Medicine Bacterial challenges and evolving antibacterial ... · enterobacteria, the gonococcus and...

Postgrad Med J (1992) 68, 6 - 21 i) The Fellowship of Postgraduate Medicine, 1992

Reviews in Medicine

Bacterial challenges and evolving antibacterial drugstrategy

B. Watt and J.G. Collee

Bacteriology Laboratory, City Hospital, Edinburgh EH10 SSB andDepartment ofMedical Microbiology,University Medical School, Edinburgh EH8 9AG, UK

Introduction

In this paper, we attempt to summarizedevelopments ofimportance for practising hospitalclinicians and for primary care doctors who mustbe aware of the ever-widening spectrum of recog-nized pathogens. This article is restricted to con-siderations of pathogenic bacteria and antibacterialdrugs that have obliged us to change our strategiesor policies in the last decade or so. There have beenmany confusing developments. Whilst basicallynew antibacterial drugs are rare, variations onpreviously successful models have been verynumerous and some significant progress has beenmade.

Over the decade, several new infective challengeshave posed problems for clinicians and micro-biologists. It is recognized that community-acquired infections differ from hospital-acquiredinfections in the range and nature and antibioticresistance profiles of the causative organisms. Theinexorable progress of bacterial drug resistance hasobliged us to reconsider first-choice therapy forsome infections.

Beta-lactamase production by various bacteriahas restricted our therapeutic options or hasobliged us to use new preparations. For example,our recognition of the pathogenic potential ofMoraxella (Branhamella) catarrhalis has requiredmodification of previous approaches to theantibiotic therapy of respiratory tract infections,and beta-lactamase-producing strains of Haemo-philus influenzae have created further problems.Worrying outbreaks of a range of infections fromlegionellosis to salmonellosis have extended us todetermine or define appropriate therapy. Our evol-ving awareness of human immunodeficiency virus(HIV) disease and associated opportunistic

bacterial infections obliges us to consider a varietyof new challenges, especially mycobacterial infec-tions.Our relative lack of success in dealing with some

aggressive infections, such as those caused by themeningococcus or Haemophilus influenzae, hascalled for a review of our prophylactic strategies,and this has been highlighted in the case ofpneumococcal challenges in compromised (as-plenic) patients. The common occurrence ofpolymicrobial or mixed bacterial infections hasbeen acknowledged, and the neglected concept ofpathogenic synergy has been revived. The problemsof antibiotic-associated diarrhoea have necessitatedscrutiny of precipitating antibiotics and studies ofthe most effective therapy. Meanwhile, the generalacceptance of the principle of peroperative anti-microbial prophylaxis and its application tospecific areas of operative surgery has had a majorimpact.

Changes in first-line choices

The sulphonamides have been largely supersededby newer drugs in the last decade, though they arestill used, often in conjunction with trimethoprim(as cotrimoxazole), in the treatment of uncompli-cated urinary tract infections. Resistance to sul-phonamides is common and it is arguable that theuse of the combination is now often irrational.Thus, trimethoprim has emerged as a single drug inits own right, but its use too has often beenovertaken by the development of resistance.Nalidixic acid has been superseded by the develop-ment of the more potent 4-quinolones, and nitro-furantoin is not favoured by many clinicians. Someofthese drugs have special roles that maintain themin our formularies for the 1990s although they arenot now in general daily use.The lincosamides, notably clindamycin, had

special virtues that endeared them to orthopaedicCorrespondence: B. Watt. M.D., F.R.C.Path.

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BACTERIAL CHALLENGES AND ANTIBACTERIAL DRUGS 7

surgeons and others who valued their efficacyagainst gram-positive cocci and anaerobes andtheir good penetration into bone. Clindamycin isstill highly regarded as an alternative to penicillinwhen such an option is sought. Unfortunately, theassociation with pseudomembranous colitis(PMC) has understandably inhibited the generaluse of clindamycin. It should be noted that thevolume of use of ampicillin ensures that ampicillinfeatures prominently in the PMC league table; ourexperience in the last decade shows that noantibiotic is exempt. Nevertheless, the associationwith the lincosamides is especially clear and is ajustifiable (though not absolute) restraint.

The staphylococcus has sequentially challengedall of the antibacterial drugs as they have beendeveloped and widely used, and has obliged us tokeep our therapeutic options open. Thus, fusidicacid (usually in combination with another drug) isstill useful. Strains of methicillin resistantStaphylococcus aureus (MRSA) have posed specialproblems. Vancomycin retains a remarkable placein our attempts to control coagulase-negativestaphylococcal infections and MRSA infections(and pseudomembranous colitis caused by Clost-ridium difficile). It is worrying that our options inthese difficult situations are so limited and that weare so dependent on such a restricted number ofactive agents.

The basic armament

Many antibacterial drugs have stood the test oftime, despite our abuse of them over the years.Accordingly, the list of those regarded as first-linechoices for the 1990s does not differ significantlyfrom the 1980 list. We now consider developmentsin antibacterial drug strategy and practice in thelast decade in relation to changing aspects ofinfection. The following account reviewsdevelopments in the use of our main-line anti-bacterial drugs and draws attention to importantnew applications.

The penicillins

Williams' recognized the following 4 groups ofpenicillins.

Group I contains benzyl penicillin (penicillin G),the original and still probably the best,2 andanalogues such as the orally active phenoxymethylpenicillin (penicillin V).

Group II contains the anti-staphylococcalmethicillin and the clinically useful orally activecloxacillin series.

Group III contains penicillins with activityagainst Gram-negative bacilli (coliform organismsand Haemophilus species etc.), but susceptible to

beta-lactamases. These include: (1) ampicillin andamoxycillin (the amino penicillins); (2) carbenicil-lin and other carboxypenicillin analogues; (3) acylureido penicillins such as mezlocillin, azlocillin andpiperacillin; and (4) amidino penicillins such asmecillinan. It is most important to note in practicethat none of the Group III penicillins is completelystable to the beta-lactamases.

Group IV holds the only true penicillin that isbeta-lactamase stable, temocillin, but the activityof this drug does not extend beyond the aerobicGram-negative bacteria.

Beta-lactamase inhibitors As bacterial resistanceto beta-lactam antibiotics is largely attributable topotent bacterial beta-lactamases, pharmaceuticalcompanies sought to develop beta-lactam drugsthat are resistant to these enzymes (q.v.). Anotherstrategy is to develop preparations in which asensitive beta-lactam drug is protected by a beta-lactamase inhibitor such as clavulanic acid orsulbactam or tazobactam.

These inhibitors have some antibacterial activityin their own right, but their role in the combinationis to shield the more active drug. This has extendedthe usefulness of drugs such as amoxycillin againstbeta-lactamase-producing staphylococci, coliformorganisms and anaerobes including Bacteroidesfragilis. However, Pseudomonas aeruginosa hasinnate resistance to amoxycillin and this still holds.The combination of amoxycillin with clavulanic

acid (co-amoxiclav) is marketed in Britain asAugmentin; ticarcillin with clavulanic acid isTimentin; and ampicillin with sulbactam is sul-tamicillin.3 Tazobactam in combination withpiperacillin is a useful development of this theme.4Meanwhile, the pharmaceutical industry wasdeveloping the cephalosporins as an alternativeanswer to the threat of the penicillinases.

The cephalosporins and related drugs

These drugs can be classified into 4 groups thatreflect an extending clinical requirement for a rangeof activity or specific efficacy.'Group I drugs (examples cephaloridine, cepha-

zolin) are highly active against Gram-negativebacteria, notably staphylococci and streptococci.Group lcephalosporins (examples cefamandole,

cefuroxime) are effective against Gram-positivecocci and (Gram-negative) coliform organisms, butnot pseudomonas.Group III drugs (examples cefotaxime, ceftazi-

dime) are active against Pseudomonas and relatedspecies, in addition to their activity againstenterobacteria. Cefotaxime is less active than cef-tazidime against Pseudomonas aeruginosa. Cef-sulodin was developed specifically as an anti-pseudomonal cephalosporin.

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8 B. WATT & J.G. COLLEE

Group IV contains the cephamycins (examplescefoxitin, latamoxef, cefotetan) with broad-spectrum efficacy that includes activity againstanaerobic bacilli such as bacteroides organisms,the clostridia, and anaerobic cocci.As in the case of the penicillins, it should be

noted that evolving bacterial resistance may limitthe usefulness of the drugs in each of these groups.

Monobactams

Aztreonam is a monocyclic beta-lactam with re-markably narrow-spectrum activity againstaerobic Gram-negative bacteria, notably theenterobacteria, the gonococcus and Haemophilusinfluenzae.6

Carbapenems

Imipenem has a remarkably broad spectrum ofactivity against the enterobacteria, and Pseudo-monas aeruginosa, Haemophilus influenzae,Bacteroides spp., staphylococci and streptococci.7Imipenem has to be given with cilastatin to inhibitthe action of renal dehydropeptidase which inacti-vates the drug. Meropenem has equivalent activityand is resistant to the action of the renal enzyme.8

For comparative data on the beta-lactamantibiotics, the reader is referred to Rolinson'sinformed paper.9 An account of the mechanismsand clinical significance of resistance to new beta-lactam antibiotics is given by Livermore andWood.'1

Aminoglycosides

These drugs are not absorbed after ingestion andare normally injected, unless a local effect on anintestinal pathogen or on the gut flora is desired. Inthe latter case, aminoglycosides are still usedirrationally because they are not effective againstanaerobic bacteria or streptococci, though theyhave a synergistic effect with penicillin when used incombination parenterally against streptococci.

Streptomycin now has only a limited place in themanagement of tuberculous infections, and it hasbeen largely replaced in the therapy ofother seriousinfections by more recent members of the seriessuch as gentamicin, tobramycin, netilmicin, andamikacin." With the exception of amikacin, theselater developments are not adequately effectiveagainst the tubercle bacillus. They all have promptand highly useful activity against coliform bacteriaincluding pseudomonas, though resistance is arecurring problem if they are not used carefully. Itshould be remembered that therapy with amino-glycosides may suppress the growth of myco-bacteria in specimens submitted for culture toexclude a diagnosis of tuberculosis. This is import-

ant in the laboratory investigation of a patient withan undiagnosed infection that might be myco-bacterial, especially at the present time whenopportunistic mycobacterial infections in compro-mised patients test our vigilance.

Mattie et al.2 argued that the relative efficacy ofdifferent aminoglycosides should be properlyquantitated and should be related to relative toxi-city.

Aminoglycosides have been widely used formany years. Although resistance is a problem inspecific areas, a recent survey in the UK'3 showedthat overall resistance rates amongst normallysensitive bacterial genera ranged from 2.4% foramikacin to 3.7% for gentamicin. For individualgenera, e.g. Serratia spp., resistance rates werehigher. In general, the lowest resistance rates wereseen for amikacin. An earlier European survey'4had revealed gentamicin resistance rates as high as30% in some countries. There is no doubt thatincreased usage of a given aminoglycoside can leadto increased resistance to that aminoglycoside, butalso to decreased resistance rates to other amino-glycosides. A recent study'5 showed that whenamikacin was the main aminoglycoside used incancer treatment centres in the USA, there was anincrease in resistance to amikacin but a decrease inresistance to gentamicin and tobramycin.Although the toxicity of the aminoglycosides for

the middle ear and the kidney limits their use andobliges the clinician to monitor peak and troughlevels during therapy, these drugs are still favouredby many clinicians for the therapy of seriousinfections. They are often used in combination witha pencillin and sometimes with metronidazole toextend the spectrum until the nature of the infec-tion is known. This is an area of current debate, asothers prefer to base therapy in such circumstanceson one of the broad-spectrum cephalosporins orrelated drugs such as ceftazidime and to add inother drugs as necessary.'6

Spectinomycin has special usefulness in the treat-ment of gonococcal infections (1) in patients whoare allergic to penicillin, or (2) in cases of infectionwith penicillinase-producing strains.'7

Tetracyclines

These drugs were active across a remarkably widespectrum, but bacterial resistance and recognizedadverse effects limit their use.'8The adverse effects of the tetracyclines are

mainly related to the gastro-intestinal tract andsuperinfection, and to the sequestering of the drugin bone and teeth so that they are not given as aroutine during pregnancy or childhood. It was laterfound that the anti-anabolic effect of tetracyclinesmay precipitate or exacerbate renal failure inpatients with impaired renal function.

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Chlortetracycline, oxytetracycline and tetra-cycline are very similar in their action. Demethyl-chlortetracycline was introduced in 1957 as along-acting variant. Doxycycline and minocyclinewere introduced more recently; they do not exacer-bate renal failure and, as they also have theadvantage of longer half-lives and marginally bet-ter activity, they are the currently preferredpreparations. Dizziness and vertigo are listedamong the adverse side effects of minocycline.Porphyria is a contraindication to the use ofdoxycycline.The tetracyclines retain rather a mixed range of

applications, having been displaced from so manyfirst-line positions.'9 They have a major role in thetreatment of infections caused by mycloplasmasand chlamydiae. They have special roles in themanagement of some serious infections such asbrucellosis, actinomycosis and plague, often incombination with other antimicrobial drugs.20 Low-dose prolonged administration of tetracyclines hasa record of some success in the treatment of acnevulgaris, and more assured success in the treatmentofacne rosacea. Tetracycline eye ointment is usefulin the treatment ofchlamydial infections ofthe eye.

Chloramphenicol

This drug's very broad spectrum of activity2' hasbeen severely limited by its potential to cause

aplastic anaemia, even when used locally in eyedrops and eye ointment.22 Its use has also beenlimited by bacterial resistance which was especiallyevident with the staphylococci. The abuse ofchloramphenicol in developing countries in recentyears has received much deserved criticism but littleeffective action.23

Chloramphenicol retains its special role in thetreatment of typhoid and of Haemophilusinfluenzae meningitis and epiglottitis, but note thatresistance in strains of Salmonella typhi24 and H.influenzae is a problem in some countries.

Chloramphenicol's favourable pharmacokineticsearn it a place in the combined therapy of cerebralabscess and in the blind treatment ofacute bacterialmeningitis (but see below).

Macrolides

Erythromycin, the first of this group, has beenwidely used against Gram-positive organisms suchas pneumococci, streptococci and staphylococci,especially in penicillin-hypersensitive patients.Since 1975, erythromycin has been shown to beactive against a number of 'new' pathogens. As itpenetrates well into cells,26 it is the drug ofchoice totreat chlamydial infections. It is very active againstLegionella pneumophila in vitro and is recom-mended for treatment of legionellosis as it

accumulates in leucocytes and other phagocytesand can suppress the multiplication of intracellularlegionellae.27 In a guinea-pig model oflegionellosis,erythromycin prevented death from the infection,but only rifampicin could clear the pathogens fromthe lungs and accelerate resolution.28 Malmborg29suggested that the 2 drugs are synergistic andshould be used in combination for the treatment ofserious legionella infections.

Erythromycin has been shown to be active invitro against most strains of Campylobacter jejuniand to clear the organism rapidly from stools; itdoes not influence the clinical outcome if givenmore than 5 days after the onset of illness.30Although erythromycin is a safe drug, it pro-

duces gastro-intestinal side effects and is rathervariably absorbed from the gut. Since 1975, severalnew macrolides have been developed (see Table I).Their comparative in vitro properties were reviewedin 1988 by Hardy et al.3"

In general, the activity of the 14-memberedmacrolides equals or exceeds that of erythromycin,whereas the 1 5-membered azithromycin is lessactive against Gram-positive but more activeagainst Gram-negative bacteria. The 1 6-memberedmacrolides are less active than erythromycin.Clarithromycin is the most active compoundagainst Steptococcus pyogenes, pneumococci,Listeria monocytogenes and Corynebacterium spp.,and it shows promising activity againstMycobacterium avium. Miocamycin, clarith-romycin and rokitamycin are the most activecompounds against L. pneomophila. Azithromycinis the most active compound against Moraxellacatarrhalis, Neisseria gonorrhoeae, andHaemophilus influenzae.

Bernstein, Roudier and Fleurette32 tested severalmacrolides against Legionella spp. on charcoal-freemedia to avoid inactivation of antibiotics by char-coal and found that the most active agentswere josamycin (0.06-0,25 mg/1), pristinamycin(0.06-0.5 mg/l) and erythromycin (0.12-0.5 mg/l).

Clarithromycin is an acid-stable 14-memberedmacrolide that achieves higher serum levels thanerythromycin and has twice the serum half-life.33 Ingeneral, the MIC's for common respiratorypathogens are 2-4-fold less than those of eryth-

Table I New macrolides

14-memberedmacrolides 15-membered 16-membered

Erythromycin Azithromycin SpiramycinClarithromycin JosamycinA-62671 MiocamycinFlurithromycin RokitamycinRoxithromycin

From Hardy et al. (1988).3'

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romycin. Against Haemophilus influenzae theMIC's of clarithyromycin are higher than those oferythromycin, yet clarithromycin is more active inanimal models. This may be explained by the recentfinding that the activity of clarithromycin againstH. influenzae appears to be enhanced by its majormetabolite, 14-hydroxy-clarithromycin.

Fusidic acid

This steroid-like compound has clinically usefulactivity against staphylococci. As any largepopulation of staphylococci is likely to containmutants resistant to fusidic acid, the drug is usuallygiven along with a penicillin or some otherantibiotic to suppress their emergence duringtherapy.34

Rifamycins

Rifampicin, the original member of this class to beused therapeutically, has for many years been thecornerstone of multi-drug regimens for the treat-ment of tuberculosis. More recently, it has beenused for the prophylaxis of meningococcal infec-tion and treatment of carriers (but see later in thispaper), and for the treatment of severe legionellainfection in combination with erythromycin. It isalso of use for the prophylaxis of Haemophilusinfluenzae meningitis among those exposed to thisinfection (see Fleming).3"The increasing problem of mycobacterial infec-

tions in acquired immunodeficiency syndrome(AIDS) patients, often with rifampicin-resistantspecies such as Mycobacterium avium, led to asearch for more active rifamycin derivatives.Dickinson and Mitchison36 reported that rifabutinand rifapentine showed good in vitro activityagainst strains of the M. avium complex. Otherworkers have shown rifabutin to be more active invitro than rifampicin, especially against M. aviumstrains3738 and to show synergy with ethambutolagainst some of them.39 However, it has beensuggested that rifabutin does not have any advant-ages over rifampicin in practice.' Clinical trials ofthe two compounds in this context are urgentlyneeded.So far, rifapentine is not available for clinical

use. Other rifamycin derivatives have been syn-thesized4' and a preliminary report suggests thatsome may merit further study.

Metronidazole and other nitro-imidazole drugs(Tinidazole, Ornidazole, Nimorazole etc.)

Metronidazole and other nitro-imidazoleanalogues have proved to be remarkably effectiveanti-anaerobe drugs.42 Their action depends on apotent reducing step and they are consequently

largely ineffective against aerobic or facultativeanaerobic organisms. They have been used foryears against Trichomonas vaginalis and againstEntamoeba histolytica and they now have anotherestablished role against a range of anaerobicbacterial infections from periodontal infectionscaused by bacteroides and fusobacterial organisms,to post-operative wound infections that have ananaerobic component. It is increasingly recognizedthat many infections are polymicrobial, involvingtwo or more pathogens, and that a component ofthese is often anaerobic. The concept ofpathogenicsynergy has been greatly advanced in recent years,and the inclusion of an anti-anaerobe drug intherapeutic or prophylactic strategy has becomeaccepted practice under various circumstances(q.v.).

Metronidazole has clinically useful activityagainst all obligate anaerobes, includingpathogenic clostridia, bacteroides, fusobacteria andanaerobic cocci. Anaerobic fuso-spirochaetalinfections respond to metronidazole. The drug hasan assured place in peroperative antimicrobialprophylactic regimens when anaerobic challengesare likely, as in abdominal and pelvic surgery.The drug's pharmacokinetic profile is good, with

effective concentrations achieved in most tissuesand body fluids after oral, rectal or intravenousadministration. The drug's half-life is about 8 h. Itpenetrates tissue well and is active in the presence ofpus. Although the drug has been used widely,resistance has not been a problem;43 false evidenceof metronidazole resistance in anaerobes is some-times attributable to imperfect anaerobic techniquein the laboratory and the growth of oxygen-tolerant isolates that are not sensitive. Some cam-pylobacter strains and some helicobacters aresensitive to the nitroimidazoles, despite theirmicroaerophilic nature, and this is also true forGardnerella vaginalis.4 At present, we do notunderstand this.

Metronidazole is potentially irritant on intra-venous injection and may cause phlebitis.Neuropathy has been reported as a possibleuntoward effect after prolonged high dosage.Nausea and mild gastrointestinal upsets have beennoted as side effects, and skin rashes andleucopenia are listed as rare adverse reactions.Patients must be warned to avoid alcohol whentaking nitro-imidazole drugs.

Quinolones

These synthetic compounds are derived fromnalidixic acid which has been used as a urinaryantimicrobial agent for many years. Nalidixic acidis given orally and achieves good levels in the urinebut low serum levels, so that its use is limited to theprophylaxis and treatment of urinary tract infec-

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tions. Its spectrum of activity includes Gram-negative urinary tract pathogens such asEscherichia coli and Proteus spp., but the drug haspoor or insignificant activity against staphylococci,enterococci and pseudomonas organisms.

Interest in the quinolones was revived with thedevelopment of 6-fluoro-7-piperazino-4-quino-lones (commonly designated the 4-quinolones) thathave greatly enhanced potency, wider spectra of invitro activity and much better pharmacokinetics.45The range of4-quinolones continues to be extended.The first of the new quinolones to be marketed in

the UK, though not the first to be developed, wasciprofloxacin,46 a compound with extremely goodactivity against a wide range of Gram-negativebacteria including Pseudomonas aeruginosa, Sal-monella and Shigella spp. and many Gram-positiveorganisms including enterococci and staphylo-cocci.47 Its very good activity against neisseriae(Table II), notably N. gonorrhoeae, has allowed itto be recommended as a single-dose treatment forgonorrhoea, including that due to penicillinase-producing strains. It is less effective against strepto-cocci, including Strept. pneumoniae, and it is notgenerally recommended for the treatment of strep-tococcal infections or pneumococcal pneumonia.Ciprofloxacin also has useful activity against somestrains of mycobacteria,4 but its activity againstanaerobes is inconsistent.49 As ciprofloxacin

achieves good serum and tissue levels and can begiven by injection, it can be used for the treatmentof systemic infections as well as gonorrhoea andurinary tract infections.

Norfloxacin has a similar spectrum of activity,50but it is less potent and, as it achieves lower tissuelevels, it is used predominantly as a urinaryantimicrobial.The 4-quinolones act by inhibiting bacterial

DNA gyrase required for supercoiling of DNA.5"Resistance to these drugs has been reviewed byLewin;52 the main mechanism of resistance ismutation in the target enzyme, but Lewin raises thepossibility that plasmid-mediated resistance mayoccur in the future. He observed that clinicallyimportant resistance to the 4-quinolones is stillrelatively uncommon, though it is well known tooccur in Pseudomonas aeruginosa and instaphylococci. As cross-resistance occurs amongthe 4-quinolones, the development of resistance toone of the series prejudices the use of any of theothers against the resistant organism.

Recognized toxic reactions to the 4-quinolonesare mainly confined to skin rashes, but there havebeen occasional reports of neurological disturb-ances. Interference with cartilage developmentnoted in the joints of young dogs givenciprofloxacin has led to a reluctance to use thecompounds in pregnancy or for young children.

Table II The comparative in vitro activity of ciprofloxacin, norfloxacinand nalidixic acid

Organism (no. ofisolates) Antibiotics Range MIC50* MIC90*

Enterobacteriaceaet Ciprofloxacin 0.004-4 0.03 0.12(375) Norfloxacin 0.016-8 0.06 0.05

Nalidixic acid 1->512 4 64

Ps. aeruginosa (35) Ciprofloxacin 0.06-1 0.12 0.5Norfloxacin 0.25-4 0.5 2Nalidixic acid 64-> 512 64 > 512

N. gonorrhoeae (55) Ciprofloxacin 0.001-0.004 0.002 0.002Norfloxacin 0.008-0.03 0.016 0.016Nalidixic acid 0.5-2 1 2

Staph. aureus (30) Ciprofloxacin 0.12-2 0.25 0.5Norfloxacin 0.25-4 1 2Nalidixic acid 32-128 64 64

Enterococci (20) Ciprofloxacin 0.5-2 1 2Norfloxacin 2-4 4 8Nalidixic acid > 512 > 512 > 512

Str. pneumoniae (19) Ciprofloxacin 0.5-2 1 2Norfloxacin 4-16 8 16Nalidixic acid 128-> 512 > 512 > 512

*MIC (mg/i); tincludes E. coli, Klebsiella spp, Proteus spp, Serratia spp,Enterobacter spp. and Citrobacter spp.Data from King, Shannon & Phillips (1984).47

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Evidence to reassure us on this point isaccumulating and an authoritative assessmentwould be very helpful.

In addition to norfloxacin and ciprofloxacin, therange of 4-quinolones includes ofloxacin,pefloxacin, fleroxacin and enoxacin which havesimilar antibacterial activities and differentpharmacokinetics. More recent developments withimproved activity against Gram-positiveorganisms include WIN 57273,53 and with activityagainst anaerobes include WIN 57273, spar-floxacin5 and clinfloxacin (PD 127,391)."Sparfloxacin also appears to have improvedactivity against mycobacteria." Lomefloxacin hasa wide range of activity against Gram-negativebacteria including multiresistant strains andPseudomonas spp.5

New challenges and changes in concept and practice

Limitations of space oblige us to be selective in thisreview of our changing use of antibiotics.

Dosage strategy

Our standard teaching on the antibiotic manage-ment of an acute infection has been to give a fullcourse of an effective antimicrobial drug at anappropriate dosage. In some cases, there is a trendaway from this dogma. For example, it is standardpractice now to give a short sharp course of asuitable drug to treat an acute primary urinaryinfection. In general, however, the principle of'strong enough for long enough' still holds. Thedosage and duration oftherapy has been advocatedin some detail for special cases and circumstances.One of the disadvantages of the clinician'sawareness of the potential toxicity of drugs is thatsome antibiotics are given in sub-optimal dosage.This merits special attention with aminoglycosidetherapy in which peak and trough levels must bemonitored to ensure not only that toxic overdosageis avoided but that underdosage does not occur."

Prophylaxis and suppression ofinfection

We have become more permissive in our ap-proaches to the borderland of prophylaxis,suppression and treatment of infection. The anti-bacterial protection of patients at risk frombacterial endocarditis while undergoing dentaltreatment or other clinical procedures is very wellestablished, with clear guidelines.58 The suppres-sion ofinfection by the periodic or long-term use ofan antibacterial drug is accepted, with properclinical surveillance, in a range of conditions fromrecurrent cystitis in sexually active women59 to

potentially damaging pyelonephritis in youngchildren.'

Peroperative antimicrobialprophylaxis

The advantages of a short-term preventive ap-proach have been clearly evident in surgical prac-tice. Several bacterial challenges can be anticipatedin a range of surgical procedures such as maxillo-facial, abdominal or pelvic operations in whichthere is contamination with oropharyngeal, intes-tinal or vaginal flora. Antibiotic prophylaxis givenat induction of anaesthesia and covering the periodof the operation (hence peroperative) hassignificantly reduced morbidity and mortality inthese circumstances.6'-63 The issue of failedantibiotic prophylaxis is reviewed in a recenteditorial.6"

New infective challenges

In the last 2 decades we have become aware ofsomenew pathogens and we have recognized some oldenemies in changed circumstances. Thus, the rangeof organisms associated with atypical pneumoniaspresently includes a recognized group ofagents (seebelow) and others that may or may not be em-braced by the term, depending upon the narrow-ness or breadth of its interpretation, but the patientwith a pneumonia that does not present typicallywill have reason to thank the clinician who is notblinkered by the niceties of terminology.

Atypicalpneumonia

The term atypical pneumonia (originally aradiological description) is now usually used todescribe pulmonary consolidation of uncertainaetiology, or from which 'conventional' bacterio-logical cultures have failed to reveal an obviouspathogen. In recent years the main causes ofatypical pneumonia have been mycoplasmas,legionellae, chlamydiae and Coxiella burnetii.

Mycoplasmas can cause a variety of humaninfections but only M. pneumoniae causeg respir-atory infection. Respiratory infection with thisorganism is world-wide in distribution, occurringin late summer and autumn. It is thought that in theUSA M. pneumoniae infects about 6% of thepopulation annually.65 Epidemic peaks are wellrecognized. In general, the organism causes mildrespiratory-tract symptoms but more serious infec-tions can occur, especially in children, with patchyconsolidation that is sometimes bilateral. Symp-toms and X-ray changes may persist for severalweeks, with frequent relapses. Although the infec-tion is rarely fatal, respiratory impairment maypersist for some months, especially in adults.

Legionnaire's disease, first described in 1976,' is

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a serious form of pneumonia, usually caused byLegionella pneumophila. Those especially at riskinclude alcoholics, diabetics, smokers, patients onimmuno-suppressive therapy and those with pre-existing lung disease. The disease may progress toinvolve virtually every organ of the body andcarries an appreciable mortality. Although mostcases are sporadic, several well-described out-breaks have occurred in association with hot-watersystems, air-conditioning systems, cooling towersand other water systems. A study by Macfarlane etal.67 in the Nottingham area indicated that theorganism was responsible for up to 15% ofcases ofpneumonia, but a repeat study68 suggested that thefigure then was nearer 5%.The best recognized chlamydial infection is psit-

tacosis, caused by C. psittacii. Although classicallyassociated with parrots, the infection may beacquired from a wide variety of species ofbirds thathave included ducks and fulmar petrels. It is nowaccepted that most species of birds can excrete theorganisms.69 Infection is acquired by the respir-atory route and some strains are highly infectiousso that brief contact with an infected bird may besufficient to ensure infection. Person-to-personspread, although described, is rare. Psittacosis maypresent abruptly with fevers, rigors and headache.Although there are few respiratory signs or symp-toms, there is often radiological evidence of exten-sive pneumonitis. In severe cases, the infection mayinvolve the liver, central nervous system andmyocardium, with an appreciable mortality rate.

In recent years, another species of chlamydia, C.pneumoniae70 has been recognized as a cause ofrespiratory tract infection, usually presenting asbronchitis or pneumonia with similar clinicalfeatures to those caused by M. pneumoniae.Q fever, caused by Coxiella burnetii is a poten-

tially serious infection that can affect manydifferent systems, including the respiratory tract.Although many cases are self-limiting, in seriouscases the disease may affect a wide variety ofsystems including the lungs, with up to 50% havingradiological signs ofpneumonia. Chronic infectionis well recognized as a cause of 'culture-negative'endocarditis. The infection is spread by inhalationof aerosols from infected sheep, goats or cattle, orby ingestion of infected unpasteurized milk.Person-to-person spread is rare but laboratory-acquired infection is well recognized in workershandling infected material.

Treatment The atypical pneumonias do not re-spond to the normal antibiotics given for respir-atory tract infections (usually beta-lactams). Qfever responds to tetracyclines, notably oxytetra-cycline; rifampicin and trimethoprim may be usefulalternatives.7' Erythromycin is effective, as are thetetracyclines, against mycoplasmas and chlamydial

infections, while erythromycin is an effective drugagainst legionellae, supplemented by rifampicin insevere cases. The fluoroquinolones showed pro-mise of efficacy against mycoplasmas and legionel-lae but their activity has not so far been confirmedin clinical trials.

Gastro-intestinal and intestinal infections

These continue to include the well-known classicsof bacillary dysentery, salmonella food poisoningand an extending range of food-borne intoxica-tions and infections, typhoid fever and relatedenteric fevers, and giardiasis. The clinician has hadto contend with a widening spectrum fromrotavirus infections, all of the variations ofenteropathogenic Escherichia coli, yersiniosis andlisteriosis, to campylobacter gastroenteritis andcolitis, antibiotic-associated diarrhoea andpseudomembranous colitis, and the now estab-lished role of Helicobacter pylori in relation topeptic ulcer.When this review was written in 1991, antibiotics

had a limited role in the clinical management ofintestinal infections but some useful applicationsare recognized.

Metronidazole has earned its place in the therapyof entamoeba infections and giardiasis. Erythro-mycin can help in the management of campylo-bacter gastro-enteritis or colitis, but the indicationsfor its use are not yet clearly drawn; parenteralgentamicin may be used for severe septicaemiccases. Vancomycin is established as the preferredagent for therapy of pseudomembranous colitis,while metronidazole is generally regarded as asecond option.Chloramphenicol seems to retain its place as the

first choice for the treatment of the enteric fevers(typhoid and paratyphoid), though some typhoidbacilli are resistant and other factors merit con-sideration.24'72 Chloramphenicol's place ischallenged by amoxycillin or cotrimoxazole ortrimethoprim which may, in turn, be replaced byciprofloxacin or by one of the third or fourthgeneration cephalosporins if these latter drugsstand the test of time and comparative trials.Success has also been claimed for pivmecillinamand moxalactam. It is clear that a clinician withresponsibilities in this difficult field needs verycompetent microbiological support to advise onlocal patterns of resistance and to monitor excre-tion and carrier rates during and after therapy andrelapse rates.2472

Specific antibacterial treatment has not beengenerally recommended for other salmonella infec-tions or for shigella infections of the gut, but severeinvasive or toxic infections may demand specifictherapy. The choice of drug is very difficult becauseresistance is so common. With the development of

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the quinolones, notably ciprofloxacin, our ap-proaches to treatment merit reappraisal and per-haps modification. Note, however, that resistanceto the quinolones is already occurring.

Diarrhoeagenic strains of Escherichia coli thatproduce the vero cytotoxin (VTEC) are associatedwith haemorrhagic colitis and a haemolyticuraemic syndrome. The serogroup is commonly0157. The increasingly complex subject ofEscherichia coli diarrhoea has been most com-petently reviewed by Gross73 who points out thatrehydration ofthe patient must be the first priority.The antimicrobial treatment of cholera cannot

displace the life-saving priority of the activereplacement of fluid and electrolytes, but tetracy-cline 0.5 g given 6-hourly for 72 h reduces theexcretion of live vibrios and moderates the diarr-hoea. The spread of cholera can be moderated bygiving a daily dose of prophylactic tetracycline 1 gfor 5 days to family contacts at risk.74The occurrence of tetracycline resistance is com-

mon in areas where the drug has been widely usedto control cholera.

Helicobacter pylori predisposes to peptic ulcera-tion and may be controlled or eradicated by treat-ment with bismuth subcitrate or subsalicylate,amoxycillin and metronidazole singly or in acombined schedule.75

Travellers' diarrhoea This causes much anxietyand inconvenience.76 It is variously ascribed toinfection with campylobacters, enterotoxigenicEscherichia coli (ETEC),73 sometimes salmonellaeor shigellae, and sometimes various viruses includ-ing small round viruses and the Norwalk virus. Anassociation between Norwalk virus, water suppliesand cruise ships is noted in the textbooks. Thus, themicrobiology is complex and recommendations foractive prophylaxis range widely and sometimeswildly. Turnberg76 has summarized the presentsituation well.

It is difficult to come off the fence in suchcontested territory. At a recent symposium, anexperienced traveller and observer discussed therelative merits of a daily dose of doxycycline100 mg, or cotrimoxazole 960 mg, or norfloxacin400 mg for the prevention of travellers' diarrhoea.On balance, norfloxacin got his vote. Microbio-logical writers must add the caution that many mayregard this as the abuse ofan important drug, whilethey discreetly note the recommendation for theirprivate consideration.

Polymicrobial infections

The antibacterial approach to our therapy ofmanysoft-tissue infections ranging from dental abscessto pelvic inflammatory disease has been revolu-tionized by awareness that many ofthese infections

are polymicrobial and that some have a significantanaerobic element (see Table III).` Accordingly,metronidazole is now established as a necessarycomponent of the treatment of such infections inhospital and in general practice.43

Cerebral abscess

This provides an illustrative example ofa conditionthat may be a mixed infection with anaerobes andfacultative organisms.

In recent years, our evolving understanding ofthe infecting organisms involved in cerebral ab-scesses has allowed a more rational approach totherapy. De Louvois, Gortvai and Hurley78'79believed that cerebral abscesses of sinusitic originwere generally frontal and yielded penicillin-sensitive streptococci, notably S. milleri, whereasabscesses derived from an otitis media were usuallytemporal and polymicrobial with an anaerobiccomponent. Ingham, Selkon and Roxby80 agreedthat many cerebral abscesses are of otitic origin,with Bacteroides fragilis as the predominantanaerobe, but Ingham et al.8' went on to point outthat many frontal abscesses may be derived fromdental sepsis and would consequently involveanaerobes as well as facultative organisms. Thus,metronidazole gained an established place in theantimicrobial management ofcerebral abscess, and

Table III Conditions in which there is often a poly-microbial infection with a significant anaerobic com-

ponent

Cerebral abscessDental abscessPeriodontal diseaseHuman and animal bite woundsParonychiaAcute necrotizing ulcerative gingivitis (Vincent's infection)Cancrum orisOropharyngeal sepsis, including Ludwig's anginaPost-operative infection after maxillo-facial tumour surgeryChronic otitis mediaSome cases of sinusitisDermal gangreneNecrotizing fasciitisNecrobacillosis, including Lemierre's disease, Fournier's

gangrene, etc.Lung abscess, bronchiectasis and aspiration pneumoniaPost-operative peritonitis (and post-perforation

peritonitis, especially involving the large bowel)Peri-anal abscessPelvic abscessPelvic inflammatory diseaseVaginosisBalano-posthitisGas gangreneBedsoresFoot ulcers in patients with diabetes

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the benefit of this progressive step was quicklyevident.82'83

Acute bacterial meningitis

The specific antimicrobial treatment ofacute puru-lent meningitis varies with the causative organism,if it is known. Clinicians in the UK recognize thatthe league leaders are the meningococcus and Hae-mophilus influenzae and that the age of the patientmust be considered in assessing the possible infec-tive agent. Thus, neonatal meningitis is likely to becaused by Escherichia coli or a Group B streptococ-cus.

It is important to check the sensitivity of thestrain involved. As resistance to ampicillin is notuncommon in H. influenzae, chloramphenicol has aspecial role here. We watch with concern theoccurrence of chloramphenicol resistance in hae-mophilus bacteria in some countries. Penicillin orchloramphenicol are generally used for the treat-ment of meningococcal meningitis. Penicillin is thedrug of choice for the treatment of pneumococcalmeningitis. Penicillin-resistant pneumococci arewell known to occur in some parts of the world.Even when the strain is fully sensitive to penicillin,it is acknowledged that the results of treatment ofpneumococcal meningitis may be disappointing.The initial blind therapy for a patient with acute

purulent meningitis takes account of the likelycauses and may include chloramphenicol and peni-cillin. Some clinicians now favour the use ofcefotaxime or ceftriaxone. The subject is very wellreviewed by Ispahani.84

Prophylaxis ofcontacts ofacute bacterialmeningitis

Until the development of sulphonamide resistancein meningococci, the prophylaxis of close contactsofa case ofmeningococcal meningitis was straight-forward. As penicillin does not eliminate meningo-cocci from the nasopharynx, a short course ofrifampicin or minocycline was chosen to deal withthe carrier state. Minocycline has some disadvan-tages and rifampicin became established in thepreventive role.85

There are good reasons to regard ciprofloxacinas a preferred alternative, because rifampicin has somany other important uses and should be protect-ed. However, the people to be protected ofteninclude young children and there is some reluctanceto give ciprofloxacin to young children. The givingof a short course may well be justified, but there isno authoritative pronouncement to date.

Meanwhile, the concept of prophylaxis haschanged. An important difference has been recog-

nized between the early colonization that repre-sents an incipient infection ('co-primary infection')and the established carrier state.86 In the formersituation, a course of penicillin would abort theattack as it is being mounted. This action would bereasonable for the immediate protection of theclose contacts of a case of meningococcal menin-gitis and it is now established practice in Norway.In Britain, rifampicin is still the standard pro-phylactic in this context and (at different dosage)we are beginning to follow accepted US practice inregarding rifampicin as the recommended anti-biotic for the protection of close contacts ofHaemophilus influenzae meningitis.87

Chlamydial infections

Chlamydiae cause infections of the eye, the genitaltract and adnexa, and the respiratory tract. Asthese organisms also cause infections in animals,there may be an occupational link in some cases(e.g. farmers, veterinary workers, abattoir workers,owners of pets). Laboratory diagnosis has improv-ed in recent years. Therapeutic options have widen-ed to include erythromycin, tetracyclines, and thequinolones - although the early promise of thelatter has still to be realized. Newer quinolonederivatives may give better results, but erythro-mycin is the first-line choice and the tetracyclinesare close alternatives.

Pelvic inflammatory disease occurs in women asa result ofan ascending infection in the genital tractwith endometritis, salpingitis and salpingo-oopho-ritis. There is a strong association with sexualintercourse and it is thought that spermatozoa mayact as carriers that allow non-motile potentialpathogens to gain access to the upper genital tract.A mixed infection often occurs in which gonococcior chlamydiae (or both) may be present withaerobic or anaerobic organisms. The anaerobiccomponent often includes bacteroides organisms.Accordingly, treatment with a single antibiotic isunlikely to be effective. Careful investigation andcombination therapy are essential.

This subject was authoritatively reviewed byPearce88 who considered that treatment with paren-teral antibiotics should include a single dose ofampicillin and probenecid to control gonorrhoea; aI -week course ofgentamicin or a second generationcephalosporin to deal with coliform opportunists; a2-week course of metronidazole to eradicate anae-robes; and a 2-week follow-up course of doxycy-cline or erythromycin to eradicate chlamydiae. Wesympathize with the patient confronted with such aregimen, but we have to call attention to the manyfailures and all of the morbidity that have attendedless thorough approaches to the therapy of thisdistressing condition.

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Compromised hosts

The term is now used too loosely and our exper-ience of opportunistic infections in the last 10 yearsteaches us to be more specific and more discrimi-nating. It may be said that any infective pathogen isopportunistic, taking advantage of circumstancesand special sets of variables in the host-parasiterelationship to express aggression and virulence. Itis increasingly recognized that certain forms ofcompromise are associated with known ranges ofpotential infections. Thus, for example, foreignbodies and prostheses inserted into tissues may actas foci for infection with Gram-positive cocci,diphtheroid organisms or yeasts, whereas neutro-penic patients are at special risk of generalizedinfections with coliform organisms or cocci (seebelow).

Patients who have inadequate spleens (hypo-splenism) or who have lost their spleens as a resultof operative removal after injury or for therapeuticreasons, are vulnerable to overwhelming infectionwith pneumococci and some other pathogens thatinclude Pseudomonas aeruginosa and Capnocyto-phaga canimorsus.89 As functional hyposplenism isknown to occur in sickle-cell anaemia, coeliacdisease and bone-marrow transplant recipients,clinicians must be vigilant.The reader is referred to a succinct reminder of

the range of patients who may be chronicallyimmunodeficient as a result of diseases rangingfrom diabetes mellitus to AIDS.90The prevention of pneumococcal infections in

those at special risk rests primarily upon awarenessof the individual's susceptibility which must beclearly recorded. Pneumococcal vaccine affordssome protection, but not for young children agedless than 2 years. As the protection afforded lastsfor about 5 years, and as revaccination is notcurrently advised,91 it is difficult to make a clearrecommendation. The prompt prophylactic use ofamoxycillin for a patient in the risk group whodevelops signs of an infective illness is perhaps amore defined and positive approach.

Antibiotic coverfor transient neutropenia

In the last decade, the provision of antibiotic coverto protect a patient whose defences are temporarilysuppressed has become fairly standard practice.Opinions vary on the specific drugs used and theindications for their use.Most clinicians agree that a patient under treat-

ment for leukaemia with cytotoxic chemotherapy orirradiation should have the benefit ofantimicrobialdrugs to provide a bridge over the troubled watersoftheir vulnerability while their granulocyte countsare abnormally low.92 Currently favoured regimenstake account of the successive reports of the

European Organisation for Research on Treat-ment of Cancer (EORTC) Antimicrobial TherapyCooperative Group93'94 and the views of otherexperienced workers."'95'96 The use of mono-therapy in neutropenia is often enthusiasticallyadvocated, but the evidence suggests that theestablished drug combinations have advantagesagainst the continuing evolution of bacterial drugresistance.

Prevention ofinfection in patients in intensive careunits

The principle of a selective parenteral and enteralantisepsis regimen (SPEAR)97 is an extension of theconcept of selective decontamination of the gut(q.v.) to prevent superinfection in severely injuredpatients.9800 Promising claims are being made andthis approach merits further study and cautiousapplication, with special attention to the drugresistance profiles of the bacterial pathogensencountered.

Antibiotic-associated diarrhoea andpseudomembranous colitis

Adverse reactions to antibiotics include gastro-intestinal upsets and diarrhoea. Antibiotic-assoc-iated diarrhoea is quite common and is usuallyself-limiting, stopping when the course ofantibioticis completed. In some cases, severe diarrhoeanecessitates premature withdrawal of the provok-ing antibiotic. It has become increasingly recog-nized that some antibiotics are more likely thanothers to upset the normal bowel flora and torender the bowel more vulnerable to invasion andovergrowth by potential pathogens. The concept ofthe colonization resistance ofthe normal bowel as afunction of its normal flora was advanced by Vander Waaij and colleagues.'0' These workers advo-cate the classification of antibiotics into 3 groups:(1) those that markedly alter the bowel flora andsuppress colonization resistance, such as ampicillinand some other penicillin derivatives; (2) those thatare intermediate in this context, such as the amino-glycosides and some parenteral cephalosporins;and (3) those that are 'indifferent' and exert noeffect on colonization resistance, such as cephra-dine and cotrimoxazole.

Loss of colonization resistance and overgrowthwith other organisms is worrying, because poten-tial pathogens may be enriched and resistancetransfer may be encouraged within and between thenew populations of organisms. Clostridium difficileis one of special concern. If this organism isenriched in the bowel, it produces a range of toxinsand gives rise to pseudomembranous colitis whichis potentially fatal.'02 If C. difficile or its cytopathictoxin is identified in the stools of a patient with

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antibiotic-associated diarrhoea, this calls forimmediate cessation of the provoking antibiotictherapy and the administration of vancomycin tocontrol the condition. In some cases, despite vanco-mycin therapy, the condition recurs.

Line infections

The increasing use of implanted materials in medi-cine and surgery carries associated risks of infec-tion. Prosthetic joints carry a well-recognized riskof infection, often necessitating removal of theprosthesis.'03 Such infections are often due to'low-grade' pathogens and become apparent weeksafter the operation. Similarly, cardiac pacemakersmay be associated with localized infection, oftenstaphylococcal, that may interfere with theirproper functioning and require removal.One of the most important sources of infection

are vascular catheters, some ofwhich may be in situfor several weeks if the patient requires totalparenteral nutrition (TPN). There is good evidencethat infection is more likely if the catheters are inplace for long periods, if the patient is very youngor if the patient is immunocompromised. Theincreasing use of broad-spectrum antibiotics maypredispose to infection with resistant organisms.

It is well recognized that some infecting strainsform a slime that is deposited on the inside of thecatheter, providing a good nidus for infection.Infection is often due to Staph. epidermidis and isthought often to be derived from the skin flora.Blood cultures are frequently positive in thesepatients. In a recent review, the importance ofprevention of catheter-associated sepsis by carefulattention to aseptic procedure was stressed. Otherpreventive measures include intravenous heparintherapy, protection ofcatheterjunctions, attentionto details of procedure and tunnelling of catheters.Once established, catheter-associated infections

may require removal ofthe catheter (often this is allthat is required) or the use of a systemic antibioticsuch as vancomycin. Balakrishnan and colleaguespointed out'04 that these infections may haveimportant cost implications that include increasedstay in hospital (usually in Intensive Care Units)and the use of expensive antibiotics such as vanco-mycin.Organisms infecting catheters or other implant-

ed devices may grow as a biofilm and create a localmicroenvironment.'05 The features of the popula-tion may be different from those of singleorganisms, making them for example more resis-tant to antibiotics and, by production of exopoly-saccharide glycocalices, more resistant to hostdefence mechanisms. It has been suggested that theadherence of coagulase-negative staphylococci topolystyrene or rubber is influenced both by anti-

biotics and by the concentration of carbon dioxidein the environment.106

Mycobacterial infections

Notifications of tuberculosis have declined steadilyin the United Kingdom, especially since the intro-duction of effective chemotherapy. It is generallyaccepted that effective chemotherapy has prevent-ed the emergence of resistant strains of M. tuber-culosis. Thus, at present, most if not all strains ofmycobacterial infection in the United Kingdomrespond to the first line antimycobacterial drugs,for example, rifampicin, isoniazid, pyrazinamideand ethambutol. Sometimes, isoniazid-resistantstrains occur and we have recently described anoutbreak occurring in Glasgow.'07 Patients fromother countries in which chemotherapy of tuber-culosis is less effective may present in the UK withtuberculosis due to resistant organisms. Accord-ingly, it is unwise to assume that all strains of M.tuberculosis isolated in the UK are always fullysensitive. Sensitivity testing of all mycobacterialisolates is essential. Current recommendations forthe chemotherapy of tuberculosis are set out indetail in a recent paper.'08The present epidemic of HIV infection has been

associated with an increase in mycobacterial infec-tions and the observed increase in notificationsboth in England and Wales and in Scotland in 1989and 1990 may be due to this but it is likely that otherfactors are also responsible. Infection with M.tuberculosis is a feature ofthe relatively early stagesof HIV infection and, although tuberculosis maypresent abnormally in these patients (as a general-ized infection with fairly non-specific lung signs) itis amenable to treatment with standard therapy. Inthe later stages of the disease when the patient hasdeveloped AIDS, infections with other mycobact-eria, notably Mycobacterium avium, are a feature.These infections are often difficult to treat and mayprove to be terminal events. It is difficult to knowwhether such an infection is merely a marker of avery severely depleted immune system or whether itprecipitates further deterioration in immunity.There are no recognized protocols for treatingthese infections and individual clinicians usedifferent drug combinations that often includeamikacin, rifampicin (or rifabutin). Much workneeds to be done to establish the best treatment forthese mycobacterial infections.Many of the 4-quinolones possess antimycobac-

terial activity. Some of the more recent ones stillunder development, for example, sparfloxacin,show considerable promise.56 To date there havebeen no formal clinical trials, but studies are tocommence in some European countries in the nearfuture. Quinolone compounds may well prove to be

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a useful addition to the therapeutic armamen-tarium of anti-mycobacterial drugs.

Bacterial drug resistance

This problem is unrelenting. In the last decade, wehave seen penicillin resistance extending into a widerange of organisms that include Haemophilusinfluenzae and Neisseria gonorrhoeae. ' It has beenknown for years that genetic information endow-ing bacteria with antibiotic resistance can betransferred by various mechanisms that includetransduction by phage, and by conjugation whichhas some parallels with sexual forms of transmis-sion. The transfer of plasmids between relatedbacteria allows packets ofresistance information tobe exchanged, and the potential harm of plasmid-mediated resistance is well recognized. There arenow examples of exchanges of resistance inform-ation between coliform bacteria that cross taxono-mic boundaries and qualify for the description ofpromiscuous behaviour. These interlinked systemsaccount for the daunting speed of the transmissionof bacterial drug resistance information so thatresistant strains are encountered rapidly across theworld."0 This has been assisted by transposonswhich are small bits ofDNA that are able to jumpbetween plasmids in the same cell."' To add furtherto the complexity of the scenario, it is now becom-ing clear that a mechanism of genetic exchangeresembling transformation may account for theexchange of plasmid-borne information in coli-form bacteria, while conjugation systems mayoperate in Gram-positive bacteria that we pre-viously thought were unable to exchange DNA inthis way.We have had to extend our understanding of the

range of pathogens that readily acquire resis-tance."2 In recent years we have recognized thatMoraxella (Branhamella) catarrhalis is not merelya respiratory commensal but can be an importantrespiratory tract pathogen."3 M. catarrhalis isresistant to some of the antibiotics commonly usedfor the treatment of respiratory tract infection,especially ampicillin/amoxycillin, due to beta-lact-amase production. Over 70% ofclinical isolates arebeta-lactamase producing, in our experience at theCity Hospital Bacteriology Laboratory, Edinburgh.Another pathogen that may be resistant to

penicillins because of beta-lactamase production isHaemophilus influenzae. A recent revieweri5 indic-ated that 10% of non-capsulate and 25% of type bstrains from blood and CSF in the UK werebeta-lactamase positive. Some non-capsulate strainsresistant to ampicillin (MIC > 1 mg/l) are beta-lactamase negative, the mechanism of resistancebeing chromosomal in nature. Such strains areoften resistant to several beta-lactams.

The oral cephalosporins have only moderateactivity against H. influenzae, and 1-4% of strainsin the UK and Eire were reported to be resistant tochloramphenicol. "14, '5 Injectable cephalosporinssuch as cefotaxime, aztreonam, the penems or the4-quinolones are all suggested by Powell as usefuldrugs in the treatment of serious infections causedby ampicillin-resistant strains of H. influenzae.By 1988, bacterial strains resistant to third-

generation cephalosporins were being encounteredacross the world and many observers expressedalarm."6 As these drugs were increasingly used,various opportunist pathogens acquired resistanceand added significantly to the gene pool of resis-tance information. Bergogne-Berezin and Joly-Guillon'" drew special attention to acinetobacterorganisms and their potential danger in hospital.We were already aware of the problems posed byklebsiellae and enterobacters and many otheropportunists in this context. Reports from variouscountries provided strangely conflicting evidenceof bacterial drug resistance."16 It is essential todevelop better surveillance and reporting systems ifwe are to control or moderate the threat to all ofour antimicrobial drugs. The staphylococcus pro-vides a frightening illustrative example.

Methicillin-resistant Staph. aureus (MRSA)

The first reports of resistance to methicillin instaphylococci appeared soon after the introductionof the drug in 1959. Although sporadic outbreaksofinfection due to these organisms occurred, it wasnot until the 1980s that they posed significantproblems in the UK and elsewhere"8 in relation tohospital infection control.Some strains are more transmissible than others

('epidemic methicillin-resistant Staph. aureus'EMRSA)."19 Such strains often belong to a singlephage group although many are untypable bystandard phages. Most MRSA strains have aspecial ability to colonize skin and anterior naresand to spread from person to person, though theyare not more virulent than methicillin-sensitivestrains. The problems that they pose relate tocontrol of spread of infection and to treatment ofestablished infections, when methicillin andflucloxacillin are inactive.

Spread of infection has to be controlled orprevented by rigorous control of infectionmeasures such as those laid down by the JointWorking Party of the Hospital Infection Societyand British Society for AntimicrobialChemotherapy.'20 In addition, the development ofmupirocin (a pseudomonic acid) as a topicalspecific anti-staphylococcal agent has enabledefforts to be made to eradicate nasal and skincarriage by applying mupirocin ointment and

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mupirocin in a polyethylene glycol base respec-tively.

Treatment of established infections may be diffi-cult, as strains of MRSA are usually resistant togentamicin and chloramphenicol as well as tomethicillin and flucloxacillin. Many authoritiessuggest vancomycin, alone or in combination withrifampicin."8-'20 Newer agents such as teicoplanina glycopeptide antibiotic with similar activity to

vancomycin) and ciprofloxacin offer promise'2'though strains of MRSA that are resistant tociprofloxacin have been described and therapeuticfailures reported. It has become clear that thepresence of an implanted prosthesis or venous linemay provide a nidus for continuing infection andthat removal of the device may be necessary toeradicate the infection.

References

The basic armament1. Williams, J.D. Antimicrobial substances used in the treat-

ment of infections. In: Linton, A.H. & Dick, H.M. (eds)Topley & Wilson's Bacteriology, Virology and Immunity, 8thed, Vol.1, chapter 5. Edward Arnold, London, 1990,pp. 105-152.

2. Anonymous. Current practice: Today's drugs. Penicillins,Benzylpenicillin. Br Med J 1963, 1: 1137-1140.

3. Bush, K., Beta-lactamase inhibitors from laboratory toclinic. Clin Microb Rev 1988, 1: 109-123.

4. Kuk, N.A., Jacobus, N.V., Petersen, P.J. et al. Comparativein vitro and in vivo activities of piperacillin combined withbeta-lactamase inhibitors tazobactam, clavulanic acid andsulbactam. Antimicrob Agents Chemother 1989, 33:1964-1969.

5. Williams, J.D. The cephalosporin antibiotics. Drugs 1987,34 (Suppl 2): 1-258.

6. Rubinstein, E. & Isturiz, R. Aztreonam: the expandingclinical profile. Rev Infect Dis 1991, 13 (Suppl 7): S581 -S654.

7. Clissold, S.P., Todd, P.A. & Campoli-Richards, D.M.Imipenem/Cilastatin: A review of its antibacterial activity,pharmacokinetic properties and therapeutic efficacy. Drugs1987, 33: 183-241.

8. Davey, P., Davies, A., Livermore, D. & Speller, D. Mero-penem (SM 7338) - a new carbapenen. J Antimicrob Chemo-ther 1989, Suppl. A, 9-29.

9. Rolinson, G.L. Beta-lactam antibiotics. J AntimicrobChemother 1986, 17: 5-36.

10. Livermore, D.M. & Wood, M.J. Mechanisms and clinicalsignificance ofresistance to new beta-lactam antibiotics. Br JHosp Med 1990, 44: 252-263.

11. Davey, P. Clinical use of the aminoglycosides in the 1990s.Rev Med Microbiol 1991, 2: 22-30.

12. Mattie, H., Craig, W.A. & Pechere, J.C. Determinants ofefficacy and toxicity of aminoglycosides. J AntimicrobChemother 1989, 24: 281-293.

13. Lovering, A.M., Bywater, M.J., Holt, H.A. et al. Resistanceofbacterial pathogens to four aminoglycosides and six otherantibacterials and prevalence of aminoglycoside modifyingenzymes, in 20 UK centres. J Antimicrob Chemother 1988,22: 823-839.

14. European Study Group on Antibiotic Resistance. In-vitrosusceptibility to aminoglycoside antibiotics in blood andurine isolates consecutively collected in 29 European labora-tories. Eur J Clin Microbiol 1987, 6: 378-385.

15. Muscato, J.J., Wilbur, D.W., Stout, J.J. & Fahrlender, R.A.An evaluation of the susceptibility patterns of Gram-negative organisms isolated in cancer centres with amino-glycoside usage. In: Davey, P.G., Finch, R.G. & Wood, M.J.(eds) Once Daily Amikacin. J Antimicrob Chemother 1991,27 (Suppl. C): 1-7.

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