dose. Antimicrobials that can be given just once

a day, such as ofloxacin and cefixime, may offer

advantages for patient compliance.

Duration of therapy

A balance must be achieved between eliminating

pathogens completely, to limit the emergence

of resistant organisms, and giving too long a

course, with which the patient may not comply,

and with the increased risk of adverse effects and

resistance.

The  usual  recommended  course  for  most

antimicrobials  is 5-10 days,  but  this  is  not

evidence-based  in  most  cases  and  there  are

numerous   exceptions   to   this   empirical

generalization.   Thus   uncomplicated   lower

urinary-tract  infections  in  women  are  usually

adequately  treated  with 3-day  courses,  but

common practice is to treat upper respiratory

tract infections, in the absence of any chronic

lung disease, with a 5-7-day course. Chlamydia

infection can be treated with a single dose of

azithromycin.  Other  treatments  may  require

weeks (e.g. endocarditis) or months (e.g. TB) of

antimicrobial treatment.

Failure of therapy

Even after the most diligent choice of antimicro-

bial, therapy may still fail. Table 8.8 summarizes the possible reasons for such failure and reflects the main points made in this section regarding appropriate therapeutic choice.

antimicrobial therapy

Some important infections

Meningitis

Aetiology

The term meningitis strictly refers to inflamma-

tion  of  the  meninges,  the  triple  membrane covering the CNS, which is not necessarily due to infection. It may also be caused by invasion of neoplastic  cells  in  association  with  cytotoxic chemotherapy (see Chapter 10), of blood after a  subarachnoid  haemorrhage,  or  rarely  by

drugs. This non-infective inflammation is more correctly called meningism, the term meningitis being reserved for infective causes.

The  causative  microorganisms  vary  with

age,  between  countries  and  regionally  within

countries. This brief account is confined toUK

experience.

In  the  first  3 months  of  life  the  common

bacteria  causing  community-acquired  menin-

gitis are group B streptococci, E. coli strain K1

and Listeria monocytogenes. Neisseria meningitidis,

Strep.  pneumoniae  and  H.  influenzae  are  less

common. However, the last three of these are

the most common species in older children up

to 14 years,  with  most  cases  being  due  to

Neisseria  meningitidis  serogroups  B  and  C.

H. influenzae is becoming rare in theUKdue to effective immunization with Hib vaccine.

Table 8.9 summarizes the probable pathogens,

which can usually be deduced from the age of

the patient and any predisposing factors, e.g.

skull fracture, ear disease and occupational or

recreational  history.  Of  the  organisms  listed,

N. meningitidis is the most likely in an adult.

Listeria meningitis is occasionally found in both neonates and the elderly. A completely different group  of  Gram-negative  bacteria  is  usually implicated in neonatal meningitis.

About 75% of teenage and adult cases of bac-

terial  meningitis  are  infected  with  Neisseria

meningitidis and Strep. pneumoniae. In the remain-

Some important infections         549

der, L. monocytogenes, E. coli K1 and H. influenzae

and  similar  Gram-negative  bacteria  predomi-

nate:   Staph.   aureus  may   also   be   involved.

Secondary infection, e.g. following a fracture of

the skull, may allow skin surface organisms to

reach  the  meninges  and  staphylococci  and

streptococci are then the usual pathogens but

occasionally Pseudomonas may cause problems,

because of its antimicrobial resistance.

However, viral meningitis is the most common

type in theUK, but it is usually mild and self-

limiting. A number of viruses may be involved

(Table 8.9). Unlike bacterial meningitis, which

causes most of the severe cases, there may be only

minimal changes in the appearance and cellular

components of the CSF, so it is sometimes erro-

neously  termed  ‘aseptic  meningitis’.  However,

this merely means that there is no growth on

laboratory media, which are designed to cultivate

non-fastidious bacteria and fungi. Viral menin-

gitis will not be discussed further here.

Other rarer forms of meningitis usually occur in  immunocompromised  patients,  caused  by fungi, mycobacteria and protozoa.

Epidemiology

Although  nasal  carriage  of  N.  meningitidis  is

common, being present in about 5% of adults,

the annual incidence of meningococcal menin-

gitis in theUKis only about 10 per 100 000.

Occasional local epidemics are caused by the

group B serotype.

The most vulnerable groups are infants up to

1 year and elderly residents in institutions and

nursing homes. Neonates are infected via the

birth canal but environmental organisms cause

most infections later in the first year, after which

the  incidence  falls  sharply  with  age  up  to

about 14 years, alongside the maturation of the

immune system, and then declines slowly due to

the acquisition of minor infections with likely

pathogens, specific immunity and nasal carriage

of the meningococcus (see Chapter 2). Above the

age of 70 the incidence increases due to impaired

health   and   infections,   notably   pneumonia,

urinary-tract infections and otitis media, and

immunosuppression, either for treating autoim-

mune diseases or as a side-effect of the manage-

ment of other diseases.

Although  the  overall  incidence  of  primary

meningitis  is  fortunately  low,  local  epidemics

are favoured by crowding, e.g. in army units,

boarding   schools,   residential   homes   and

prisons, due to the ease of transmission from

an  index  case.  Secondary  meningitis  usually

occurs following spread in the blood of non-

CNS  infection (e.g.  urinary-tract  infections,

otitis media and pneumonia), or accidental or

surgical  trauma  to  the  head,  neck  or  spinal

cord.

Pathology and clinical features

The outermost layer of the meninges, the dura

mater, is in intimate contact with the skull and

vertebral column. The innermost pia mater is in

contact with the brain and spinal cord. Sand-

wiched between these is the arachnoid. Between

the arachnoid and pia mater is the subarachnoid

space that contains CSF. This has little intrinsic

immunological activity, containing only small

numbers of leucocytes. Consequently, if even a

few organisms reach the CSF they proliferate

very rapidly.

antimicrobial therapy

Bacterial  infection  causes  leucocyte  recruit-

ment, the pia and arachnoid becoming engorged with polymorphs (see Chapter 2).

Acute bacterial meningitis

Primary bacterial meningitis is usually a sequel to

sore throat or an ear or respiratory tract infection,

which is followed abruptly by only mild general-

ized malaise and possibly drowsiness, so diag-

nosis in the early stages is difficult, especially in

infants. Rapid diagnosis is essential because the

disease can progress very quickly, particularly in

fulminating (explosive)  meningococcal  infec-

tion, and a brief delay may result in the death of

young  children  or  permanent  brain  damage.

Later, a high fever together with symptoms indi-

cating  CNS  involvement (headache,  photo-

phobia,  neck  stiffness  and  other  neurological

signs, e.g. Kernig’s sign (inability to extend the leg

when sitting or when the thigh is flexed against

the  abdomen)),  will  confirm  the  diagnosis.

However, these classical diagnostic neurological

features are seen in only 50% of cases.

N. meningitidis from the nasopharynx, which

may be transported via the bloodstream to the

CSF, produces meningeal inflammation. As with

any  acute  inflammation,  WBCs  and  protein

then pass from the bloodstream into the CSF

and examination of this by lumbar puncture

produces a turbid sample instead of being clear,

with a low glucose level in bacterial meningitis.

Most of the damage to the CNS is not actually

due  to  the  microorganism,  but  to  the  host

inflammatory    response,    allowing    vascular

leakage and a raised intracranial pressure. Endo-

toxins (i.e.  lipopolysaccharides  from  bacterial

cell walls and engulfed bacteria in leucocytes)

also play a role, causing fever. The increased cere-

bral pressure from inflammatory exudation is

responsible for most of the neurological signs.

Meningococcal infection is often accompanied

by the appearance of a haemorrhagic (purpuric)

skin rash within the first 18 h, which can be

distinguished   from   an   inflammatory   rash

because it does not blanch under pressure with a

drinking glass or a clear plastic ruler. The combi-

nation of the rash with fever and headache is

pathognomonic of meningococcal meningitis.

However,  diagnosis  cannot  wait  for  classical

signs  because  of  the  rapid  progress  of  the

disease,  particularly  in  fulminating  meningo-

coccal infection. In this case, there are severe

systemic  complications,  e.g.  shock,  dissemi-

nated intravascular coagulation (see Chapter 2) and  renal  failure.  Death  may  occur  within 24-36 h  of  the  onset  of  symptoms.  Most

mortality is due to meningococcal septicaemia rather than direct CNS damage.

The complications of meningococcal sepsis are believed to result from endotoxin production

(see Chapter 2). Patients may occasionally dete-

riorate rapidly on initial treatment with antimi-

crobials owing to a release of endotoxins from killed bacteria. If prompt appropriate treatment is given, healthy adults will suffer no permanent CNS  damage.  In  children,  however,  serious neurological  sequelae  such  as  blindness  and mental retardation may occur in up to 30%

cases, despite antibacterial therapy.

Chronic   microbial   meningitis   develops

slowly and is usually caused by M. tuberculosis or Cryptococcus neoformans (a yeast), the latter especially in AIDS patients.

Diagnosis

Apart from the clinical signs described above,

a lumbar  puncture  is  performed  before  initi-

ating  therapy,  if  possible  and  advisable,  and

the  CSF  examined  by  direct  Gram  staining,

culturing,  sensitivity  testing  and  immunoelec-

trophoresis  for  antigens.  Both  N.  meningitidis

and  Strep.  pneumoniae  are  diplococci,  but  the

former is Gram-negative and the latter Gram-

positive.  Prior  treatment  usually  results  in

negative  CSF  findings  but  diagnosis  is  still

possible  through  serological  tests  for  bacterial

antigens in the CSF.

Lumbar puncture may be contra-indicated if

there is clinical suspicion of raised intracranial

pressure, e.g. papilloedema with headache and

vomiting. It is often avoided in meningococcal

meningitis.

It   may   be   difficult   to   distinguish   the

headache of meningitis from that of migraine

and subarachnoid haemorrhage. Differentiation

is important because of the imperative of the

different treatments of these two conditions. A

first attack of migraine is very unusual over the

age of 50.

Some important infections         551

Bacterial DNA testing, using the polymerase chain reaction, offers improved speed and accu-

racy of diagnosis in doubtful cases, but should not delay immediate empirical antibiotics.

Pharmacotherapy

Because the CSF has a low intrinsic immuno-

logical activity, some time will elapse after the

invasion of the organism before an effective

immunological response can be mounted, and

this can result in an overwhelming infection.

Therefore, it is important to achieve high CSF

concentrations  of  antimicrobials  promptly.  A

limiting factor in the choice of antibacterials is

their  ability  to  cross  the  blood-brain  barrier

sufficiently to achieve adequate CSF levels. Some

antibacterials (e.g.  chloramphenicol,  antituber-

cular drugs and amphotericin) readily enter the

CSF  whereas  others (e.g.  cephalosporins  and

penicillins) will provide high CSF levels only if

the meninges are inflamed, as they are in menin-

gitis. The more polar antibacterials (e.g. amino-

glycosides and sodium fusidate) always achieve

poor CSF concentrations and must be adminis-

tered  intrathecally  if  they  are  needed.  This

procedure requires careful aseptic technique, is

technically difficult to perform on neonates and

should only be used with specialist advice.

Immediate empirical treatment

If there is a delay of more than 1 h before a

lumbar  puncture  can  be  performed,  then  IV empirical  antibacterial  therapy  is  usually

administered immediately because of the poten-

tially serious consequences of delay. Because of this and the severity of the condition there are no RCTs to guide best treatment.

If meningitis is suspected, GPs are now recom-

mended to administer an initial high dose of

benzylpenicillin (e.g. 1.2 g in adults, preferably by

slow  IV  injection),  after  obtaining  a  blood

sample. Urgent transfer to hospital is manda-

tory. Alternatively, and if there is a history of

penicillin  allergy,  cefotaxime (2 g  in  adults)  or

cefuroxime  (1.5 g  in  adults)  should  be  used.

Cefotaxime  is  likely  to  be  effective  against

meningococci,  streptococci  and  H.  influenzae.

Chloramphenicol may be substituted if there is

allergy to both penicillins and cephalosporins

(see  below).  These  recommendations  may  be varied according to local policy.

Steroid   therapy  is  contentious,  but  may

improve  survival  in  bacterial  meningitis  by

reducing cerebral oedema. Dexamethasone phos-

phate, e.g. 0.15 mg/kg four times daily in adults,

should be given by IM or slow IV injection

before or with the first antimicrobial dose. The

benefit of this is unknown in meningococcal

disease, but reduces the overall risks of severe

hearing loss in children and all-risk mortality

in  adults.  However,  dexamethasone  is  contra-

indicated in immunocompromised patients, if

there is septic shock or if meningitis occurs after

surgery.

Acute infection

The initial treatment in hospital will depend to

some extent upon the age of the patient and the

results of direct CSF examination (Table 8.9). The

third-generation, broad-spectrum cephalosporins

(e.g. cefotaxime and ceftriaxone) are widely used.

Their  spectrum  of  activity  offers  a  superior

alternative to the benzylpenicillin regimen used

previously. They are active against N. meningi-

tidis, streptococci and the Gram-negative organ-

isms that may be responsible. If L. monocytogenes

is  suspected,  e.g.  in  the  young  and  elderly,

amoxicillin  plus gentamicin  are used for 10-14

days. If penicillin-resistant strains of pneumo-

cocci are suspected or proven, vancomycin  or

rifampicin is added to ceftriaxone. Dexamethasone

may  be  helpful,  but  reduces  penetration  of

vancomycin into the CSF.

Cefotaxime is used if H. influenzae is implicated,

but chloramphenicol is indicated if the patient is

hypersensitive to penicillins and cephalosporins,

or if the organism is resistant to cefotaxime. This

is one of the few indications for chloramphenicol,

because the severity of the disease outweighs the

risk of chloramphenicol-induced agranulocytosis.

Rifampicin  is given for 4 days before hospital

discharge in cases of proven H. influenzae type b

(Hib)  infection,  though  this  is  increasingly

uncommon.

Treatment  of  neonatal  meningitis  is  more

problematic than that of other age groups owing

to  the  variety  of  possible  pathogens,  and

initial therapy is often a matter of local policy.

The  combination  of  amoxicillin  and  a  third-

antimicrobial therapy

generation cephalosporin is effective against a wide  range  of  Gram-negative  organisms  and provides adequate cover against streptococci. If Lancefield group B streptococci are implicated, IV benzylpenicillin plus gentamicin are used.

Once the results from lumbar puncture have been obtained, therapy can be continued for the specific organism.

Following   a   head   injury,   the   risk   of

secondary  meningitis  may  require  different antimicrobial  treatment.  Thus,  a  high-dose

regimen  of  flucloxacillin  and  ampicillin  would be required to cover staphylococci and strepto-

cocci. Occasionally, an anaerobic organism may be implicated and metronidazole, which crosses readily into the CSF, is used.

Chronic disease  is treated as usual for the

identified organisms.

Prophylaxis

Meningococci   are   highly   transmissible,   so

prophylaxis is advised for close family contacts

or for those living in closed communities such as

residential care homes, boarding schools and

prisons. Rifampicin is the drug of choice, owing

to an increased incidence of sulphonamide resis-

tance. Ciprofloxacin  or ceftriaxone  are off-label

alternatives.

Vaccines have been developed against the A,

C, W135 and Y meningococcal polysaccharide

serotypes  of  meningococci  and  this 4-valent

vaccine is recommended as routine prophylaxis

for  travellers  to  endemic  areas,  i.e.  most  of

Africa.Saudi Arabiarequires proof of vaccination

for all Muslims making the Hajj and Umrah

pilgrimages toMecca. Guidelines for the public

health management of meningococcal disease in

theUKhave been published (see References and

further reading).

Meningococcal Group C Conjugate Vaccine

and  Haemophilus  Type  b  Conjugate  Vaccine

(Hib vaccine) are included in the immunization

schedule for the first year of life and give satis-

factory protection against the relevant organ-

isms. In 2006 it was announced that a 7-valent

pneumococcal vaccine is to be provided for all

infants in theUK.

There is currently no vaccine against meningo-

coccal group B organisms.

Summary

The   treatment   of   meningitis   illustrates   the following general points:

•  Vaccination  against  the  commonest  types

            of  bacteria  that  may  cause  meningitis  is

preferable to the antimicrobial treatment of infection.

•  This type of infection is a medical emergency.

            Prompt empirical treatment with an appro-

priate  antimicrobial  is  essential,  based  on patient age.

•  Risks of the infection may outweigh the poten-

            tial adverse effects of treatment if  chloram-

phenicol is required to treat severe disease. The risk-benefit balance is always a consideration in treatment selection.

•  Samples for culturing and sensitivity testing

            should be obtained before initiating therapy

but treatment must not await the results.

Immediate   microscopical   examination   of

Some important infections         553

Gram-stained CSF may provide valuable clues to appropriate therapy.

•  Factors other than the site of infection may

            indicate the most likely organism involved.

In  meningitis  age  is  the  most  important determinant.

•  Adjunctive treatment with dexamethasone is

            often given to reduce elevated intracranial

pressure due to meningeal inflammation, but may interfere with antimicrobial penetration into the CSF. The evidence of benefit for this intervention is inconclusive.

Influenza

Viral structure and physiology

This mostly respiratory disease is caused by an

enveloped, roughly spherical RNA virus, about

125 nm in diameter (Figure 8.3). Each virion

consists  of  eight  RNA  molecules  of  different

lengths, surrounded by an inner protein shell

and an outer lipid bilayer. There are three major

types of the virus that are defined by the proteins

of their inner shells. Type A strains are geneti-

cally labile and are responsible for all the major

epidemics and pandemics. Type B is also geneti-

cally labile and causes occasional milder, more

localized epidemics. Type C is genetically stable

and is rarely implicated in outbreaks.

The  surface  carries  two  different  types  of

protein   projections,   comprising   about          500

haemagglutinin (H) ‘spikes’, which are respon-

sible for the recognition of the target respiratory

cells  and  attachment  to  them (incidentally

causing the agglutination (clumping) of RBCs),

and about 100 neuraminidase (N) spikes, which

are concerned with the release of newly-formed

mature virions from infected cells. There are 16

types of haemagglutinin, of which H1-H3 are

found in human virions, H1-H12 in domesti-

cated poultry and H13-H16 in wild birds. Of the

nine types of neuraminidase only N1, N2 and N8

occur in human strains and all are found in

domesticated poultry and in pigs. Thus most

human outbreaks originate from poultry.

Small  changes  in  these  spikes  are  described as  antigenic  drift  and  are  probably  due  to single  amino  acid  changes.  This  may  mean that  host  resistance  is  partial,  because  some immunity  has  been  acquired  by  previous

contact with the parent strain. Major changes in  the  spikes (antigenic  shift)  denote  the

antimicrobial therapy

emergence   of   new   virulent,   potentially

epidemic or pandemic strains characterized by

the  precise  physicochemical  structure  of  each

of these spikes, e.g. the H3N2 strain of ‘Hong

Kong’ virus responsible for the 1968 pandemic.

Because humans in South-East Asia often live

in close contact with domestic poultry and pigs

it is possible for an avian strain to infect pigs that

are also carrying specific swine strains. There can

then be reassortment of RNA strands between

the two strains of virus, with the potential for

the creation of a novel strain that can infect

humans.  The  likelihood  of  this  is  increased

because the avian virus has already made the

jump   to   mammals.   Further,   infected   bird

carcases are often fed to other domestic animals,

and cats develop a syndrome that resembles

human  influenza  closely.  It  is  therefore  not

surprising that all modern epidemics arise in

South-East Asia and are spread from there by

infected wild fowl and human carriage. The ease

of transcontinental air travel greatly facilitates

the latter, so that epidemics can now spread very

rapidly to cause a global pandemic.

Thus there are potentially about 150 strains or serovars (serological variants). Those associated with epidemics that occurred in the 20th century are given in Table 8.10.

At the time of writing, the virulent H5N1

strain of avian virus is causing great anxiety

because of its novel surface structure, its ability

to  cause  severe  human  respiratory  infections

with a 30-50% fatality rate and its ready spread

by  migratory  birds.  Although  it  appeared  in

Hong Kong as long ago as 1997, with 18 human

cases and 6 deaths, the fact that there was no

major epidemic, even in that crowded city, leads

to cautious optimism that it has only a limited

ability   for   bird-to-human   spread,   even   less

chance of human-to-human spread and presents

only a low risk of a pandemic. All of the humans

involved in outbreaks in South-East Asia have

been   infected   by   very   close   contact   with

domestic poultry, in which the disease spreads

throughout all their tissues. However, a new

virulent human serovar may emerge at any time.

The H1, H3, H4, H7 and the N1, N2 and N7 strains are also of particular concern, because all of these have been able to jump the species

barrier into mammals, especially pigs, horses and seals. These phenotypes are therefore potentially capable of transmission into humans.

Clinical features

There are two basic forms of presentation of the infection,   conjunctival   and   respiratory.   The former is associated with H7 strains, which are of low pathogenicity.

H5N1 infection in birds spreads rapidly to all

their organs, causing death within about 48 h. In

humans, the infection has an incubation period

of up to 7 days, followed by high fever, cough

and shortness of breath and over 80% of patients

have a severe illness with a brief or longer period

of respiratory failure and signs of multi-organ

failure, e.g. abnormal liver function tests and

lymphopenia. A small number of H5N1 cases

have  presented  with  early  fever  and  gastro-

intestinal disturbance, including diarrhoea, but

obvious  respiratory  symptoms  developed  late

and caused acute respiratory distress. A high

index  of  suspicion  is  needed  for  these  early

symptoms to be recognized as influenza.

Virus shedding in influenza A infection peaks at about 7 days after symptom onset and may

continue for up to 10 days. Neutralizing anti-

bodies  are  detectable  about 10-14 days  after infection,  so  these  cannot  be  used  for  early specific diagnosis, which can be done reliably only  by  genomic  identification  using  the

reverse transcriptase polymerase chain reaction on lower respiratory tract samples.

Some important infections         555

Recovery from the infection may be followed by  a  prolonged  post-viral  syndrome,  causing debility and depression.

Pharmacotherapy and prophylaxis

Oseltamivir  may  be  used  for  the  treatment  of

influenza A and B in adults and children over

1 year, but only if given within 48 h of the onset

of symptoms. It is recommended primarily for use

in at-risk patients, e.g. those who are immuno-

suppressed, the elderly, or people who live in

residential homes where influenza is current. In

otherwise healthy individuals the drug shortens

the duration of symptoms by 1-1.5 days.

Oseltamivir is also licensed for the prophylaxis

of influenza in at-risk adults and adolescents over

13 years, if given within 48 h of exposure during epidemics. The timing of treatment is critical: if used  outside  the  window  of  opportunity  the benefit is lost. In epidemics, prophylaxis may need to be continued for up to 6 weeks.

Further,   it   has   recently   been   shown   in

Vietnamthat resistance of the H5N1 strain to

oseltamivir can arise during treatment in about

1% of cases, and this is more common in chil-

dren.  However,  the  infected  population  was

small and the resistant strain was not trans-

mitted  between  humans,  so  this  observation

needs further investigation. If this is replicated

in  a  larger  cohort  the  implications  are  far-

reaching,  e.g.  stockpiling  of  oseltamivir  may

prove to be a waste of resources and raises expec-

tations of beneficial treatment that may not be

achievable. Further, it may be necessary to use

higher doses or to institute combined treatment

with other antiviral agents.

If oseltamivir cannot be used because of intol-

erable side-effects, zanamivir is licensed for use in

adults and adolescents aged      12 years, and is less

toxic. Zanamivir is available only as a dry powder

inhalation for twice-daily use. However, it may

cause  bronchospasm,  respiratory  impairment,

angioedema (see Chapter 2), urticaria or other

rashes, so a short-acting bronchodilator should

be  available  immediately (e.g.  salbutamol  or

terbutaline  sulphate),  and  patients  should  be

monitored carefully, at least initially. If patients

are already taking other agents by inhalation,

zanamivir  should be inhaled last and care is needed in patients with asthma or other respira-

tory diseases. This may limit its usefulness in those patients who might need it most.

Both  of  these  agents  inhibit  viral  neura-

minidase and so prevent the release of new

virions from infected cells.

The  anti-Parkinson  drug  amantadine  is  no

longer recommended by NICE, although it is

licensed for the prophylaxis and treatment of

influenza A infections, the most common type.

It has been supplanted by the drugs mentioned

above.

Nebulized  ribavirin  has  been  shown  to  be

effective  against  influenza  A  and  B  in  adults

(unlicensed  indication)  and  may  be  appro-

priate in those with severe infection. However,

it may cause respiratory deterioration, bacterial

pneumonia,       pneumothorax, non-specific

anaemia  and  haemolysis,  so  its  use  needs  to

be confined to hospitals with full facilities for

respiratory  support  and  fluid  and  electrolyte

management.   Pregnant   women   and   those

planning  conception  should  not  be  exposed

to the aerosol, because of teratogenic risk.

Vaccination

Pharmacotherapy of influenza is no substitute

for annual autumnal vaccination. Both H and

N molecules  are  highly  antigenic,  especially

the  haemagglutinins.  Influenza  vaccines  are

prepared  using  a  WHO-recommended  strain

grown in hens’ eggs, with added neomycin and

polymyxin B antimicrobials, and possibly thio-

mersal antiseptic to suppress bacterial contamin-

ation  during  processing.  They  contain  either

purified  virus  inactivated  with  formaldehyde

(Split Virion vaccine) or purified H÷N particles

inactivated with propiolactone (Surface Antigen

vaccine). Neither is capable of causing influenza,

but must not be given to individuals who are

sensitive to egg protein or the antimicrobials

used in manufacture. Although the vaccines are

effective, the problem is to identify the strain(s)

current in humans and to produce adequate

stocks of vaccine. This takes about 7 months at

present, though faster production methods using

tissue culture fermentation are being explored.

Tissue culture has the additional advantages of a

much cleaner microbiological process than egg

culture and a reduced need for antimicrobial and

antimicrobial therapy

antiseptic cover. Because all outbreaks start in

the Far East, this may give the UK sufficient time

to develop and produce stocks of vaccine, but

whether these would be adequate for large-scale

immunization depends on the rate of spread of

the virus.

There  is  also  the  ethical  problem  that  all

influenza vaccine production is done in Australia,

the UK and the USA, and no policy has been

proposed to deal with the needs of the developing

world. This is not an entirely altruistic question,

because the existence of very large unprotected

populations promotes the spread and long-term

carriage of the virus. India has a large and efficient

pharmaceutical industry with good UK industry

connections and it seems logical that vaccine

manufacture should be established there.

The UK Biological Products Research Labora-

tory has a novel approach to the need to accel-

erate   vaccine   production.   They   have   used

genetic manipulation to create a bank of a viru-

lent strains of the H5N1 serovar in the expecta-

tion that at least one of these will match the

characteristics of the next virulent pandemic

strain when it arrives, as it surely will. This will

save at least 2 months of lead time for vaccine

production.

The experimental vaccines produced to date

require the addition of an immunological adju-

vant and two doses are needed to produce an

adequate   antibody   response.   One   British

company has already tested a vaccine (GSK, mid-

2006)  that  has  given  a  satisfactory  response

using one-quarter of the dose of the normal

influenza vaccine, thus enabling the vaccine to

be available to a much larger population.

Annual  immunization     is          currently recommended for:

•  All people aged over 65 years.

•  Residents and staff in residential or nursing

            homes  for  the  elderly  or  other  long-stay

facilities.

•  Healthcare  workers  and  those  caring  for

            people whose welfare would be compromised

if the carer falls ill.

•  Individuals aged over 6 months with any of

            the following chronic conditions:

-  Asthma or any chronic respiratory disease.

-  Heart, liver and renal disease.

-  Diabetes mellitus.

-  Immunosuppression, including prolonged

            corticosteroid treatment and asplenia or

splenic dysfunction.

-  HIV infection, regardless of immune status.

Epidemic spread of H5N1 influenza in 2005/06 was  aborted  in  Indonesia  by  rigorous  public health   measures,   i.e.   large-scale   culling   of domestic  poultry  and  banning  the  sale  of

poultry in open markets.

Summary

In the absence of effective specific treatment the management of influenza illustrates:

•  The  importance  of  rigorous  public  health

            measures to prevent disease dissemination.

•  The  value  of  large-scale  immunization  of

at-risk groups to protect individuals and the general population.

•  The importance of rapid characterization of

            epidemic strains to permit early manufacture

of effective vaccines.

•  The value of good medical records to identify

            those at risk.

•  The  importance  of  prompt  diagnosis  to

            enable  the  most  effective  use  of  drugs  to

abort  influenza  and  opportunistic  bacterial infections.

HIV/AIDS

This  is  a  specialist  field  (see  References  and further reading), but the general principles of

treatment are discussed here.

The virus

The human immunodeficiency virus (HIV) is a

two-stranded RNA virus enclosed in an envelope

composed of the usual bilamellar lipopolysac-

charide layer with surface globular proteins that

are concerned with attachment to host cells. A

molecule of reverse transcriptase is attached to

each RNA molecule and, after penetration into

CD4÷  T-lymphocytes (TH [helper]  cells;  see

Chapter 2), the enzyme synthesizes a comple-

mentary   DNA   molecule   on   the   viral   RNA

Some important infections         557

template.  This  process  is  the  reverse  of  the

process of transcription in human cells (DNA ➞

RNA), hence the generic name ‘retrovirus’. The

viral  DNA  is  converted  into  double-stranded

form by host enzymes and incorporated into the

host cell genome as a provirus and may remain

in this protected environment for many years.

Some  later  event,  e.g.  immunosuppression,

triggers activation of proviral DNA, which then

directs the synthesis of virus intermediates, e.g.

viral proteases that break down host cell compo-

nents and synthesize viral core and envelope

proteins, viral RNA and reverse transcriptase,

and the viral components are assembled into

new virions. Only the viral complementary DNA

is active in infected cells, because the reverse

transcriptase also breaks down host RNA and so

prevents new host protein synthesis. The new

virions that are released invade other CD4÷

immune cells, e.g. macrophages, APCs, some

monocytes and B cells. The infected cells are not

usually killed but their functioning is impaired

profoundly, eventually causing severe immuno-

suppression. Infected individuals die of infec-

tions and neoplasms against which they cannot

mount an effective immune response.

Antiretroviral  therapy  aims  to  reduce  the

plasma viral load (virions plus viral RNA), and

keep it low for as long as possible, and to prolong

life of a good quality: there is no current cure.

Although there have been many attempts to

produce a vaccine, the virus mutates readily to

change   the   characteristics   of   its   envelope.

Combination therapy with antiretroviral drugs

from two or more classes, i.e. highly active anti-

retroviral therapy (HAART), is the most effec-

tive current treatment for the management of

HIV-positive individuals.

Treatment  benefit,  i.e.  survival,  has  to  be

balanced against drug toxicity, because the drugs

used are very toxic, particularly to the liver. Any

infections  that  occur  need  their  usual,  but

aggressive,  treatment  in  the  absence  of  the

patient’s ability to mount an immune response.

A recent report indicates that some drugs in

HAART do not penetrate all areas of the body,

e.g. the brain, where the virus selectively attacks

the motor, language and cognitive centres, and

testicles. If these findings are replicated, it is clear

that we need new lipophilic drugs that penetrate

the  CNS  or  an  effective  vaccine  for  at-risk subjects  if  we  are  to  deal  adequately  with HIV/AIDS.

Antiretroviral pharmacotherapy

Four classes of drugs are available (Table 8.11):

•  Nucleoside reverse transcriptase inhibitors,

            which  interfere  with  synthesis  of  proviral

DNA and the functioning of viral RNA.

•  Non-nucleoside reverse transcriptase inhib-

itors, which bind irreversibly to the enzyme.

•  Protease   inhibitors,   which   prevent   viral

damage to host cells.

•  Fusion inhibitor. Only one of these is avail-

            able currently. This prevents the fusion of

virions with the host cell envelope, and so the

release of mature virions from infected cells

and their penetration into uninfected cells.

Drug regimens

Treatment  should  be  initiated  by  specialists

before there is irrevocable damage to the immune

system. The factors involved in a decision to treat

are:

•  CD4÷ lymphocyte count. •  Plasma viral load.

•  Clinical condition of the patient.

            HAART (Table 8.11) consists of:

antimicrobial therapy

•  Two nucleoside reverse transcriptase inhibitors

            plus

•  A non-nucleoside reverse transcriptase inhib-

            itor or a protease inhibitor, which is often

administered with a small dose of ritonavir (another protease inhibitor) to increase blood levels of the former.

•  Enfuvirtide  is used as third-line therapy, if

            there is an inadequate response to any of the

other agents, or when the patient is unable to tolerate a drug.

Ensuring adequate doses will minimize the

possibility of drug resistance and the patient is monitored carefully for drug toxicity and inter-

actions with any other drugs. Drug interactions are  likely  because  most  of  these  agents  are metabolized in the liver, protease inhibitors and non-nucleoside reverse transcriptase inhibitors via the cytochrome P450 system.

Side-effects  such  as  hepatitis,  pancreatitis,

anaemia and glucose intolerance can be moni-

tored by haematology tests. Discontinuation or

treatment  for  them  is  instituted  before  they

become  a  major  problem.  Antimicrobial  and

general support is given as required, for as long

as required, but the severe immunodeficiency

caused  by  the  underlying  disease  commonly

predisposes to unusual infections and tumours.

Kaposi’s sarcoma causes widespread lesions of

the   skin,   mouth,   bowel   and   lungs.   Non-

Hodgkin’s lymphoma of the brain also occurs. Unusual infections include Pneumocystis jiroveci, which is treated with IV co-trimoxazole, inhaled pentamidine isetionate or other drugs (p. 560). The latter is a very toxic agent that requires special care  in  handling.  Infections  by  Cryptococcus neoformans require treatment with amphotericin, with or without flucytocine. Prophylactic anti-

microbials are often necessary.

Clinical deterioration requires a change of the

drugs used, but a stage will come when the

effects of drug toxicity outweigh the benefits of

treatment. Treatment benefit, i.e. survival, has to

be balanced against drug toxicity, because the

drugs used are very toxic, particularly to the

liver. Any infections that occur need usual, but

aggressive, treatment.

Pneumonia

Definitions and epidemiology

The absolute mortality from pneumonia in the UK is greater than for any other common type of infection,  despite  the  availability  of  effective treatments and the continuing sensitivity of the organisms to antimicrobials. This largely reflects the  types  of  patient  most  susceptible -  the

elderly and the very young.

In the UK, pneumonia accounts for about

50000   hospital   admissions   per   year,   the

majority  being  elderly.  The  mortality  rate  is

16-40%. Pneumonia also causes greater prob-

lems in chronically ill, frail patients and those

with otherwise impaired immunity, e.g. patients

with  lymphomas  or  AIDS  and  those  taking

immunosuppressants, in whom it is a common

secondary opportunistic complication.

The term pneumonia indicates inflammation

of the lung alveoli and associated airways (see

Chapter 5), accompanied by exudation into the

alveoli that produces consolidation (hardening

and non-compliance) of the lung parenchyma.

Pneumonia is usually a result of infection,

often following aspiration of bacteria from the

upper respiratory tract into the lower airways

and alveoli. However, it may be caused by any

physical, chemical or allergic irritant, e.g. lipoid

Some important infections         559

pneumonia (pneumonitis) caused by accidental

aspiration of liquid paraffin from laxatives or

nose drops. Aspiration pneumonitis is a conse-

quence  of  the  inhalation  of  gastric  contents

during   sleep,   especially   sleep   induced   by

hypnotics,   but   sometimes   following   reflux

oesophagitis with an oesophageal stricture (see

Chapter 3). There is a high mortality due to the

destructive effect of gastric acid and pepsin on

the delicate lung parenchyma, and the inevitable

associated infection.

The term ‘chest infection’ is often used to

indicate  pneumonia,  but  it  is  important  to

distinguish  pneumonia  from  other  causes  of

respiratory distress, because it is a serious disease

and it may not be necessary to treat uncompli-

cated lower respiratory tract infections with an

antimicrobial, e.g. most viral pneumonia.

Although pneumonia has been classified by its old anatomical terms, bronchopneumonia

(widespread  and  involving  the  airways  and alveoli) and lobar pneumonia (localized to one or more lobes), these terms are of little clinical relevance.   The   usual   classification   is   into community-  or  hospital-acquired  and  oppor-

tunistic pneumonia (Table 8.12).

This is another example of a disease which, like  meningitis,  may  be  life-threatening,  and which, because of its associated severity and

mortality, must be treated immediately on an

empirical basis before the results from sensitivity testing are known.

Aetiology

In  community-acquired  infection  the  most

likely  organism  is  Strep.  pneumoniae,  causing pneumococcal   pneumonia.   If   bacteraemia develops  as  a  complication,  there  is  a 25% mortality  rate.  Influenza  A  is  an  occasional cause of viral pneumonia and although this will not respond to antibacterial therapy, complica-

tion  with  opportunistic  bacterial  infections, especially Staph. aureus, is serious and requires prompt antimicrobial treatment.

Community-acquired    infection    due    to

Mycoplasma  pneumoniae  and  Legionella  pneu-

mophila, for example, also occur. The former

is  probably  the  second  most  common  cause

of  pneumonia,  with  epidemics  occurring  in

4-yearly   cycles.   Legionella  infection   is   now

recognized as originating overwhelmingly from

water-cooled air-conditioning systems. Both of

these used to be described as ‘atypical’ pneu-

monias, but the term has been dropped because

there   is   considerable   overlap   in   symptoms

between pneumonia caused by all of the organ-

isms. These are all examples of primary infec-

tions where the initial infecting organism alone

is responsible for the illness.

Common  examples  of  secondary  (oppor-

tunistic) pneumonias are those that occur as

complications  of  COPD (see  Chapter 5).  H.

influenzae  may  be  aspirated  from  the  upper

respiratory  tract  in  COPD  patients,  although

pneumococci may also be implicated. Aspiration

pneumonitis   following   the   inhalation   of

stomach contents or vomit can be associated

with staphylococcal, streptococcal and, rarely,

anaerobic organisms. Staphylococcal pneumonia

is  often  associated  with  an  underlying  viral

infection, e.g. influenza, and carries a very high

mortality.

A different range of organisms is likely to be

responsible for hospital-acquired pneumonia.

MRSA is often carried as a nasal commensal and

is an organism of low virulence that can cause a

severe pneumonia, and wound infections, which

are very difficult to treat when it is imported into

the   hospital   environment   where   it   infects

patients with poor resistance and many avenues

for infection, e.g. catheters, IV lines and surgical

wounds. Artificial ventilation of patients is asso-

ciated with a high mortality in intensive care

units because the patient’s defences are breached

by the equipment. Multiply-resistant MRSA and

Gram-negative organisms are more prevalent in

the hospital environment, and the risk of infec-

tion by these organisms is increased greatly by

the  immobility  and  sedation  of  seriously  ill

patients.

Yet another group of organisms is encountered

in  immunocompromised  patients.  Cytotoxic

chemotherapy  renders  patients  susceptible  to

pneumonias caused by Klebsiella pneumoniae or,

particularly seriously, fungi such Aspergillus. AIDS

patients often contract pneumonias that previ-

ously were rarely seen. Pneumocystis jiroveci (see

above) is one such organism, which carries a high

mortality and was previously seen only in some

patients  with  abdominal  cancer.  Other  types

of  pneumonias  contracted  by  AIDS  patients

include those caused by Mycoplasma pneumoniae,

Actinomyces israeli and cytomegalovirus.

Clinical features

The symptoms and signs vary with the pathogen

involved and the prior immune status of the

patient. There is often a prior upper respiratory

tract infection, followed usually by an abrupt

onset of a chill and then high fever (38-40°C). A

dry cough, high shallow respiration rate and

pleuritic pain on coughing develop over a few

days.  Sputum  production,  sometimes  haemo-

ptysis (coughing  of  blood  or  blood-streaked

sputum), acute dyspnoea and hypotension with

a blood pressure           60 mmHg develop later, if

inadequately treated. Herpes labialis often occurs

(see below).

Diagnosis

Diagnosis is based primarily on the symptoms

and clinical signs outlined above, but some of

these may not be present. In particular, elderly

patients may not have fever and present with

confusion. L. pneumophila infection is often asso-

ciated with a non-productive cough and in 60%

of  Mycoplasma  infections  there  are  minimal

respiratory signs.

In severe infections with an at-risk patient, or in   hospital-acquired   infection,   appropriate investigations must be carried out immediately, e.g. CXR, sputum for microscopy, culture and antimicrobial sensitivity testing, and blood for a full blood count and microbiology. If sputum is not produced readily it can be induced by giving nebulized hypertonic saline.

In  doubtful  cases  fibre-optic  bronchoscopy may be required to obtain specimens of secretions and bronchoalveolar lavage specimens.

If  the  pneumonia  is  community-acquired

and the patient is seriously ill, particularly if

immunosuppressed,   has   HIV/AIDS,   is   over

65 years or has other predisposing factors (e.g.

smoking,  excessive  alcohol  consumption  or

pre-existing lung disease), urgent admission to

hospital is required. Pneumonia in previously

well  patients  with  influenza  or  chickenpox

carries the possibility of serious Staph. aureus

infection.

In  such  patients,  and  those  with  hospital-

acquired infection, empirical treatment must be commenced immediately. This must be aggres-

sive if there is any indication of serious systemic disease, e.g. septicaemia, confusion, a high res-

piratory rate or a fall in blood pressure suggestive of septic shock (see Chapter 2).

Some important infections         561

Management

General measures

Patients with fever and pleuritic pain require

analgesics, but opioids must not be used because they may depress respiration.

Patients  should  be  well  hydrated,  possibly intravenously, and well nourished. Oxygen  by assisted ventilation is often required.

Pharmacotherapy

Prompt  treatment  is  essential.  Unfortunately there  are  few  adequately  powered  controlled trials comparing antimicrobial regimens to guide treatment. Trials that have been done indicate the probable equivalence of all proposed treat-

ments. In the UK, some guidelines for treatment of community-acquired pneumonia are included in the BNF (Section 5.1, Table 1).

In uncomplicated infection, high-dose amoxi-

cillin, or benzylpenicillin  in previously healthy patients, given for 7 days, is felt to be sufficient to deal with the pneumococci responsible for

most mild to moderate cases. Erythromycin  is used if there is a history of penicillin allergy and is  also  used  with  the  penicillin  if  atypical pathogens are suspected. Flucloxacillin is added if staphylococci are possibly involved.

In more severe cases hospital admission is

usual, and treatment with cefuroxime  or cefo-

taxime  plus  erythromycin  is  used,  flucloxacillin being added if staphylococci are suspected. If pneumonia is a sequel to influenza or measles, flucloxacillin  is   added   because   Staph.   aureus infection is more likely.

Because  high-level  penicillin  resistance  in

pneumococci  is  uncommon  in  the  UK,  and

less  than 20%  of  H.  influenzae  are  resistant,

empirical treatment of mild to moderate pneu-

monia  with  antimicrobials  other  than  amoxi-

cillin  remains  controversial.  In  areas  where

penicillin  resistance  is  a  greater  problem,  a

macrolide  or  tetracycline  are  often  given  as

first-line therapy.

For  severe  infection  of  unknown  aetiology,

quinolones (e.g. levofloxacin or moxifloxacin) have

recently been added to the armoury and these

are likely to be used increasingly as the level of

penicillin resistance increases. Cefuroxime or cefo-

taxime plus erythromycin or clarithromycin are also

used.  Flucloxacillin  is  added  if  staphylococcal

infection is suspected. Erythromycin is used if an

‘atypical’ pathogen is possible and rifampicin is

added if Legionella is likely. A tetracycline is used

for infection suspected to be caused by Chlamydia

or Mycoplasma.

This regimen is occasionally varied in those

who  have  co-morbidity  (e.g.  COPD,  diabetes

or renal/hepatic failure), to cover the possibility

of  encountering  resistant  organisms.  In  such

cases co-amoxiclav (amoxicillin  plus  clavulanic

acid) or clarithromycin are sometimes used, due

to  the  possibility  of  beta-lactamase-producing

H. influenzae.

For  seriously  ill  patients  who  cannot  be

managed  at  home,  IV  antimicrobial  therapy

should  be  instituted  as  soon  as  possible  in

hospital.  The  suggested  regimen  is  to  use  a

second-generation cephalosporin, e.g. cefuroxime,

which  would  provide  good  cover  against

H.  influenzae,  combined  with  erythromycin,

azithromycin or clarithromycin in atypical infec-

tion. If a pneumococcal infection is confirmed,

benzylpenicillin  should  be  used,  but  there  are

increasing  reports  of  resistance.  If  the  patient

responds, oral therapy may be substituted after a

few days.

Treatment is longer than normal, 7-10 days

being usual. In severe infections, e.g. suspected

or proven infection with Staph. aureus, L. pneu-

mophila,    Gram-negative    enteric    bacteria,

Chlamydia or Mycoplasma, 14-21 days’ treatment

is required.

For  hospital-acquired  (nosocomial)  pneu-

monia, treatment using agents effective against

Gram-negative organisms is indicated, the choice

being dependent on the prevailing antimicrobial

policy.  A  third-generation  cephalosporin,  e.g.

cefotaxime or ceftazidime, or a ureidopenicillin,

may be used, with the addition of an aminogly-

coside in severe illness. Vancomycin is often added

empirically if the patient is carrying MRSA.

Hospitals often have a protocol in place to

cover the progression from first-line empirical

cover, through second- and third-line agents. For

example,  if  the  first-line  treatment  with  a

cephalosporin fails, a quinolone may be used

and if that fails in turn or septicaemia super-

venes,  cover  may  be  broadened  to  include

antimicrobial therapy

piperacillin  with  tazobactam,  a  beta-lactamase inhibitor. The combination of the last two agents is available commercially.

Other antibacterials are occasionally indicated for certain atypical infections e.g. co-trimoxazole for Pn. jiroveci.

Prophylaxis

Two types of pneumococcal vaccine are available

and are provided in the UK via the NHS. The

23-valent pneumococcal polysaccharide vaccine

(unconjugated)  contains  purified  polysaccha-

rides from the 23 most common capsular types

of Strep. pneumoniae. It is used to immunize all

those over 5 years who are at special risk, i.e.

those who:

•           are aged over 65 years;

•           are asplenic or who have splenic dysfunction,

including those with homozygous sickle-cell

anaemia (see Chapter 11), and those with

coeliac syndrome (see Chapter 3) that may lead to splenic dysfunction;

•           have a chronic respiratory disease, including

asthma, requiring frequent or regular treat-

ment with an inhaled or oral corticosteroid

(see Chapter 5);

•           have  diabetes  mellitus  or  chronic  cardiac,

renal or hepatic disease;

•           are immunodeficient due to HIV infection

(see  p.  557),  prolonged  systemic  cortico-

steroid   treatment,   or   immunosuppressive treatment, e.g. following organ transplanta-

tion (see Chapter 14) or neoplastic disease

(see Chapter 10);

•           have a permanent implant for certain types of

deafness (cochlear) or to shunt CSF from a

distal site to the brain (CSF shunt), e.g. in

spina bifida, due to a developmental failure of

the vertebral canal to close, or a peritoneo-

venous shunt in hepatic failure (see Chapter

3) with ascites (fluid in the peritoneal cavity).

A single dose of the 23-valent vaccine is given, preferably 2 weeks  before  initiating  planned treatment, for example:

•  Chemotherapy, because of the risk of neutro-

            penia and immunosuppression.

•  Surgery  for  splenectomy,  because  asplenic

            patients are at special risk from infection by

capsulated bacteria.

•  Implantation of a device, if possible.

The  7-valent  pneumococcal  polysaccharide

conjugated  vaccine  is  prepared  from  capsular

polysaccharide-diphtheria   toxoid   complexes

adsorbed onto aluminium phosphate, to increase

antigenicity. Two doses at least 1 month apart are

given to at-risk children under 5 years, plus a

booster  dose  after  their  first  birthday,  i.e.  to

infants 2 to        6 months, starting at 2 months of

age  and  unimmunized  infants 6-11 months.

Unimmunized children 1-5 years should receive

two doses 2 months apart.

All children who have received this 7-valent

conjugated vaccine should be given a single

booster  dose  of  the 23-valent  unconjugated

vaccine  after  their  second  birthday,  at  least

2 months after the final dose of the conjugated vaccine.

Revaccination of immunized individuals is not

generally recommended, because of the risk of

severe  adverse  reactions.  However,  those  at

special  risk,  e.g.  asplenic  patients,  those  with

splenic   dysfunction   and   with   nephrotic

syndrome (see  Chapter 14),  should  receive

regular revaccination at 5-year intervals.

Summary

The treatment of pneumonia can be summarized as follows:

•  Empirical   treatment   of   likely   organisms

            dictates the initial antimicrobial therapy.

•  The environment in which the infection was

contracted, i.e. hospital or community, and the age and immune status of the patient

indicate the most likely pathogen.

•  Results  of  laboratory  tests  determine  the

            definitive treatment.

•  Implantation    of    a    device    increases

            susceptibility to infection.

•  Prophylaxis by active immunization is given

            to  young  children  and  others  at  risk  of

            pneumococcal infection.

Some important infections         563

Infective endocarditis (IE)

This is an infection of the endocardium, espe-

cially   the   heart   valves,   usually   caused   by bacteria, but sometimes by fungi. It is a serious disease   that   requires   prompt,   prolonged

antimicrobial treatment.

Aetiology and pathology

Two factors interact to enable infection to be

established: microorganisms must gain access to the blood and the endocardium must permit

their attachment and growth.

The underlying predisposition may be due to a

prosthetic heart valve, or to previous heart valve

damage, e.g. prior rheumatic fever, mitral valve

prolapse or congenital heart disease (see Chapter

4). All of these cause local turbulent blood flow and  consequent  small  intracardiac  thrombi, often on the heart valves which provide sites for the attachment of bacteria. Most microorgan-

isms  cannot  attach  to  healthy  endocardium. Thrombi with adherent or embedded microbial growths are known as vegetations. Antimicro-

bials penetrate poorly into these, hence the need for prolonged bactericidal treatment.

Diabetic patients are also an at-risk group, as are hospital patients with an indwelling venous cannula, IV drug abusers and those with poor dental hygiene.

The organisms usually involved include oral

alpha-haemolytic streptococci (‘Strep. viridans’;

about 30-50%  of  cases),  Enterococcus  faecalis

(about 20%) and Staph. aureus (about 30%, espe-

cially if hospital-acquired; 50% of those with

prosthetic valves). MRSA is reported increasingly,

but a large range of occasional organisms has

been implicated.

Clinical features

The  symptoms  and  signs  may  be  very  non-

specific, but fever and a new heart murmur are the most common signs (90% of cases). The

patient may present with malaise, night sweats, fatigue, weight loss, muscle and joint pain and haematuria. The left side of the heart is usually more involved than the right.

The   disease   often   follows   a   prolonged,

moderate  course,  hence  the  term ‘subacute

bacterial endocarditis’ (SBE), but this term is

falling into disuse because not all the infections

are bacterial. In subacute disease, heart failure,

finger clubbing (see Chapter 5), a haemorrhagic

(petechial) rash and ‘splinter haemorrhages’ of

the nail bed often develop. Strokes and MI are a

result  of  embolization  from  vegetations,  and

occur in about 20% of cases.

However, Staph. aureus infections often cause severe, acute disease and MRSA is increasingly common. Infected aneurysms may occur.

Investigation

The following tests are very useful:

•  Blood for culturing, serology, antimicrobial

            sensitivity tests, and ESR or CRP. If cultures

are negative (about 25% of cases), at least two further sets of samples are taken. A negative result does not exclude a diagnosis of IE if appropriate   clinical   signs   are   present. Serology may provide evidence of infection when cultures are negative.

•  Echocardiography will show vegetations and

            blood  regurgitation  across  abnormal  heart

valves and may identify those patients needing

urgent surgery. Trans-oesophageal echocardio-

graphy is sensitive for small lesions and is 90%

specific.

•  Serial ECGs may show evidence of developing

            conduction defects, due to valve ring involve-

ment, or MI. Embolization from vegetations is responsible for many deaths.

•  CXR.

•  Urine, for proteinuria and haematuria, which

            occur in about 70% of patients as a result of

renal infarction.

Pharmacotherapy

Treatment  with  bactericidal  antimicrobials  is desirable to prevent relapse, if they are suitable for the patient.

Initial empirical treatment is with benzylpeni-

cillin plus gentamicin. Flucloxacillin is substituted

for benzylpenicillin if symptoms are more severe,

in   anticipation   of   staphylococcal   infection.

antimicrobial therapy

Vancomycin plus rifampicin are substituted for the penicillin if the patient is allergic to penicillins, if there is an artificial heart valve, or if MRSA is  suspected.  If  flucloxacillin  is  being  used, rifampicin is added for at least 2 weeks.

If fully sensitive streptococci are confirmed,

benzylpenicillin,  or  vancomycin  if  the  patient

is  allergic  to  penicillin,  alone  for 4 weeks  is

satisfactory.   Alternatively,   benzylpenicillin   or

vancomycin, plus gentamicin for 2 weeks are used

if the organism is highly penicillin-resistant. If

the organisms are more resistant, if Enterococcus

faecalis is suspected or proven, or if there are

complications, gentamicin plus either amoxicillin

or  vancomycin  is  used.  If  the  organisms  are

gentamicin-resistant, streptomycin is substituted,

one of its very few indications nowadays.

There is a group of difficult-to-treat bacteria,

known collectively as ‘HACEK’ organisms, i.e.

Haemophilus,    Actinobacillus,    Cardiobacterium,

Eikenella and Kingella species, for which amoxi-

cillin (or ceftriaxone if amoxicillin-resistant) plus

low-dose gentamicin is used. The combination is

used for 2 weeks, the gentamicin is stopped and

treatment with either amoxicillin or ceftriaxone is

continued for a further 2 weeks. If the patient has

a prosthetic heart valve, treatment is prolonged

to a total of 6 weeks.

Summary

The treatment of IE illustrates:

•  The need for prompt treatment to prevent

            serious cardiac damage and stroke.

•  The necessity for prolonged treatment with

            bactericidal antimicrobials to ensure the elim-

ination of the infectious agent from protected sites in the vegetations.

•  The role of prosthetic devices, heart valves in

            this case, acting as a focus for infection.

Rheumatic fever

Rheumatic fever (RhF) has been described as a

disease that licks the joints but grips the heart,

i.e. the joint problems are minor and the delayed

cardiac consequences are the major problem.

This syndrome follows infection with group A

streptococci.  It  is  probably  an  autoimmune

disease, triggered by a cross-reaction between

streptococcal antigen(s) and the laminin in the

basement  membrane  of  human  heart  valves.

There is a less important reaction against cardiac

myosin.

Epidemiology

Acute rheumatic fever (ARhF) is a disease of

poor living conditions, including malnutrition, overcrowding and lack of hygiene. Consequently it is now uncommon in Western, developed

countries, having started to decline in the late 19th century, a process that was accelerated by the introduction of antimicrobials.

However, it remains a major public health

problem in the Third World and the WHO esti-

mates that about 5        105  people acquire the

condition annually. Children and adolescents

aged 5-15 years are most at risk and high inci-

dences (between 80 and 500 per 100 000 chil-

dren)  have  been  recorded  in  the  indigenous

populations of Australia and New Zealand. It is

rare in adults over 30 years of age. Attacks may

recur  in  adolescents  and  young  adults,  but

become increasingly less frequent in adults and

are rare over the age of 40-45.

Pathogenesis

Infections by many strains of group A beta-

haemolytic streptococci are the trigger event and

outbreaks of ARhF follow those of streptococcal

pharyngitis, so-called ‘strep sore throat’, but not

all patients notice this. However, it is known that

ARhF may follow other streptococcal infections,

e.g.  impetigo.  There  is  no  specific  test  for

causative strains, nor is it possible to identify

those who will subsequently develop chronic

rheumatic fever (CRhF). Familial clustering is a

reflection of shared poor living conditions.

The cardiac complications involve all tissues, i.e. endocardium, myocardium, valves (especially the mitral valve) and pericardium.

Some important infections         565

Clinical features

The initial presenting symptom is the sudden

onset of a fleeting palindromic arthropathy of the larger joints (see Chapter 12). There may also be non-specific symptoms, e.g. abdominal pain, fever  with  apparently  excessive  tachycardia, epistaxis, raised ESR and CRP, etc. that are not of diagnostic value. The anaemia of chronic disease (see Chapter 11) is common.

Arthritic symptoms

The  migratory  polyarthritis  affects  the  large joints,  initially  of  the  legs,  each  joint  being affected for about a week. Joint involvements tend to overlap. However, a monoarthritis is

common in endemic regions.

Cardiac involvement

Symptoms may be difficult to detect in mild

disease. Auscultation may give the signs of a

pericardial  rub,  due  to  inflammation,  valve

murmurs, due to regurgitation initially but valve

stenosis later. There is usually some pericardial

pain. The ECG commonly shows a sinus tachy-

cardia faster than that expected from the fever,

but with a paradoxical, prolonged PR interval -

the PR interval is expected to be shorter than

normal  in  tachycardia.  Heart  failure  may  be

life-threatening.

Central nervous system involvement

Chorea  (i.e.   neurogenic,   rapid,   involuntary,

jerking limb movements that disappear during

sleep)  may  be  the  sole  manifestation,  and

develops later. Other CNS involvement may be

associated with muscular weakness. Very labile

moods, with restlessness, crying bouts and anger

or other inappropriate behaviour often occur.

Skin symptoms and signs

SC   firm,   painless,   uninflamed   rheumatoid

nodules (see   Chapter 12)   appear   over   the

tendons or bony  surfaces  after  several  weeks.

Erythema marginatum occurs in about 10% of

patients. It is a usually fleeting, pinkish rash,

lasting a few hours that extends centrifugally,

reminiscent   of   urticaria   or   ringworm           (see

Chapter 13).

Diagnosis

The WHO criteria are as follows:

•           Chorea and indolent (persistent) carditis do not

require evidence of prior group A streptococcal

infection.

•           First episode

-  Major criteria: carditis, arthritis, chorea,

            erythema marginatum, SC nodules.

-  Minor   criteria:   arthralgia     (joint   pain

without inflammation), fever, raised ESR or

CRP levels, prolonged PR interval on ECG.

-  Evidence of prior group A streptococcal

infection, i.e. a positive throat culture or rapid  antigen  test  for  group  A  strepto-

coccus or a raised or rising streptococcal antibody titre.

•           Diagnosis requires: two major criteria or one

major and two minor criteria

•           Recurrent episode

In a patient without established rheumatic heart disease as first episode, or in a patient with  established  rheumatic  heart  disease, requires  two  or  more  minor  criteria,  plus evidence of prior group A streptococcal infec-

tion (by serology).

•           Differential diagnoses include:

-  Reactive arthritis  (see Chapter 12). Post-

streptococcal reactive arthritis is difficult to distinguish from ARhF and is best treated as the latter.

-  Joint   infection:   septic   arthritis,   viral

            arthropathy.

-  Infective endocarditis (see above).

-  Lyme disease (pp. 523, 526).

-  Sickle-cell anaemia (see Chapter 11).

-  Neoplastic disease: leukaemia or lymphoma

Unfortunately the criteria were established for

epidemiological and not for diagnostic purposes.

In  many  parts  of  the  world  where  ARhF  is

common, the prompt availability of laboratory

tests, ECG and echocardiography is limited, so

diagnosis must be based on clinical judgement.

This enables treatment to be initiated promptly

and so helps to avoid the possibility of serious

sequelae.

antimicrobial therapy

Treatment

The aims are to:

•  give symptomatic relief;

•  minimize inflammation and so serious heart

            damage;

•  eliminate  carriage  of  streptococci  in  the

            nasopharynx.

These are accomplished by:

•  Rest (bed or chair).

•  Phenoxymethylpenicillin         for        10 days    or

erythromycin if penicillin-sensitive.

•  Anti-inflammatories  when  the  diagnosis  is

            clear, e.g. aspirin 100 mg/kg/day in children

(risk  of  Reye’s  syndrome  in  those  under

16), up to 8 g/day in adults or prednisolone

2 mg/kg/day,  for  about  14 days,  and  then reduced gradually (20%/week) according to clinical improvement or levels of ESR or CRP. Cover  prednisolone  withdrawal  with  aspirin if  necessary.  There  is  no  permanent  joint damage after the arthropathy.

•  Treat heart failure if present (see Chapter 4).

•  Valve replacement, if available, if there is

regurgitation or significant stenosis.

Prophylaxis  with  twice-daily  phenoxymethyl-

penicillin is maintained until 5 years after the last attack or age 20-21, whichever is the longer.

Patients  who  have  had  a  valve  replacement require warfarin (see Chapter 11).

Inadequate treatment or prophylaxis may lead to death 20-30 years after the initial attack.

Gastroenteritis and acute diarrhoea

The human bowel, being in contact with the

external environment, contains a range of non-

pathogenic commensals, but some of these are

potentially pathogenic if they gain access to

another site. These organisms live in a state of

balanced competition with each other for food.

However, problems arise when this balance, or

that between them and their host, is upset (e.g.

by broad-spectrum antimicrobial treatment) or

an unusual organism is involved. The predomi-

nant  potentially  pathogenic  bacteria  include

anaerobes (e.g. Bacteroides fragilis or Cl. difficile),

and there are also coliforms (e.g. E. coli and Kleb-

siella spp., Ent. faecalis and Proteus spp.). Fungi

(e.g. Candida  spp.), viruses and protozoa (e.g.

Entamoeba   histolytica  and   Giardia   intestinalis

(formerly G. lamblia)) may also be involved.

The term gastroenteritis describes any non-

specific  inflammation  of  the  stomach  and

bowel, but is often applied to any bowel infec-

tion resulting in diarrhoea. The causative organ-

isms tend to be different for adults and infants.

Other species are responsible for specific infec-

tions, e.g. cholera, dysentery and typhoid. This

section  deals  only  with  acute,  non-specific

infective diarrhoeas; non-infective chronic diar-

rhoeas and those of other origins are covered in

Chapter 3.

Antimicrobials are used for gut infections only if  symptoms  are  severe  and  prolonged,  if  a specific pathogen is confirmed, or in immuno-

suppressed and elderly subjects. Antimicrobial treatments are discussed below.

Treatment  with  antidiarrhoeals,  i.e.  lopera-

mide,   diphenoxylate   or   opioids,   should   be avoided if at all possible, as this will tend to

retain inflammatory exudate in the bowel and prolong symptoms.

Acute diarrhoea in children (infantile gastroenteritis)

This is rarely fatal in otherwise healthy children,

but  with  malnourishment  and  poor  housing

there is a high risk of mortality. Viruses (espe-

cially rotaviruses) are usually responsible. An

important feature of infantile gastroenteritis is

the   depression   of   gastrointestinal   luminal

disaccharidase levels, resulting in an osmotic

diarrhoea (see  Chapter 3).  Oral  rehydration

therapy is the mainstay of treatment, as the

young are particularly vulnerable to dehydra-

tion. Antimicrobial therapy is likely to be useless

and may prolong symptoms by causing further

disturbance of the gastrointestinal flora.

Some important infections         567

Bacterial  gastroenteritis  in  infants  is  often

caused by self-infection from their own bowel

with enteropathogenic strains of E. coli. These

either   produce   an   exotoxin   that   increases

gastrointestinal fluid secretion, resulting in the

production  of  a  watery  diarrhoea,  or  cause

damage to the mucosa that results in a bloody

diarrhoea.  E.  coli  infections  are  usually  self-

limiting and require only simple oral rehydra-

tion therapy, which provides sodium, potassium

and chloride, usually with glucose to provide

energy and assist electrolyte absorption (see BNF,

Section 9.2.1).  However,  certain  uncommon

strains, e.g. enterohaemorrhagic E. coli O157:H7

(EHEC), can cause a more severe or even fatal

outcome. This has occurred in food poisoning

outbreaks in several countries, where this strain

caused a high incidence of complications, even

including renal failure. Enterotoxigenic E. coli

(ETEC) is the most common cause of travellers’

diarrhoea (see below).

The organisms are transmitted via the faecal-

oral route. Campylobacter jejuni is a worldwide

commensal in many farm animals and dogs and

may  be  ingested  from  animal  faeces,  often

through children playing in contaminated soil or

with pets. Camp. jejuni causes severe abdominal

pain and antimicrobials may be required.

Antimicrobial treatments are similar to those used in adults.

Acute adult diarrhoea

Acute infective gastroenteritis is usually attrib-

uted to ‘food poisoning’ or ‘travellers’ diarrhoea’

in the lay mind. However, toxins are involved

only occasionally, the symptoms usually being

caused  by  microbial  overgrowth.  Table 8.13

shows that a variety of organisms may be respon-

sible, but antimicrobial therapy is rarely indi-

cated. In other cases, e.g. dysentery, typhoid

fever or giardiasis, the organism responds to

specific antimicrobial therapy.

Salmonella infections

Infection   by   Salmonella   enteritidis   and   S.

typhimurium, but not S. typhi or S. paratyphi, are

still an important cause of food poisoning, but

Campylobacter  infections  are  now  the  major

cause of diarrhoea in developed countries. S.

enteritidis and S. typhimurium strains are some-

times named after the location in which they

were  first  isolated,  e.g.  S.  enteritidis  serotype

Dublin, a common cattle commensal. Lack of

basic hygiene after toileting, e.g. hand washing,

including nail scrubbing, is the usual cause of

human-to-human spread or self-infection. Symp-

toms usually last for a few days, rarely a week, and

range from a watery stool to a severe diarrhoea

with abdominal pains, vomiting, fever, blood and

pus. The latter symptoms are caused by invasion

of the bowel wall, usually by Campylobacter or

virulent  strains  of  E.  coli,  and  may  lead  to

systemic disease.

Even for severe attacks healthy adults usually require only oral rehydration. Indeed, antibac-

terials may increase the duration of symptoms, by further disturbance of the bowel flora, and prolong intestinal carriage. However, if there is severe sepsis, symptoms lasting more than 3 days, or if the patient has some underlying problem, e.g. is frail and elderly or immunocompromised, antimicrobials may be indicated.

Oral rehydration therapy (see above) is still

required as a first-line treatment. Ciprofloxacin

is usually the first choice if antimicrobial treat-

ment is required, but resistance is an increasing

problem.  Erythromycin  or  co-trimoxazole  are

alternatives, but the latter may cause serious

side-effects.

Severe disease causing dehydration is an indi-

cation for hospital admission, where patients

should be isolated and barrier-nursed. Children

under 2 years are rarely given antimicrobials, but

should be supervised by a Paediatric Consultant.

Travellers’ diarrhoea

This may be caused by a variety of organisms,

depending on local conditions, although ETEC is

usually responsible. If the symptoms are severe

(e.g.   nausea,   vomiting   and   bloody   stools),

prolonged, or if signs of septicaemia are present,

ciprofloxacin may lessen the severity and reduce

duration  of  symptoms  from  about  5 days  to

24 h.  The  once  popular  prophylactic  use  of sulphonamides is undesirable as the risk of infec-

tion is reduced by only 50% and adverse effects are common.

Typhoid fever

Clinical features

In contrast to food-borne salmonellosis, Salmo-

nella typhi infections require antimicrobial treat-

ment. A similar but milder disease is caused by S.

paratyphi. Infection is usually spread by sewage-

contaminated water. Man is the only natural

host for the organisms, so personal hygiene is

very important.

Typhoid fever is not always associated with

diarrhoea. Patients may have constipation in the

early stages, and the systemic complications are

more important than local gut symptoms. This is

because the organism can penetrate the gastro-

intestinal  mucosa  and  proliferate  within  the

local reticuloendothelial cells before spreading

throughout the body. After about 3 weeks, the

gut wall is damaged and penetrated by sufficient

bacteria to cause the initial symptoms of dehy-

dration, fever and confusion. The most serious

complications are gastrointestinal haemorrhage

and perforation.

Following recovery, some 5-10% of patients become convalescent carriers and continue to excrete  typhoid  bacteria,  and 1-4%  become chronic carriers, who continue to excrete organ-

isms  for  many  years.  Gallbladder  carriage  is usual in the West and is associated with gallstone formation (see Chapter 3).

In the Third World up to 30% of patients die

and a further 10% relapse after apparent recovery.

This contrasts with 1-2% deaths in developed

countries.

Treatment

Ciprofloxacin is the antibacterial of choice. Broad-

spectrum  antibacterials (ampicillin,  sulphon-

amides and chloramphenicol) are active against

some strains of S. typhi, but resistance is a major

problem. Indiscriminate use in some Third World

countries has led to the loss of previously effec-

tive  antimicrobials,  e.g.  chloramphenicol.  Thus

treatment  must  be  guided  by  early  diagnosis,

sensitivity testing and local knowledge.

IM immunization with capsular polysaccha-

ride antigen of S. typhi must be renewed every

3 years to maintain immunity. A live, attenu-

ated, oral vaccine is available (Ty21a) and gives superior immunity.

Cholera

The insidious onset of typhoid fever contrasts

markedly with infection by Vibrio cholerae. The

current  strain  has  been  the  El  Tor  biotype,

named for the Red Sea port from which it was

first identified. This organism does not invade

the gut wall and the tissues, but produces a toxin

Some important infections         569

that acts rapidly on the bowel to induce an

intense, watery diarrhoea, resulting in dehydra-

tion.  Over  the  years  cholera  has  tended  to

become less virulent than the ‘classic cholera’

encountered earlier in the last century, when

diarrhoea and death from dehydration could

follow quite rapidly. In otherwise healthy people

the course is often mild. Cholera is very rare in

Western travellers to endemic areas and may

even pass as a bout of simple travellers’ diar-

rhoea.  However,  present-day  cholera,  which

tends to cause epidemics when sanitary condi-

tions are very poor, does cause many fatalities

amongst the young, elderly or malnourished in

developing countries.

A new pathogenic strain, V. cholerae O139, has

been identified and may cause future epidemics.

Oral rehydration can be life-saving, but IV

fluids are needed in very ill patients. The disease is otherwise self-limiting.

Antimicrobial therapy plays only a small part

in the management of cholera. Antibacterials

such as the tetracyclines will reduce fluid loss to

some extent, but availability is limited in coun-

tries where cholera is endemic, and resistance is

a problem.

Because the organism does not invade the

tissues, immunity following natural infection is

poor.

Prophylaxis with current vaccines give poor immunity and a new killed whole cell vaccine is available and an attenuated live vaccine is being investigated.

Chemoprophylaxis with tetracycline is effective but is not a substitute for scrupulous personal and food hygiene.

Dysentery

Bacterial dysentery

Classical  bacillary  dysentery  (shigellosis)  is

caused by Shigella spp., which are found only in

the  bowel  of  man  and  the  higher  primates.

Similar symptoms may be caused by Campy-

lobacter, Yersinia or enteroinvasive E. coli (EIEC).

The  disease  is  associated  with  overcrowding,

poor sanitation and hygiene and is usually seen

in the UK in kindergartens, nursery schools and

residential homes.

Shigella   sonnei   and   Sh.   flexneri   are   the commonest species in the UK and usually cause a mild to moderate diarrhoeal disease, often

indistinguishable from gastroenteritis.

Sh. shigae causes severe, bloody diarrhoea, with

dehydration   and   prostration   and   a   high

mortality   if   untreated.   The   stools   contain

inflammatory exudate, WBCs, blood and mucus.

Arthritis and renal damage may also occur. Fluid

replacement is essential, using oral rehydration

salts, or IV fluids if dehydration is sufficiently

severe.

In  terms  of  antimicrobial  treatment,  cipro-

floxacin  is again the treatment of choice, but there have been reports of resistance to this, so sensitivity testing is an essential guide to therapy in severe disease.

Protozoal dysentery

Amoebic  dysentery  is  caused  by  Entamoeba

histolytica and has similar symptoms to shigel-

losis but systemic effects are uncommon. Only a

small proportion of those carrying amoebic cysts

develop  invasive  disease.  Part  of  the  reason

for this is that the cysts are those of a non-

pathogenic species, Ent. dispar, which cannot be

differentiated from Ent. histolytica microscopic-

ally. Identification is by serology using fluo-

rescent  antibody.  It  is  not  known  why  the

asymptomatic carrier state is so common and

the epidemiology of amoebic dysentery remains

uncertain.

Transmission  is  mostly  by  the  faecal-oral

route,  but  person-to-person  transmission  can

occur  by  vaginal  and  anal  intercourse  and

cunnilingus. The condition tends to be longer-

lasting  than  shigellosis  and  may  be  mild  or

severe. Severe infection may be indistinguishable

from severe UC (see Chapter 3) and may require

colonic   biopsy.   Important   complications   of

severe   infection   are   toxic   megacolon   and

intestinal perforation. Invasion of the liver to

cause  abscesses  may  occur (mostly  in  men),

without prior gastrointestinal symptoms, and

infection may break through into the peritoneal,

pleural   and   pericardial   cavities,   with   life-

threatening consequences.

The treatment of choice for invasive disease is

metronidazole  in  high  doses  for 5-10 days  or

tinidazole for 2-6 days. This should be followed

antimicrobial therapy

by diloxanide furoate or paromomycin to eradicate

cysts from the gut lumen. The latter can also be

used to eliminate the asymptomatic carrier state.

Giardia   intestinalis  (formerly   G.  lamblia)

causes diarrhoea of long duration, sometimes

months if untreated, referred to as giardiasis.

There is no blood in the stools, but owing to

malabsorption a frothy foul-smelling diarrhoea

with copious wind (steatorrhoea) may result. G.

intestinalis is common in the water supplies in

the Third World and in areas affected by war and

economic deprivation. Diagnosis is by the clin-

ical symptoms and signs and a history of travel

to an endemic area, faecal microscopy and more

specifically by enzyme-linked immunoassay.

Initial treatment is with a nitroimidazole, i.e. metronidazole for 3-5 days or single-dose tinida-

zole. Albendazole and mepacrine are second line drugs in the event of treatment failure.

Other protozoal infections have become impor-

tant with the rise of HIV/AIDS, e.g. those due to

Cryptosporidium cayetanensis, Isospora belli, Dienta-

moeba fragilis and the microsporidium Encephalito-

zoon  intestinalis.  Cryptosporidium  may  cause

life-threatening diarrhoea with high mortality in

HIV/AIDS patients not on HAART (Table 8.11).

Treatment is with co-trimoxazole  for Crypto-

sporidium and Isospora infections and albendazole for Encephalitozoon.

Dientamoeba   is   co-transmitted   with   the

pinworm  Enterobius  vermicularis,  so  treatment

needs to cover both organisms, i.e. metronidazole

or tinidazole for Dientamoeba, and mebendazole,

in patients aged over 2 years, for Enterobius.

Antibiotic-associated colitis

The use of oral broad-spectrum antibacterials, particularly if poorly absorbed, can lead to over-

growth of resistant organisms in the gut lumen. This may cause a mild diarrhoea that resolves on discontinuation of treatment. In some cases the disturbance  is  drug-specific,  e.g.  erythromycin causes a decrease in drug transit time and tetra-

cyclines can inactivate lipases. The latter action prevents fat absorption, which then passes into the colon to produce steatorrhoea.

AAC is more serious and is the result of over-

growth with Clostridium difficile. This organism

releases an exotoxin that causes a local inflam-

mation and formation of a membrane of necrotic

tissue over the bowel wall, which in about 20% of

cases leads to a form of chronic diarrhoea, some-

times called pseudomembranous colitis. This is

an   intense,   potentially   fatal   diarrhoea   that

requires   oral   treatment   with   vancomycin  or

metronidazole and is currently a serious problem

in the UK.

Summary of acute diarrhoea treatment

•           Most  cases  of  diarrhoea  will  not  require

antimicrobial treatment. Exceptions to this

are when:

-  Systemic effects are present.

-  The patient is either very young or elderly.

-  The patient has some other debilitating

condition.

•           Oral or IV rehydration are the most important

treatments for the management of severe or

persistent diarrhoea.

•           Antimicrobial  therapy  may  benefit  patients

suffering  from  infection  caused  by  certain

specific organisms, particularly when there are

systemic complications. Conversely, the indis-

criminate use of antimicrobials may exacer-

bate symptoms. Although the 4-quinolones

are the treatment of choice for most bacterial

infections, if indicated by the clinical condi-

tion of the patient, metronidazole is used to

treat  anaerobic  bacterial  infections,  e.g.  by

Bacteroides and Clostridium spp., giardiasis and

amoebic dysentery.

Tuberculosis

Epidemiology

During the 19th and early 20th centuries, tuber-

culosis (TB) was the cause of 50% of all deaths

and   morbidity   and   was   described   as “The

Captain of the Armies of Death”. The old term

for  the  disease,  consumption,  describes  the

extreme wasting of the tissues of those with

untreated disease. Today it is far less common in

the UK, affecting 5-10 per 100 000 of the native

population, though it is much more prevalent

among some immigrant groups. Although the

Some important infections         571

fall over the last century in the incidence of TB

in the West can be linked to general improve-

ments in nutrition, hygiene and general living

standards,   immunization   and   antimicrobial

chemotherapy have played an important part

since the 1950s, so that death from TB is now

rare in the West.

Recently, however, TB has again become a

serious worldwide health issue. The WHO has

declared the disease to be a global emergency. It

estimates that TB is now responsible globally for

4 million deaths annually, and rising. TB is the

major  cause  of  death  from  infectious  illness

among those over 5 years of age in developing

countries. Much of the problem is related to the

emergence of HIV/AIDS, which renders affected

individuals  highly  susceptible.  Approximately

10% of cases, rising to 30-50% in some sub-

Saharan African countries, are related to HIV

infection. In Third World countries overall, TB is

responsible for some 25% of avoidable deaths.

India and China have 1.8 and 1.3 million cases,

respectively, but these figures are likely to be

considerable   underestimates.   The   financial,

logistical  and  manpower  burdens  of  TB  and

its  treatment  are  a  significant  constraint  on

economic development.

Aetiology

Pulmonary TB is caused by Mycobacterium tubercu-

losis transmitted via airborne droplets coughed or

sneezed by infected individuals. Rarely, bovine

TB,  transmitted  via  cow’s  milk,  causes  TB  of

the GIT. Mycobacteria are unusual in that they

possess an outer waxy coat, which makes them

particularly resistant to drying, the host’s defence

mechanisms  and  to  most  antimicrobials.  The

bacterium becomes a focus for chronic inflamma-

tion, and granuloma (tubercle) formation (see

Chapter 2) is a particular feature.

Pathogenesis

The progression of TB is summarized in Figure

8.4. Following primary infection, usually in the

lungs, neutrophils are attracted to the site of

infection  and  replaced  by  macrophages  after

about a week. These cells engulf and attempt to

digest   the   organisms,   which   however   may

remain unharmed and viable owing to their

waxy coat. T cells are also activated and their

lymphokines attract and maintain the popula-

tion of macrophages around the focus of infec-

tion. Two groups of T helper cells are known to

be involved in this immune response; the TH1

and TH2 cells are distinguished by their CD anti-

gens and the different cytokines that they release

(see Chapter 2). It is believed that TH1 activity is

responsible for macrophage activation, but that

the action of TH2, or a mixed TH1/TH2  activity,

renders cells highly susceptible to killing by TNF.

This  activity  of  the  immune  system  and  its

proinflammatory  cytokines  is  responsible  for

much of the lung damage associated with TB.

This process eventually leads either to the forma-

tion of tubercles, which may heal completely

leaving a small, often calcified, scar, or to spread

via the lymphatics into the lymph nodes, where

the bacteria form a more widespread ‘primary

complex’. In immunosuppressed patients or the

elderly, mycobacteria occasionally spread via the

bloodstream to various tissues, e.g. the spleen,

liver, kidneys and eyes, a condition known as

miliary TB. Bacteria may also reach the CNS,

causing  tuberculous  meningitis,  or  become

sequestered in bones (usually the spine) where

they become centres for granulomatous lesions

and cause deformity.

At  about  1-2 months  after  infection,  indi-

viduals   become   sensitized   to   mycobacterial

proteins, displaying a local type IV hypersensi-

tivity reaction that causes further tissue damage.

This  is  the  basis  of  the  Mantoux  test  for

immunity to TB. At this stage all the character-

istic clinical features of TB are apparent (see

below).

The  major  complications  usually  occur  on

reactivation of the disease (post-primary TB),

as  a  result  of  reduced  immunity  or  another

concurrent infection. Post-primary infection of

the  lung  produces  the  typical  symptoms  of

pulmonary  TB,  the  primary  infection  often

having been mild or asymptomatic. Re-infection

Some important infections         573

is another uncommon cause for post-primary

infection.

High-dose corticosteroid and other immuno-

suppressive treatments and diabetes mellitus can trigger post-primary TB, so many clinicians give prophylactic isoniazid (see below) before initi-

ating such therapy in patients with evidence of previous TB infection.

Although it is estimated that about 30% of

people worldwide are carriers of M. tuberculosis,

only about 10% of these develop symptoms,

because  of  containment  by  carriers’  immune

response or differences in the pathogenicity of

different strains. A major TB school outbreak in

Leicester, England, in 2001 was caused by the CH

strain and affected over 250 pupils. This strain is

more pathogenic than usual, causing symptoms

in about 25% of those infected. It has recently

been discovered that, surprisingly, this increased

virulence is probably due to a single gene dele-

tion that, although the CH strain grows less well

in culture, makes it less immunogenic. Thus the

CH-infected patient does not mount a normal

inmmune response.

In this connection, it is known that a heat

shock protein of M. tuberculosis (Hsp70) modu-

lates the patient’s immune response by stimu-

lating   the   CCR5   receptors   of   dendritic,

antigen-presenting cells to group together with T

cells, thus activating more T cells and increasing

the immune response. Hsp70 is now being eval-

uated as a new agent for the treatment of TB and,

incidentally,   for   enhancing   the   immune

response to cancer cells. Other possible agents

for stimulating the CCR5 receptors of dendritic

cells are also being investigated.

Clinical features

In most subjects, primary infections are asympto-

matic or mild, i.e. a vague malaise, sometimes

with cough and wheezing. Symptoms normally

disappear as the tissues heal, but viable mycobac-

teria persist for years in the tubercles. Although

patients become tuberculin-positive, i.e. hyper-

sensitive to mycobacterial protein, the immunity

may not be complete, leading to more severe lung

problems. If the bacterial load is heavy, miliary

disease, tubercular pneumonia, and tubercular

meningitis may occur within the first year. If the

bacterial load is light, the lymph nodes, bones

and  joints,  the  gut  and  kidneys  may  become

infected within 5 years.

In   young   children   the   disease   progresses rapidly and early diagnosis is essential to avoid mortality.

Advancing age, with declining immunocom-

petence, chronic disease and immunosuppres-

sion may allow reactivation of the mycobacteria

in granulomas years later, to cause post-primary

infection. The classic respiratory symptoms of a

post-primary infection include the slow develop-

ment of tiredness, weight loss, fever and a cough

productive  of  mucoid  or  purulent  sputum,

which may be bloodstained. There may also be

chest wall pain, dyspnoea and wheeze, and a

history of recurrent colds. Finger clubbing (see

Chapter 5) occurs in advanced disease. The CXR

is abnormal but is not necessarily diagnostic, so

bacteriological evidence is needed.

Without adequate therapy, lung damage will

lead to progressive disability and a slow, lingering

death.

Diagnosis

This depends on the following:

•  Symptoms and signs.

•  CXR, and CT scan if the X-ray is equivocal.

•  Sputum   microbiology.   Lung   washings   or

biopsy specimens of suspected lung lesions, lymph nodes and pleura may be necessary in doubtful cases.

-  Microscopy for acid-fast rods.

-  Culture and sensitivity testing

•  DNA testing, if speed is required or if micro-

            biology is negative in a patient with suggestive

symptoms.

The Mantoux test cannot usually be used in the  UK  to  diagnose  active  TB,  because  of widespread BCG vaccination (see below).

antimicrobial therapy

Prophylaxis

Immunization

In the UK, Bacillus Calmette-Guérin (BCG), a

live attenuated vaccine against TB, has been

offered to all tuberculin-negative children aged

10-13 years, reducing the risk of overt TB by up

to 75%. However, the low incidence of TB in

some areas has caused this to be stopped. In

deprived areas, and where there is a high immi-

grant population, immunization is being offered

to children at birth, reducing new infections

considerably. In other countries efficacy may be

much higher (e.g. in Scandinavia) or much lower

(e.g. in the tropics), and a more effective vaccine

is being investigated. In addition, immunity may

be lost in later life, but the efficacy of BCG in

older adults has been less well studied.

TB is spread from person to person, so contact tracing of all newly diagnosed patients is essen-

tial to reduce the risk of disease spread. All those in the same house, and sometimes people in the same school or workplace, are screened for TB. If they are unwell, rigorous investigation for TB is required. If they are well, a CXR and tuber-

culin test are done. If the CXR is negative in

adults no further action is required, even if they are tuberculin-positive (see above).

If the tuberculin test is negative in children

and young adults, the test should be repeated

after 6-8 weeks and if it is still negative BCG

vaccination should be given. However, if it has

become positive, and if BCG vaccine has not

been given, this indicates active infection and

treatment should be started immediately.

All  medical  and  paramedical  hospital  staff

should  be  immunized  with  BCG  if  they  are

tuberculin-negative. BCG immunization is not

given to tuberculin-positive subjects because this

is likely to provoke a severe hypersensitivity

reaction.

Chemoprophylaxis

People at high risk who are in contact with the

public in areas with high levels of TB, e.g. teachers

and catering staff, are often given isoniazid for

6 months, which reduces the infection risk but

there  is  a  risk  of  hepatotoxicity.  This  is  also

required for patients who are taking immunosup-

pressive  agents,  including  high-dose  cortico-

steroids,  and  are  starting  renal  dialysis.  Some

consultants routinely give isoniazid before starting

prolonged or high-dose corticosteroid treatment.

HIV infection is immunosuppressive by defin-

ition and patients cannot respond to BCG vacci-

nation, so all are given isoniazid. There is a risk of peripheral neuropathy in this situation, but

pyridoxine may help prevent this. An isoniazid-

resistant strain of BCG vaccine must be used if a patient is to be given isoniazid later.

Liver  function  tests  should  be  done  before starting   isoniazid   treatment   and   regularly thereafter during therapy.

Pharmacotherapy

The purpose of chemotherapy is to eradicate the

organism completely, but there are major prob-

lems associated with this. It can take 6-8 weeks

to culture the slow-growing Mycobacterium, and

a further 4-6 weeks for sensitivity testing. This

means that therapy must be started empirically.

However, newer DNA probe techniques are being

developed that reduce this to about 48 h and

should lead to earlier, more effective treatment.

M. tuberculosis is resistant to many common

antibacterials owing to poor penetration of the

agents. Moreover, because resistance is so wide-

spread, treatment failure is inevitable if a single

agent is used. During active disease, the growing

bacteria must be dealt with quickly, but there

will also be dormant or semi-dormant bacteria

that require protracted therapy for elimination.

Antitubercular drugs are rather toxic, and must

be used long term: both of these factors tend to

reduce compliance. In addition, compliance is

often poor because patients tend to feel much

better soon after initiating chemotherapy: they

become   non-infective   after    2 weeks.   Poor

compliance results in an incomplete kill of the

organisms and, almost inevitably, future relapse

with drug-resistant disease.

There has been much interest in finding ways

of  improving  compliance.  Uniquely  this  has

become very much a public health issue, where

it has been shown that good compliance with a

Some important infections         575

regimen actually reduces the rate of TB notifica-

tion. A useful strategy might be to monitor urine levels of the various agents. A directly observed therapy, short course scheme (DOTS) has also been  used  successfully.  In  this,  patients  are invited to attend clinics three times each week, the dosages being adjusted accordingly to allow for the increased interval between them. This is one situation in which combination products

are preferred to aid compliance, unless that is not possible due to drug toxicity.

Figure 8.5 summarizes the current recommen-

dations made by the WHO for the treatment of pulmonary TB.

It  is  assumed  that  the  organism  will  be

drug-resistant,  so  a  combination  of  isoniazid,

rifampicin, pyrazinamide and ethambutol is given

for the first 2 months. Isoniazid and rifampicin

are then usually given for another 4 months, if

laboratory results indicate that these two agents

are effective. It is important to continue with

all four  agents  until  efficacy  is  confirmed  by

laboratory  tests.  Rifampicin  and  isoniazid  are

somewhat  faster-acting  than  ethambutol  or

pyrazinamide.  All  drugs  are  administered  as

a single  daily  dose, 30 min  before  breakfast

and often as combined preparations (rifampicin/

isoniazid or rifampicin/isoniazid/pyrazinamide) in

order to improve compliance.

Rifampicin, isoniazid and pyrazinamide can all

cause liver damage, so liver function must be

monitored throughout treatment. Ethambutol at

high  doses  has  been  associated  with  retinal

damage and should be discontinued if visual

disturbance occurs. Isoniazid-induced peripheral

neuropathy can be avoided by giving pyridoxine.

Rifampicin can turn urine or tears an orange-

red colour and patients must be warned of this

to avoid undue alarm and unnecessary visits to

the doctor. It may also cause staining of contact

lenses.

If sputum samples are still positive by acid-fast staining and microscopy or by culture in months 5-6, or relapse occurs, an 8-9-month treatment regimen  incorporating  second-line  agents  is necessary (see below).

Multiple resistance

The emergence of multiple drug-resistant strains

of TB (MDRTB) is of great concern. In the UK,

resistance to isoniazid alone occurs in about 3%

of isolates, and dual resistance to isoniazid and

rifampicin in about 0.6%. Overall, the prevalence

of MDRTB is about 0.8% of cases in the UK and

about 3.4% in India but these figures mask large

differences in the absolute number of cases, i.e.

about 55 cases annually in England and Wales

and about 63 000 in India. Resistance may be

primary, where a person has been infected by a

resistant strain, or strains, or secondary where a

resistant strain has emerged owing to incomplete

treatment.

If  isoniazid  resistance  has  been  confirmed,

treatment should continue with rifampicin and

ethambutol for a year. If rifampicin resistance is

confirmed, treatment with isoniazid and ethamb-

utol should be continued for 18 months. In both

cases pyrazinamide is added for the first 2 months

of treatment.

If a patient’s strain is known to be resistant to

isoniazid at the outset, streptomycin or amikacin

may be substituted for isoniazid in initial treat-

ment, but this involves IM or IV injections and

serum level monitoring to ensure an appropriate

peak level 1 h after injection and trough (pre-

dose)  concentration.  If  there  is  renal  impair-

ment or the patient is aged over 50 years, the

trough  concentration  needs  to  be  reduced

considerably.  Streptomycin,  unlicensed  in  the

UK, is used only rarely, and is available only

through the named-patient mechanism.

The high costs of patient monitoring of liver

function,  and  possibly  aminoglycoside  blood

levels, clearly causes problems of supplying the

facilities and trained personnel in Third World

countries.

Strains of TB resistant to the usual combina-

tion of first-line drugs are rare in the UK, except

in immigrants, but are increasingly common in

some other countries. In such cases, second-line

antimicrobial therapy

drugs  such  as  capreomycin,  cycloserine  (neuro-

toxic) and ethionamide  are added to the drug cocktail.  Encouraging  results  have  also  been obtained with 4-quinolones, e.g. ciprofloxacin. Amikacin  and  clarithromycin  have  been  used rarely (unlicensed indications).

In the UK, people with drug-resistant disease

are treated as in-patients in specialized units,

where second-line drugs are commonly used. At

least five drugs, including amikacin, are used

until   cultures   are   negative,   followed   by   a

minimum of three drugs for up to 9 months. The

cost of such treatment is considerable (about

£60000 per patient).

Summary

The treatment of TB illustrates the following:

•  Need for multiple agents to overcome drug

            resistance.

•  Importance  to  patients  and  contacts  of

            completing courses of treatment even though

they   feel   well   soon   after   treatment

commences.

•  Problems of poor compliance associated with

            prolonged courses of treatment with agents

that have serious or unpleasant side-effects.

•  Benefit  of  closely  supervised  treatment  to

ensure compliance.

Urinary-tract infection

Symptoms and diagnosis

Infection of the lower urinary tract (see Chapter

14,  Figure 14.1)  occurs  either  in  the  bladder

(cystitis) or the urethra (urethritis) and is esti-

mated to affect 15% of women each year and

occur in up to 50% of women at some time in

their lives. Their very short urethra predisposes

to ascending infection with perineal bacteria.

The  symptoms  of  frequency,  haematuria,

suprapubic   pain   and   dysuria            (i.e.   painful

micturition), though not life-threatening, may

be  extremely  uncomfortable  and  have  a  50%

probability  of  cystitis.  The  urine  may  appear

turbid  due  to  the  presence  of  bacteria  and

pus, and may have an unpleasant fishy smell

due  to  the  production  of  microbial  metabo-

lites. Recurrence (2%) and reinfection (8%) are common.

The condition is uncommon in men because

their longer urethra acts as a barrier to ascending

infection from the penis. Consequently, urinary-

tract  infections  in  men  are  regarded  more

seriously.

Despite apparently minor symptoms, urinary-

tract   infections   may   involve   the   kidney (pyelonephritis), even causing renal failure, and pathogens may then gain access to the circulation and cause septicaemia.

Diagnosis  may  be  difficult  if  symptoms  are

present but bacteria cannot be seen microscopi-

cally in the urine nor cultured. This is known as

abacterial cystitis, which can occur in up to 50%

of cases. Conversely, because bacteria are often

isolated from the urine in the absence of any

overt   symptoms          (covert   bacteriuria),   the

diagnostic  criterion  for  significant  bacteriuria

is   normally   taken   to   be   more   than 100

coliforms/mL  plus        10  leucocytes/mm3  (in  a

microscope counting chamber) or          100000/mL

of any pathogens. The coliform count alone is

insufficient. More vigorous treatment may be

indicated for certain groups of patients, partic-

ularly in the presence of recurrent or ascending

infections: this includes pregnant women, chil-

dren, patients with learning difficulties and all

men. The elderly may also be prone to compli-

cations,  which  may  present  as  confusion  in

the  absence  of  the  usual  signs  of  infection.

Undiagnosed urinary-tract infections in infants

and  young  children  may  have  serious  renal

consequences in later life.

The full spectrum of urinary-tract infections,

including pyelonephritis, is discussed in Chapter

14. Here, we will discuss only the treatment of cystitis.

Aetiology

The  majority  (90%)  of  acute  uncomplicated

cases of cystitis are due to self-infection with

E. coli from the anus that colonize the perineal

area.  Other  Gram-negatives,  e.g.  Proteus  and

Klebsiella  may  be  implicated,  particularly  if

infections are chronic. Infections due to staphy-

lococci are the second most common in the

community  but  are  less  usual  in  hospital.

Some important infections         577

Pseudomonas infection is usually associated with

an anatomical abnormality of the urinary tract.

Organisms other than E. coli  are also more

likely in hospital-acquired infections, especially

in catheterized patients. In cases that fail to

respond to usual treatment, organisms such as

Chlamydia or Candida should be considered.

Investigation

A urine specimen that is minimally contami-

nated by commensals from the genitalia is neces-

sary for culturing and sensitivity tests. This is

obtained   through   a ‘clean-catch   midstream

urine’ (MSU) sample, usually collected into a

sterile sample jar at home by the patient: the

genital area is first washed with mild soap and

dried, and the first and final parts of urine are

rejected. The sample is collected first thing in the

morning when the bacterial count is likely to be

highest due to undisturbed overnight growth.

However, an uncontaminated sample is difficult

to collect in some circumstances, e.g. young chil-

dren and the elderly, and a more reliable method

is via a catheter, although this may itself intro-

duce infection into the bladder. Rarely, supra-

pubic bladder aspiration with a syringe may be

required when it is difficult to collect a sample,

e.g. from a young infant.

Apart from culturing, which may take some time, other changes in the urine can indicate the presence of microorganisms. Reagent strips can be used to detect the presence of nitrite produced as a result of bacterial metabolism. The pH of the urine may be low in the presence of E. coli or high if due to Proteus spp. or other urease-positive, ammonia-producing, species.

Further  investigations  for  potential  compli-

cations are indicated in all cases of male or

childhood  urinary-tract  infection,  in  women with recurrent or persistent symptoms and when sterile urine has not been achieved after standard therapy (see Chapter 14).

Management

Aims

The  immediate  aim  of  treatment,  from  the

patient’s view, is the rapid relief of uncomfort-

able symptoms. This is best achieved by the

eradication of the responsible organism using a

short  course  of  an  appropriate  antibacterial

agent. The prevention of recurrent and chronic

infections and of subsequent renal damage is a

further aim that may require longer courses of

treatment.

Choice of antibacterial

Samples for laboratory investigation must be

taken before treatment is commenced. As E. coli

is the most likely organism, the initial antibacte-

rial choice is relatively simple. The final decision

will depend on local, known patterns of resis-

tance. Trimethoprim may be appropriate for blind

treatment and achieves high urine concentra-

tions. Strains of bacteria resistant to trimethoprim

are becoming increasingly common in hospitals

and, to a lesser extent, in the community, and a

first-generation cephalosporin, e.g. cefalexin, is a

useful alternative.

Nitrofurantoin is also suitable, although its use

is limited by toxicity and good renal function

is required. Proteus spp. are also resistant. The

4-quinolones are active against a wide range of

organisms including pseudomonads, but should

be reserved for infection of proven sensitivity

that are resistant to other agents, or for treat-

ment  failures.  The  quinolone  norfloxacin  is

restricted  to  treating  urinary-tract  infections

because it achieves sub-therapeutic blood levels,

but a high urine concentration.

The last dose of the day of any agent should be

taken just before going to bed in order to achieve

high urine concentrations when bacterial count

is  likely  to  be  maximal.  Symptoms  should

begin to clear within 48 h, and a 3-day course is

usually sufficient for uncomplicated cystitis in

women; 5-days’ treatment is necessary in men.

Frequent urinary-tract infections may require prophylactic use of antibacterials. In children, low-dose trimethoprim  can be used, given last thing  at  night  for  many  months.  In  adults, prophylaxis with low-dose nitrofurantoin  is an alternative and rarely causes problems.

Other treatment modes include alkalinization

of the urine with potassium or sodium citrate or

sodium bicarbonate may provide some sympto-

matic relief if the urine is very acid (pH 4), and

will inhibit growth of E. coli. However, the use of

potassium or sodium citrate may be hazardous in

antimicrobial therapy

elderly patients and others with impaired renal function, owing to the cardiovascular effects of accumulated sodium or potassium. Moreover, Proteus spp. thrive in a high pH, but not under acid conditions, so acidification of the urine

with ammonium chloride is then appropriate.

Thus, simple pH testing with indicator paper

should guide this type of treatment.

Advice should always be given to increase fluid

intake and to ensure regular voiding in order to

obtain maximum washout of organisms from

the bladder. Also, women should be advised to

wipe from front to back after toileting, though

the value of this has been questioned. ‘Pushing’

fluids,  e.g. 200 mL  three  times  an  hour  for

several hours, may wash out the bacteria and

abort an infection without the need for anti-

microbial treatments, provided that it is started

promptly  when  symptoms  occur.  It  is  also

important to void completely in order to leave

the minimum of infected urine in the bladder.

Summary of urinary-tract infections

Treatment of urinary-tract infections illustrate the following general principles:

•  E. coli is responsible for the majority of acute

            urinary-tract infections, so initial empirical

therapy can be chosen with a high degree of confidence.

•  Local  patterns  of  resistance  will  indicate

            which of a number of possible antimicrobial

agents should be used.

•  The antimicrobial must be present in high

            concentrations  in  the  urine.  Only  those

agents that are rapidly excreted unchanged

in  adequate concentration in the urine are

suitable  for  the  treatment  of  urinary-tract

infections.