Postgrad Med J: first published as 10.1136/pgmj.68.795.6 on 1 January 1992. Downloaded from Postgrad Med J (1992) 68, 6 - 21 i) The Fellowship of Postgraduate Medicine, 1992

Reviews in Medicine Bacterial challenges and evolving antibacterial drug strategy 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 summarize bacterial infections obliges us to consider a variety developments ofimportance for practising hospital of new challenges, especially mycobacterial infec- clinicians and for primary care doctors who must tions. be aware of the ever-widening spectrum of recog- Our relative lack of success in dealing with some nized pathogens. This article is restricted to con- aggressive infections, such as those caused by the siderations ofpathogenic bacteria and antibacterial meningococcus or Haemophilus influenzae, has drugs that have obliged us to change our strategies called for a review of our prophylactic strategies, or policies in the last decade or so. There have been and this has been highlighted in the case of many confusing developments. Whilst basically pneumococcal challenges in compromised (as- new antibacterial drugs are rare, variations on plenic) patients. The common occurrence of previously successful models have been very polymicrobial or mixed bacterial infections has copyright. numerous and some significant progress has been been acknowledged, and the neglected concept of made. pathogenic synergy has been revived. The problems Over the decade, several new infective challenges of antibiotic-associated diarrhoea have necessitated have posed problems for clinicians and micro- scrutiny of precipitating antibiotics and studies of biologists. It is recognized that community- the most effective therapy. Meanwhile, the general acquired infections differ from hospital-acquired acceptance of the principle of peroperative anti- infections in the range and nature and antibiotic microbial prophylaxis and its application to resistance profiles of the causative organisms. The specific areas of operative surgery has had a major http://pmj.bmj.com/ inexorable progress ofbacterial drug resistance has impact. obliged us to reconsider first-choice therapy for some infections. Beta-lactamase production by various bacteria Changes in first-line choices has restricted our therapeutic options or has obliged us to use new preparations. For example, The sulphonamides have been largely superseded

our recognition of the pathogenic potential of by newer drugs in the last decade, though they are on September 30, 2021 by guest. Protected Moraxella (Branhamella) catarrhalis has required still used, often in conjunction with trimethoprim modification of previous approaches to the (as cotrimoxazole), in the treatment of uncompli- antibiotic therapy of respiratory tract infections, cated urinary tract infections. Resistance to sul- and beta-lactamase-producing strains of Haemo- phonamides is common and it is arguable that the philus influenzae have created further problems. use of the combination is now often irrational. Worrying outbreaks of a range of infections from Thus, trimethoprim has emerged as a single drug in legionellosis to salmonellosis have extended us to its own right, but its use too has often been determine or define appropriate therapy. Our evol- overtaken by the development of resistance. ving awareness of human immunodeficiency virus Nalidixic acid has been superseded by the develop- (HIV) disease and associated opportunistic ment of the more potent 4-quinolones, and nitro- furantoin is not favoured by many clinicians. Some ofthese drugs have special roles that maintain them in our formularies for the 1990s although they are not now in general daily use. The lincosamides, notably clindamycin, had Correspondence: B. Watt. M.D., F.R.C.Path. special virtues that endeared them to orthopaedic Postgrad Med J: first published as 10.1136/pgmj.68.795.6 on 1 January 1992. Downloaded from BACTERIAL CHALLENGES AND ANTIBACTERIAL DRUGS 7 surgeons and others who valued their efficacy beta-lactamases. These include: (1) ampicillin and against gram-positive cocci and anaerobes and amoxycillin (the amino penicillins); (2) carbenicil- their good penetration into bone. Clindamycin is lin and other carboxypenicillin analogues; (3) acyl still highly regarded as an alternative to penicillin ureido penicillins such as mezlocillin, azlocillin and when such an option is sought. Unfortunately, the piperacillin; and (4) amidino penicillins such as association with pseudomembranous colitis mecillinan. It is most important to note in practice (PMC) has understandably inhibited the general that none ofthe Group III penicillins is completely use of clindamycin. It should be noted that the stable to the beta-lactamases. volume of use of ampicillin ensures that ampicillin Group IV holds the only true penicillin that is features prominently in the PMC league table; our beta-lactamase stable, temocillin, but the activity experience in the last decade shows that no of this drug does not extend beyond the aerobic antibiotic is exempt. Nevertheless, the association Gram-negative bacteria. with the lincosamides is especially clear and is a justifiable (though not absolute) restraint. Beta-lactamase inhibitors As bacterial resistance The staphylococcus has sequentially challenged to beta-lactam antibiotics is largely attributable to all of the antibacterial drugs as they have been potent bacterial beta-lactamases, pharmaceutical developed and widely used, and has obliged us to companies sought to develop beta-lactam drugs keep our therapeutic options open. Thus, fusidic that are resistant to these enzymes (q.v.). Another acid (usually in combination with another drug) is strategy is to develop preparations in which a still useful. Strains of methicillin resistant sensitive beta-lactam drug is protected by a beta- Staphylococcus aureus (MRSA) have posed special lactamase inhibitor such as clavulanic acid or problems. Vancomycin retains a remarkable place sulbactam or tazobactam. in our attempts to control coagulase-negative These inhibitors have some antibacterial activity staphylococcal infections and MRSA infections in their own right, but their role in the combination (and pseudomembranous colitis caused by Clost- is to shield the more active drug. This has extended ridium difficile). It is worrying that our options in the usefulness ofdrugs such as amoxycillin against these difficult situations are so limited and that we beta-lactamase-producing staphylococci, coliform copyright. are so dependent on such a restricted number of organisms and anaerobes including Bacteroides active agents. fragilis. However, Pseudomonas aeruginosa has innate resistance to amoxycillin and this still holds. The combination of amoxycillin with clavulanic The basic armament acid (co-amoxiclav) is marketed in Britain as Augmentin; ticarcillin with clavulanic acid is Many antibacterial drugs have stood the test of Timentin; and ampicillin with sulbactam is sul- time, despite our abuse of them over the years. tamicillin.3 Tazobactam in combination with http://pmj.bmj.com/ Accordingly, the list of those regarded as first-line piperacillin is a useful development of this theme.4 choices for the 1990s does not differ significantly Meanwhile, the pharmaceutical industry was from the 1980 list. We now consider developments developing the cephalosporins as an alternative in antibacterial drug strategy and practice in the answer to the threat of the penicillinases. last decade in relation to changing aspects of infection. The following account reviews The cephalosporins and related drugs developments in the use of our main-line anti- bacterial drugs and draws attention to important These drugs can be classified into 4 groups that on September 30, 2021 by guest. Protected new applications. reflect an extending clinical requirement for a range of activity or specific efficacy.' The penicillins Group I drugs (examples cephaloridine, cepha- zolin) are highly active against Gram-negative Williams' recognized the following 4 groups of bacteria, notably staphylococci and streptococci. penicillins. Group lcephalosporins (examples cefamandole, Group I contains benzyl penicillin (penicillin G), cefuroxime) are effective against Gram-positive the original and still probably the best,2 and cocci and (Gram-negative) coliform organisms, but analogues such as the orally active phenoxymethyl not pseudomonas. penicillin (penicillin V). Group III drugs (examples cefotaxime, ceftazi- Group II contains the anti-staphylococcal dime) are active against Pseudomonas and related methicillin and the clinically useful orally active species, in addition to their activity against cloxacillin series. enterobacteria. Cefotaxime is less active than cef- Group III contains penicillins with activity tazidime against Pseudomonas aeruginosa. Cef- against Gram-negative bacilli (coliform organisms sulodin was developed specifically as an anti- and Haemophilus species etc.), but susceptible to pseudomonal cephalosporin. Postgrad Med J: first published as 10.1136/pgmj.68.795.6 on 1 January 1992. Downloaded from 8 B. WATT & J.G. COLLEE

Group IV contains the cephamycins (examples ant in the laboratory investigation ofa patient with cefoxitin, latamoxef, cefotetan) with broad- an undiagnosed infection that might be myco- spectrum efficacy that includes activity against bacterial, especially at the present time when anaerobic bacilli such as bacteroides organisms, opportunistic mycobacterial infections in compro- the clostridia, and anaerobic cocci. mised patients test our vigilance. As in the case of the penicillins, it should be Mattie et al.2 argued that the relative efficacy of noted that evolving bacterial resistance may limit different aminoglycosides should be properly the usefulness of the drugs in each of these groups. quantitated and should be related to relative toxi- city. Monobactams Aminoglycosides have been widely used for many years. Although resistance is a problem in Aztreonam is a monocyclic beta-lactam with re- specific areas, a recent survey in the UK'3 showed markably narrow-spectrum activity against that overall resistance rates amongst normally aerobic Gram-negative bacteria, notably the sensitive bacterial genera ranged from 2.4% for enterobacteria, the gonococcus and Haemophilus amikacin to 3.7% for gentamicin. For individual influenzae.6 genera, e.g. Serratia spp., resistance rates were higher. In general, the lowest resistance rates were Carbapenems seen for amikacin. An earlier European survey'4 had revealed gentamicin resistance rates as high as Imipenem has a remarkably broad spectrum of 30% in some countries. There is no doubt that activity against the enterobacteria, and Pseudo- increased usage ofa given aminoglycoside can lead monas aeruginosa, Haemophilus influenzae, to increased resistance to that aminoglycoside, but Bacteroides spp., staphylococci and streptococci.7 also to decreased resistance rates to other amino- Imipenem has to be given with cilastatin to inhibit glycosides. A recent study'5 showed that when the action of renal dehydropeptidase which inacti- amikacin was the main aminoglycoside used in vates the drug. Meropenem has equivalent activity cancer treatment centres in the USA, there was an and is resistant to the action of the renal enzyme.8 increase in resistance to amikacin but a decrease in copyright. For comparative data on the beta-lactam resistance to gentamicin and tobramycin. antibiotics, the reader is referred to Rolinson's Although the toxicity of the aminoglycosides for informed paper.9 An account of the mechanisms the middle ear and the kidney limits their use and and clinical significance of resistance to new beta- obliges the clinician to monitor peak and trough lactam antibiotics is given by Livermore and levels during therapy, these drugs are still favoured Wood.'1 by many clinicians for the therapy of serious infections. They are often used in combination with Aminoglycosides a pencillin and sometimes with to

metronidazole http://pmj.bmj.com/ extend the spectrum until the nature of the infec- These drugs are not absorbed after ingestion and tion is known. This is an area of current debate, as are normally injected, unless a local effect on an others prefer to base therapy in such circumstances intestinal pathogen or on the gut flora is desired. In on one of the broad-spectrum cephalosporins or the latter case, aminoglycosides are still used related drugs such as ceftazidime and to add in irrationally because they are not effective against other drugs as necessary.'6 anaerobic bacteria or streptococci, though they Spectinomycin has special usefulness in the treat- have a synergistic effect with penicillin when used in ment of gonococcal infections (1) in patients who on September 30, 2021 by guest. Protected combination parenterally against streptococci. are allergic to penicillin, or (2) in cases of infection Streptomycin now has only a limited place in the with penicillinase-producing strains.'7 management of tuberculous infections, and it has been largely replaced in the therapy ofother serious Tetracyclines infections by more recent members of the series such as gentamicin, tobramycin, netilmicin, and These drugs were active across a remarkably wide amikacin." With the exception of amikacin, these spectrum, but bacterial resistance and recognized later developments are not adequately effective adverse effects limit their use.'8 against the tubercle bacillus. They all have prompt The adverse effects of the tetracyclines are and highly useful activity against coliform bacteria mainly related to the gastro-intestinal tract and including pseudomonas, though resistance is a superinfection, and to the sequestering of the drug recurring problem if they are not used carefully. It in bone and teeth so that they are not given as a should be remembered that therapy with amino- routine during pregnancy or childhood. It was later glycosides may suppress the growth of myco- found that the anti-anabolic effect of tetracyclines bacteria in specimens submitted for culture to may precipitate or exacerbate renal failure in exclude a diagnosis of tuberculosis. This is import- patients with impaired renal function. Postgrad Med J: first published as 10.1136/pgmj.68.795.6 on 1 January 1992. Downloaded from BACTERIAL CHALLENGES AND ANTIBACTERIAL DRUGS 9

Chlortetracycline, oxytetracycline and tetra- accumulates in leucocytes and other phagocytes cycline are very similar in their action. Demethyl- and can suppress the multiplication ofintracellular chlortetracycline was introduced in 1957 as a legionellae.27 In a guinea-pig model oflegionellosis, long-acting variant. Doxycycline and minocycline erythromycin prevented death from the infection, were introduced more recently; they do not exacer- but only rifampicin could clear the pathogens from bate renal failure and, as they also have the the lungs and accelerate resolution.28 Malmborg29 advantage of longer half-lives and marginally bet- suggested that the 2 drugs are synergistic and ter activity, they are the currently preferred should be used in combination for the treatment of preparations. Dizziness and vertigo are listed serious legionella infections. among the adverse side effects of minocycline. Erythromycin has been shown to be active in Porphyria is a contraindication to the use of vitro against most strains of Campylobacter jejuni doxycycline. and to clear the organism rapidly from stools; it The tetracyclines retain rather a mixed range of does not influence the clinical outcome if given applications, having been displaced from so many more than 5 days after the onset of illness.30 first-line positions.'9 They have a major role in the Although erythromycin is a safe drug, it pro- treatment of infections caused by mycloplasmas duces gastro-intestinal side effects and is rather and chlamydiae. They have special roles in the variably absorbed from the gut. Since 1975, several management of some serious infections such as new macrolides have been developed (see Table I). brucellosis, actinomycosis and plague, often in Their comparative in vitro properties were reviewed combination with other antimicrobial drugs.20 Low- in 1988 by Hardy et al.3" dose prolonged administration of tetracyclines has In general, the activity of the 14-membered a record of some success in the treatment of acne macrolides equals or exceeds that oferythromycin, vulgaris, and more assured success in the treatment whereas the 1 5-membered azithromycin is less of acne rosacea. Tetracycline eye ointment is useful active against Gram-positive but more active in the treatment ofchlamydial infections ofthe eye. against Gram-negative bacteria. The 1 6-membered macrolides are less active than erythromycin.

Chloramphenicol Clarithromycin is the most active compound copyright. against Steptococcus pyogenes, pneumococci, This drug's very broad spectrum of activity2' has Listeria monocytogenes and Corynebacterium spp., been severely limited by its potential to cause and it shows promising activity against aplastic anaemia, even when used locally in eye Mycobacterium avium. Miocamycin, clarith- drops and eye ointment.22 Its use has also been romycin and rokitamycin are the most active limited by bacterial resistance which was especially compounds against L. pneomophila. Azithromycin evident with the staphylococci. The abuse of is the most active compound against Moraxella

chloramphenicol in developing countries in recent catarrhalis, Neisseria gonorrhoeae, and http://pmj.bmj.com/ years has received much deserved criticism but little Haemophilus influenzae. effective action.23 Bernstein, Roudier and Fleurette32 tested several Chloramphenicol retains its special role in the macrolides against Legionella spp. on charcoal-free treatment of typhoid and of Haemophilus media to avoid inactivation of antibiotics by char- influenzae meningitis and epiglottitis, but note that coal and found that the most active agents resistance in strains of Salmonella typhi24 and H. were josamycin (0.06-0,25 mg/1), pristinamycin influenzae is a problem in some countries. (0.06-0.5 mg/l) and erythromycin (0.12-0.5 mg/l). Chloramphenicol's favourable pharmacokinetics Clarithromycin is an acid-stable 14-membered on September 30, 2021 by guest. Protected earn it a place in the combined therapy of cerebral macrolide that achieves higher serum levels than abscess and in the blind treatment ofacute bacterial erythromycin and has twice the serum half-life.33 In meningitis (but see below). general, the MIC's for common respiratory pathogens are 2-4-fold less than those of eryth- Macrolides Table I New macrolides Erythromycin, the first of this group, has been widely used against Gram-positive organisms such 14-membered as pneumococci, streptococci and staphylococci, macrolides 15-membered 16-membered especially in penicillin-hypersensitive patients. Erythromycin Azithromycin Spiramycin Since 1975, erythromycin has been shown to be Clarithromycin Josamycin active against a number of 'new' pathogens. As it A-62671 Miocamycin penetrates well into cells,26 it is the drug ofchoice to Flurithromycin Rokitamycin treat chlamydial infections. It is very active against Roxithromycin Legionella pneumophila in vitro and is recom- mended for treatment of legionellosis as it From Hardy et al. (1988).3' Postgrad Med J: first published as 10.1136/pgmj.68.795.6 on 1 January 1992. Downloaded from 10 B. WATT & J.G. COLLEE romycin. Against Haemophilus influenzae the largely ineffective against aerobic or facultative MIC's of clarithyromycin are higher than those of anaerobic organisms. They have been used for erythromycin, yet clarithromycin is more active in years against Trichomonas vaginalis and against animal models. This may be explained by the recent Entamoeba histolytica and they now have another finding that the activity of clarithromycin against established role against a range of anaerobic H. influenzae appears to be enhanced by its major bacterial infections from periodontal infections metabolite, 14-hydroxy-clarithromycin. caused by bacteroides and fusobacterial organisms, to post-operative wound infections that have an Fusidic acid anaerobic component. It is increasingly recognized that many infections are polymicrobial, involving This steroid-like compound has clinically useful two or more pathogens, and that a component of activity against staphylococci. As any large these is often anaerobic. The concept ofpathogenic population of staphylococci is likely to contain synergy has been greatly advanced in recent years, mutants resistant to fusidic acid, the drug is usually and the inclusion of an anti-anaerobe drug in given along with a penicillin or some other therapeutic or prophylactic strategy has become antibiotic to suppress their emergence during accepted practice under various circumstances therapy.34 (q.v.). Metronidazole has clinically useful activity Rifamycins against all obligate anaerobes, including pathogenic clostridia, bacteroides, fusobacteria and Rifampicin, the original member of this class to be anaerobic cocci. Anaerobic fuso-spirochaetal used therapeutically, has for many years been the infections respond to metronidazole. The drug has cornerstone of multi-drug regimens for the treat- an assured place in peroperative antimicrobial ment of tuberculosis. More recently, it has been prophylactic regimens when anaerobic challenges used for the prophylaxis of meningococcal infec- are likely, as in abdominal and pelvic surgery. tion and treatment of carriers (but see later in this The drug's pharmacokinetic profile is good, with paper), and for the treatment of severe legionella effective concentrations achieved in most tissues infection in combination with erythromycin. It is and body fluids after oral, rectal or intravenous copyright. also of use for the prophylaxis of Haemophilus administration. The drug's half-life is about 8 h. It influenzae meningitis among those exposed to this penetrates tissue well and is active in the presence of infection (see Fleming).3" pus. Although the drug has been used widely, The increasing problem of mycobacterial infec- resistance has not been a problem;43 false evidence tions in acquired immunodeficiency syndrome of metronidazole resistance in anaerobes is some- (AIDS) patients, often with rifampicin-resistant times attributable to imperfect anaerobic technique species such as Mycobacterium avium, led to a in the laboratory and the growth of oxygen- search for more active rifamycin derivatives. tolerant isolates that are not sensitive. Some cam- http://pmj.bmj.com/ Dickinson and Mitchison36 reported that rifabutin pylobacter strains and some helicobacters are and rifapentine showed good in vitro activity sensitive to the nitroimidazoles, despite their against strains of the M. avium complex. Other microaerophilic nature, and this is also true for workers have shown rifabutin to be more active in Gardnerella vaginalis.4 At present, we do not vitro than rifampicin, especially against M. avium understand this. strains3738 and to show synergy with ethambutol Metronidazole is potentially irritant on intra- against some of them.39 However, it has been venous injection and may cause phlebitis. on September 30, 2021 by guest. Protected suggested that rifabutin does not have any advant- Neuropathy has been reported as a possible ages over rifampicin in practice.' Clinical trials of untoward effect after prolonged high dosage. the two compounds in this context are urgently Nausea and mild gastrointestinal upsets have been needed. noted as side effects, and skin rashes and So far, rifapentine is not available for clinical leucopenia are listed as rare adverse reactions. use. Other rifamycin derivatives have been syn- Patients must be warned to avoid alcohol when thesized4' and a preliminary report suggests that taking nitro-imidazole drugs. some may merit further study. Quinolones Metronidazole and other nitro-imidazole drugs (Tinidazole, Ornidazole, Nimorazole etc.) These synthetic compounds are derived from nalidixic acid which has been used as a urinary Metronidazole and other nitro-imidazole antimicrobial agent for many years. Nalidixic acid analogues have proved to be remarkably effective is given orally and achieves good levels in the urine anti-anaerobe drugs.42 Their action depends on a but low serum levels, so that its use is limited to the potent reducing step and they are consequently prophylaxis and treatment of urinary tract infec- Postgrad Med J: first published as 10.1136/pgmj.68.795.6 on 1 January 1992. Downloaded from BACTERIAL CHALLENGES AND ANTIBACTERIAL DRUGS 11 tions. Its spectrum of activity includes Gram- achieves good serum and tissue levels and can be negative urinary tract pathogens such as given by injection, it can be used for the treatment Escherichia coli and Proteus spp., but the drug has of systemic infections as well as gonorrhoea and poor or insignificant activity against staphylococci, urinary tract infections. enterococci and pseudomonas organisms. Norfloxacin has a similar spectrum of activity,50 Interest in the quinolones was revived with the but it is less potent and, as it achieves lower tissue development of 6-fluoro-7-piperazino-4-quino- levels, it is used predominantly as a urinary lones (commonly designated the 4-quinolones) that antimicrobial. have greatly enhanced potency, wider spectra of in The 4-quinolones act by inhibiting bacterial vitro activity and much better pharmacokinetics.45 DNA gyrase required for supercoiling of DNA.5" The range of4-quinolones continues to be extended. Resistance to these drugs has been reviewed by The first ofthe new quinolones to be marketed in Lewin;52 the main mechanism of resistance is the UK, though not the first to be developed, was mutation in the target enzyme, but Lewin raises the ciprofloxacin,46 a compound with extremely good possibility that plasmid-mediated resistance may activity against a wide range of Gram-negative occur in the future. He observed that clinically bacteria including Pseudomonas aeruginosa, Sal- important resistance to the 4-quinolones is still monella and Shigella spp. and many Gram-positive relatively uncommon, though it is well known to organisms including enterococci and staphylo- occur in Pseudomonas aeruginosa and in cocci.47 Its very good activity against neisseriae staphylococci. As cross-resistance occurs among (Table II), notably N. gonorrhoeae, has allowed it the 4-quinolones, the development of resistance to to be recommended as a single-dose treatment for one of the series prejudices the use of any of the gonorrhoea, including that due to penicillinase- others against the resistant organism. producing strains. It is less effective against strepto- Recognized toxic reactions to the 4-quinolones cocci, including Strept. pneumoniae, and it is not are mainly confined to skin rashes, but there have generally recommended for the treatment of strep- been occasional reports of neurological disturb- tococcal infections or pneumococcal pneumonia. ances. Interference with cartilage development some noted in young Ciprofloxacin also has useful activity against the joints of dogs given copyright. strains of mycobacteria,4 but its activity against ciprofloxacin has led to a reluctance to use the anaerobes is inconsistent.49 As ciprofloxacin compounds in pregnancy or for young children.

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

Organism (no. of http://pmj.bmj.com/ isolates) 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 0.5 Norfloxacin 0.25-4 0.5 2 64-> 64 > Nalidixic acid 512 512 on September 30, 2021 by guest. Protected N. gonorrhoeae (55) Ciprofloxacin 0.001-0.004 0.002 0.002 Norfloxacin 0.008-0.03 0.016 0.016 Nalidixic acid 0.5-2 1 2 Staph. aureus (30) Ciprofloxacin 0.12-2 0.25 0.5 Norfloxacin 0.25-4 1 2 Nalidixic acid 32-128 64 64 Enterococci (20) Ciprofloxacin 0.5-2 1 2 Norfloxacin 2-4 4 8 Nalidixic acid > 512 > 512 > 512 Str. pneumoniae (19) Ciprofloxacin 0.5-2 1 2 Norfloxacin 4-16 8 16 Nalidixic 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 Postgrad Med J: first published as 10.1136/pgmj.68.795.6 on 1 January 1992. Downloaded from 12 B. WATT & J.G. COLLEE

Evidence to reassure us on this point is potentially damaging pyelonephritis in young accumulating and an authoritative assessment children.' would be very helpful. In addition to norfloxacin and ciprofloxacin, the Peroperative antimicrobialprophylaxis range of 4-quinolones includes ofloxacin, pefloxacin, fleroxacin and enoxacin which have The advantages of a short-term preventive ap- similar antibacterial activities and different proach have been clearly evident in surgical prac- pharmacokinetics. More recent developments with tice. Several bacterial challenges can be anticipated improved activity against Gram-positive in a range of surgical procedures such as maxillo- organisms include WIN 57273,53 and with activity facial, abdominal or pelvic operations in which against anaerobes include WIN 57273, spar- there is contamination with oropharyngeal, intes- floxacin5 and clinfloxacin (PD 127,391)." tinal or vaginal flora. Antibiotic prophylaxis given Sparfloxacin also appears to have improved at induction ofanaesthesia and covering the period activity against mycobacteria." Lomefloxacin has of the operation (hence peroperative) has a wide range of activity against Gram-negative significantly reduced morbidity and mortality in bacteria including multiresistant strains and these circumstances.6'-63 The issue of failed Pseudomonas spp.5 antibiotic prophylaxis is reviewed in a recent editorial.6" New infective challenges New challenges and changes in concept and practice In the last 2 decades we have become aware ofsome Limitations ofspace oblige us to be selective in this new pathogens and we have recognized some old review of our changing use of antibiotics. enemies in changed circumstances. Thus, the range of organisms associated with atypical pneumonias Dosage strategy presently includes a recognized group ofagents (see below) and others that may or may not be em- Our standard teaching on the antibiotic manage- braced by the term, depending upon the narrow- copyright. ment of an acute infection has been to give a full ness or breadth ofits interpretation, but the patient course of an effective antimicrobial drug at an with a pneumonia that does not present typically appropriate dosage. In some cases, there is a trend will have reason to thank the clinician who is not away from this dogma. For example, it is standard blinkered by the niceties of terminology. practice now to give a short sharp course of a suitable drug to treat an acute primary urinary Atypicalpneumonia infection. In general, however, the principle of 'strong enough for long enough' still holds. The The term atypical pneumonia (originally a http://pmj.bmj.com/ dosage and duration oftherapy has been advocated radiological description) is now usually used to in some detail for special cases and circumstances. describe pulmonary consolidation of uncertain One of the disadvantages of the clinician's aetiology, or from which 'conventional' bacterio- awareness of the potential toxicity of drugs is that logical cultures have failed to reveal an obvious some antibiotics are given in sub-optimal dosage. pathogen. In recent years the main causes of This merits special attention with aminoglycoside atypical pneumonia have been mycoplasmas, therapy in which peak and trough levels must legionellae, be chlamydiae and Coxiella burnetii. on September 30, 2021 by guest. Protected monitored to ensure not only that toxic overdosage Mycoplasmas can cause a variety of human is avoided but that underdosage does not occur." infections but only M. pneumoniae causeg respir- atory infection. Respiratory infection with this Prophylaxis andsuppression ofinfection organism is world-wide in distribution, occurring in late summer and autumn. It is thought that in the We have become more permissive in our ap- USA M. pneumoniae infects about 6% of the proaches to the borderland of prophylaxis, population annually.65 Epidemic peaks are well suppression and treatment of infection. The anti- recognized. In general, the organism causes mild bacterial protection of patients at risk from respiratory-tract symptoms but more serious infec- bacterial endocarditis while undergoing dental tions can occur, especially in children, with patchy treatment or other clinical procedures is very well consolidation that is sometimes bilateral. Symp- established, with clear guidelines.58 The suppres- toms and X-ray changes may persist for several sion ofinfection by the periodic or long-term use of weeks, with frequent relapses. Although the infec- an antibacterial drug is accepted, with proper tion is rarely fatal, respiratory impairment may clinical surveillance, in a range of conditions from persist for some months, especially in adults. recurrent cystitis in sexually active women59 to Legionnaire's disease, first described in 1976,' is Postgrad Med J: first published as 10.1136/pgmj.68.795.6 on 1 January 1992. Downloaded from BACTERIAL CHALLENGES AND ANTIBACTERIAL DRUGS 13 a serious form of pneumonia, usually caused by infections, while erythromycin is an effective drug Legionella pneumophila. Those especially at risk against legionellae, supplemented by rifampicin in include alcoholics, diabetics, smokers, patients on severe cases. The fluoroquinolones showed pro- immuno-suppressive therapy and those with pre- mise ofefficacy against mycoplasmas and legionel- existing lung disease. The disease may progress to lae but their activity has not so far been confirmed involve virtually every organ of the body and in clinical trials. carries an appreciable mortality. Although most cases are sporadic, several well-described out- Gastro-intestinal and intestinal infections breaks have occurred in association with hot-water systems, air-conditioning systems, cooling towers These continue to include the well-known classics and other water systems. A study by Macfarlane et of bacillary dysentery, salmonella food poisoning al.67 in the Nottingham area indicated that the and an extending range of food-borne intoxica- organism was responsible for up to 15% ofcases of tions and infections, typhoid fever and related pneumonia, but a repeat study68 suggested that the enteric fevers, and giardiasis. The clinician has had figure then was nearer 5%. to contend with a widening spectrum from The best recognized chlamydial infection is psit- rotavirus infections, all of the variations of tacosis, caused by C. psittacii. Although classically enteropathogenic Escherichia coli, yersiniosis and associated with parrots, the infection may be listeriosis, to campylobacter gastroenteritis and acquired from a wide variety ofspecies ofbirds that colitis, antibiotic-associated diarrhoea and have included ducks and fulmar petrels. It is now pseudomembranous colitis, and the now estab- accepted that most species of birds can excrete the lished role of Helicobacter pylori in relation to organisms.69 Infection is acquired by the respir- peptic ulcer. atory route and some strains are highly infectious When this review was written in 1991, antibiotics so that brief contact with an infected bird may be had a limited role in the clinical management of sufficient to ensure infection. Person-to-person intestinal infections but some useful applications spread, although described, is rare. Psittacosis may are recognized. present abruptly with fevers, rigors and headache. Metronidazole has earned its place in the therapy copyright. Although there are few respiratory signs or symp- of entamoeba infections and giardiasis. Erythro- toms, there is often radiological evidence of exten- mycin can help in the management of campylo- sive pneumonitis. In severe cases, the infection may bacter gastro-enteritis or colitis, but the indications involve the liver, central nervous system and for its use are not yet clearly drawn; parenteral myocardium, with an appreciable mortality rate. gentamicin may be used for severe septicaemic In recent years, another species ofchlamydia, C. cases. Vancomycin is established as the preferred pneumoniae70 has been recognized as a cause of agent for therapy of pseudomembranous colitis, respiratory tract infection, usually presenting as while metronidazole is generally regarded as a http://pmj.bmj.com/ bronchitis or pneumonia with similar clinical second option. features to those caused by M. pneumoniae. Chloramphenicol seems to retain its place as the Q fever, caused by Coxiella burnetii is a poten- first choice for the treatment of the enteric fevers tially serious infection that can affect many (typhoid and paratyphoid), though some typhoid different systems, including the respiratory tract. bacilli are resistant and other factors merit con- Although many cases are self-limiting, in serious sideration.24'72 Chloramphenicol's place is cases the disease may affect a wide variety of challenged by amoxycillin or cotrimoxazole or systems including the lungs, with up to 50% having trimethoprim which may, in turn, be replaced by on September 30, 2021 by guest. Protected radiological signs ofpneumonia. Chronic infection ciprofloxacin or by one of the third or fourth is well recognized as a cause of 'culture-negative' generation cephalosporins if these latter drugs endocarditis. The infection is spread by inhalation stand the test of time and comparative trials. of aerosols from infected sheep, goats or cattle, or Success has also been claimed for pivmecillinam by ingestion of infected unpasteurized milk. and moxalactam. It is clear that a clinician with Person-to-person spread is rare but laboratory- responsibilities in this difficult field needs very acquired infection is well recognized in workers competent microbiological support to advise on handling infected material. local patterns of resistance and to monitor excre- tion and carrier rates during and after therapy and Treatment The atypical pneumonias do not re- relapse rates.2472 spond to the normal antibiotics given for respir- Specific antibacterial treatment has not been atory tract infections (usually beta-lactams). Q generally recommended for other salmonella infec- fever responds to tetracyclines, notably oxytetra- tions or for shigella infections ofthe gut, but severe cycline; rifampicin and trimethoprim may be useful invasive or toxic infections may demand specific alternatives.7' Erythromycin is effective, as are the therapy. The choice ofdrug is very difficult because tetracyclines, against mycoplasmas and chlamydial resistance is so common. With the development of Postgrad Med J: first published as 10.1136/pgmj.68.795.6 on 1 January 1992. Downloaded from 14 B. WATT & J.G. COLLEE the quinolones, notably ciprofloxacin, our ap- are polymicrobial and that some have a significant proaches to treatment merit reappraisal and per- anaerobic element (see Table III).` Accordingly, haps modification. Note, however, that resistance metronidazole is now established as a necessary to the quinolones is already occurring. component of the treatment of such infections in Diarrhoeagenic strains of Escherichia coli that hospital and in general practice.43 produce the vero cytotoxin (VTEC) are associated with haemorrhagic colitis and a haemolytic Cerebral abscess uraemic syndrome. The serogroup is commonly 0157. The increasingly complex subject of This provides an illustrative example ofa condition Escherichia coli diarrhoea has been most com- that may be a mixed infection with anaerobes and petently reviewed by Gross73 who points out that facultative organisms. rehydration ofthe patient must be the first priority. In recent years, our evolving understanding of The antimicrobial treatment of cholera cannot the infecting organisms involved in cerebral ab- displace the life-saving priority of the active scesses has allowed a more rational approach to replacement of fluid and electrolytes, but tetracy- therapy. De Louvois, Gortvai and Hurley78'79 cline 0.5 g given 6-hourly for 72 h reduces the believed that cerebral abscesses of sinusitic origin excretion of live vibrios and moderates the diarr- were generally frontal and yielded penicillin- hoea. The spread of cholera can be moderated by sensitive streptococci, notably S. milleri, whereas giving a daily dose of prophylactic tetracycline 1 g abscesses derived from an otitis media were usually for 5 days to family contacts at risk.74 temporal and polymicrobial with an anaerobic The occurrence oftetracycline resistance is com- component. Ingham, Selkon and Roxby80 agreed mon in areas where the drug has been widely used that many cerebral abscesses are of otitic origin, to control cholera. with Bacteroides fragilis as the predominant Helicobacter pylori predisposes to peptic ulcera- anaerobe, but Ingham et al.8' went on to point out tion and may be controlled or eradicated by treat- that many frontal abscesses may be derived from ment with bismuth subcitrate or subsalicylate, dental sepsis and would consequently involve amoxycillin and metronidazole singly or in a anaerobes as well as facultative organisms. Thus,copyright. combined schedule.75 metronidazole gained an established place in the antimicrobial management ofcerebral abscess, and Travellers' diarrhoea This causes much anxiety and inconvenience.76 It is variously ascribed to infection with campylobacters, enterotoxigenic Table III Conditions in which there is often a poly- Escherichia coli (ETEC),73 sometimes salmonellae microbial infection with a significant anaerobic com- or shigellae, and sometimes various viruses includ- ponent small round An ing viruses and the Norwalk virus. http://pmj.bmj.com/ association between Norwalk virus, water supplies Cerebral abscess and cruise ships is noted in the textbooks. Thus, the Dental abscess is and Periodontal disease microbiology complex recommendations for Human and animal bite wounds active prophylaxis range widely and sometimes Paronychia wildly. Turnberg76 has summarized the present Acute necrotizing ulcerative gingivitis (Vincent's infection) situation well. Cancrum oris It is difficult to come off the fence in such Oropharyngeal sepsis, including Ludwig's angina contested territory. At a recent symposium, an Post-operative infection after maxillo-facial tumour surgery on September 30, 2021 by guest. Protected experienced traveller and observer discussed the Chronic otitis media relative merits of a daily dose of doxycycline Some cases of sinusitis 100 mg, or cotrimoxazole 960 mg, or norfloxacin Dermal gangrene 400 mg for the of travellers' Necrotizing fasciitis prevention diarrhoea. Necrobacillosis, including Lemierre's disease, Fournier's On balance, norfloxacin got his vote. Microbio- gangrene, etc. logical writers must add the caution that many may Lung abscess, bronchiectasis and aspiration pneumonia regard this as the abuse ofan important drug, while Post-operative peritonitis (and post-perforation they discreetly note the recommendation for their peritonitis, especially involving the large bowel) private consideration. Peri-anal abscess Pelvic abscess Polymicrobial infections Pelvic inflammatory disease Vaginosis The antibacterial to our many Balano-posthitis approach therapy of Gas gangrene soft-tissue infections ranging from dental abscess Bedsores to pelvic inflammatory disease has been revolu- Foot ulcers in patients with diabetes tionized by awareness that many ofthese infections Postgrad Med J: first published as 10.1136/pgmj.68.795.6 on 1 January 1992. Downloaded from BACTERIAL CHALLENGES AND ANTIBACTERIAL DRUGS 15 the benefit of this progressive step was quickly nized between the early colonization that repre- evident.82'83 sents an incipient infection ('co-primary infection') and the established carrier state.86 In the former situation, a course of penicillin would abort the Acute bacterial meningitis attack as it is being mounted. This action would be reasonable for the immediate protection of the The specific antimicrobial treatment ofacute puru- close contacts of a case of meningococcal menin- lent meningitis varies with the causative organism, gitis and it is now established practice in Norway. if it is known. Clinicians in the UK recognize that In Britain, rifampicin is still the standard pro- the league leaders are the meningococcus and Hae- phylactic in this context and (at different dosage) mophilus influenzae and that the age of the patient we are beginning to follow accepted US practice in must be considered in assessing the possible infec- regarding rifampicin as the recommended anti- tive agent. Thus, neonatal meningitis is likely to be biotic for the protection of close contacts of caused by Escherichia coli or a Group B streptococ- Haemophilus influenzae meningitis.87 cus. It is important to check the sensitivity of the strain involved. As resistance to ampicillin is not Chlamydial infections uncommon in H. influenzae, chloramphenicol has a special role here. We watch with concern the Chlamydiae cause infections of the eye, the genital occurrence of chloramphenicol resistance in hae- tract and adnexa, and the respiratory tract. As mophilus bacteria in some countries. Penicillin or these organisms also cause infections in animals, chloramphenicol are generally used for the treat- there may be an occupational link in some cases ment of meningococcal meningitis. Penicillin is the (e.g. farmers, veterinary workers, abattoir workers, drug of choice for the treatment of pneumococcal owners ofpets). Laboratory diagnosis has improv- meningitis. Penicillin-resistant pneumococci are ed in recent years. Therapeutic options have widen- well known to occur in some parts of the world. ed to include erythromycin, tetracyclines, and the

Even when the strain is fully sensitive to penicillin, quinolones - although the early promise of the copyright. it is acknowledged that the results of treatment of latter has still to be realized. Newer quinolone pneumococcal meningitis may be disappointing. derivatives may give better results, but erythro- The initial blind therapy for a patient with acute mycin is the first-line choice and the tetracyclines purulent meningitis takes account of the likely are close alternatives. causes and may include chloramphenicol and peni- Pelvic inflammatory disease occurs in women as cillin. Some clinicians now favour the use of a result ofan ascending infection in the genital tract cefotaxime or ceftriaxone. The subject is very well with endometritis, salpingitis and salpingo-oopho- reviewed by Ispahani.84 ritis. There is a strong association with sexual http://pmj.bmj.com/ intercourse and it is thought that spermatozoa may act as carriers that allow non-motile potential Prophylaxis ofcontacts ofacute bacterial pathogens to gain access to the upper genital tract. meningitis A mixed infection often occurs in which gonococci or chlamydiae (or both) may be present with Until the development of sulphonamide resistance aerobic or anaerobic organisms. The anaerobic in meningococci, the prophylaxis of close contacts component often includes bacteroides organisms. ofa case ofmeningococcal meningitis was straight- Accordingly, treatment with a single antibiotic is on September 30, 2021 by guest. Protected forward. As penicillin does not eliminate meningo- unlikely to be effective. Careful investigation and cocci from the nasopharynx, a short course of combination therapy are essential. rifampicin or minocycline was chosen to deal with This subject was authoritatively reviewed by the carrier state. Minocycline has some disadvan- Pearce88 who considered that treatment with paren- tages and rifampicin became established in the teral antibiotics should include a single dose of preventive role.85 ampicillin and probenecid to control gonorrhoea; a There are good reasons to regard ciprofloxacin I-week course ofgentamicin or a second generation as a preferred alternative, because rifampicin has so cephalosporin to deal with coliform opportunists; a many other important uses and should be protect- 2-week course of metronidazole to eradicate anae- ed. However, the people to be protected often robes; and a 2-week follow-up course of doxycy- include young children and there is some reluctance cline or erythromycin to eradicate chlamydiae. We to give ciprofloxacin to young children. The giving sympathize with the patient confronted with such a of a short course may well be justified, but there is regimen, but we have to call attention to the many no authoritative pronouncement to date. failures and all ofthe morbidity that have attended Meanwhile, the concept of prophylaxis has less thorough approaches to the therapy of this changed. An important difference has been recog- distressing condition. Postgrad Med J: first published as 10.1136/pgmj.68.795.6 on 1 January 1992. Downloaded from 16 B. WATT & J.G. COLLEE

Compromised hosts European Organisation for Research on Treat- ment of Cancer (EORTC) Antimicrobial Therapy The term is now used too loosely and our exper- Cooperative Group93'94 and the views of other ience ofopportunistic infections in the last 10 years experienced workers."'95'96 The use of mono- teaches us to be more specific and more discrimi- therapy in neutropenia is often enthusiastically nating. It may be said that any infective pathogen is advocated, but the evidence suggests that the opportunistic, taking advantage of circumstances established drug combinations have advantages and special sets of variables in the host-parasite against the continuing evolution of bacterial drug relationship to express aggression and virulence. It resistance. is increasingly recognized that certain forms of compromise are associated with known ranges of Prevention ofinfection in patients in intensive care potential infections. Thus, for example, foreign units bodies and prostheses inserted into tissues may act as foci for infection with Gram-positive cocci, The principle of a selective parenteral and enteral diphtheroid organisms or yeasts, whereas neutro- antisepsis regimen (SPEAR)97 is an extension ofthe penic patients are at special risk of generalized concept of selective decontamination of the gut infections with coliform organisms or cocci (see (q.v.) to prevent superinfection in severely injured below). patients.9800 Promising claims are being made and Patients who have inadequate spleens (hypo- this approach merits further study and cautious splenism) or who have lost their spleens as a result application, with special attention to the drug ofoperative removal after injury or for therapeutic resistance profiles of the bacterial pathogens reasons, are vulnerable to overwhelming infection encountered. with pneumococci and some other pathogens that include Pseudomonas aeruginosa and Capnocyto- Antibiotic-associated diarrhoea and phaga canimorsus.89 As functional hyposplenism is pseudomembranous colitis known to occur in sickle-cell anaemia, coeliac

disease and bone-marrow transplant recipients, Adverse reactions to antibiotics include gastro-copyright. clinicians must be vigilant. intestinal upsets and diarrhoea. Antibiotic-assoc- The reader is referred to a succinct reminder of iated diarrhoea is quite common and is usually the range of patients who may be chronically self-limiting, stopping when the course ofantibiotic immunodeficient as a result of diseases ranging is completed. In some cases, severe diarrhoea from diabetes mellitus to AIDS.90 necessitates premature withdrawal of the provok- The prevention of pneumococcal infections in ing antibiotic. It has become increasingly recog- those at special risk rests primarily upon awareness nized that some antibiotics are more likely than of the individual's which must be susceptibility others to upset the normal bowel flora and to http://pmj.bmj.com/ clearly recorded. Pneumococcal vaccine affords render the bowel more vulnerable to invasion and some protection, but not for young children aged overgrowth by potential pathogens. The concept of less than 2 years. As the protection afforded lasts the colonization resistance ofthe normal bowel as a for about 5 years, and as revaccination is not function of its normal flora was advanced by Van currently advised,91 it is difficult to make a clear der Waaij and colleagues.'0' These workers advo- recommendation. The prompt prophylactic use of cate the classification of antibiotics into 3 groups: amoxycillin for a patient in the risk group who (1) those that markedly alter the bowel flora and develops signs of an infective illness is perhaps a suppress colonization resistance, such as ampicillin on September 30, 2021 by guest. Protected more defined and positive approach. and some other penicillin derivatives; (2) those that are intermediate in this context, such as the amino- Antibiotic coverfor transient neutropenia glycosides and some parenteral cephalosporins; and (3) those that are 'indifferent' and exert no In the last decade, the provision of antibiotic cover effect on colonization resistance, such as cephra- to protect a patient whose defences are temporarily dine and cotrimoxazole. suppressed has become fairly standard practice. Loss of colonization resistance and overgrowth Opinions vary on the specific drugs used and the with other organisms is worrying, because poten- indications for their use. tial pathogens may be enriched and resistance Most clinicians agree that a patient under treat- transfer may be encouraged within and between the ment for leukaemia with cytotoxic chemotherapy or new populations of organisms. Clostridium difficile irradiation should have the benefit ofantimicrobial is one of special concern. If this organism is drugs to provide a bridge over the troubled waters enriched in the bowel, it produces a range of toxins oftheir vulnerability while their granulocyte counts and gives rise to pseudomembranous colitis which are abnormally low.92 Currently favoured regimens is potentially fatal.'02 If C. difficile or its cytopathic take account of the successive reports of the toxin is identified in the stools of a patient with Postgrad Med J: first published as 10.1136/pgmj.68.795.6 on 1 January 1992. Downloaded from BACTERIAL CHALLENGES AND ANTIBACTERIAL DRUGS 17 antibiotic-associated diarrhoea, this calls for biotics and by the concentration of carbon dioxide immediate cessation of the provoking antibiotic in the environment.106 therapy and the administration of vancomycin to control the condition. In some cases, despite vanco- mycin therapy, the condition recurs. Mycobacterial infections Notifications oftuberculosis have declined steadily Line infections in the United Kingdom, especially since the intro- duction of effective chemotherapy. It is generally The increasing use of implanted materials in medi- accepted that effective chemotherapy has prevent- cine and surgery carries associated risks of infec- ed the emergence of resistant strains of M. tuber- tion. Prosthetic joints carry a well-recognized risk culosis. Thus, at present, most if not all strains of of infection, often necessitating removal of the mycobacterial infection in the United Kingdom prosthesis.'03 Such infections are often due to respond to the first line antimycobacterial drugs, 'low-grade' pathogens and become apparent weeks for example, rifampicin, isoniazid, pyrazinamide after the operation. Similarly, cardiac pacemakers and ethambutol. Sometimes, isoniazid-resistant may be associated with localized infection, often strains occur and we have recently described an staphylococcal, that may interfere with their outbreak occurring in Glasgow.'07 Patients from proper functioning and require removal. other countries in which chemotherapy of tuber- One of the most important sources of infection culosis is less effective may present in the UK with are vascular catheters, some ofwhich may be in situ tuberculosis due to resistant organisms. Accord- for several weeks if the patient requires total ingly, it is unwise to assume that all strains of M. parenteral nutrition (TPN). There is good evidence tuberculosis isolated in the UK are always fully that infection is more likely if the catheters are in sensitive. Sensitivity testing of all mycobacterial place for long periods, if the patient is very young isolates is essential. Current recommendations for or if the patient is immunocompromised. The the chemotherapy of tuberculosis are set out in increasing use of broad-spectrum antibiotics may detail in a recent paper.'08 predispose to infection with resistant organisms. The present epidemic of HIV infection has been copyright. It is well recognized that some infecting strains associated with an increase in mycobacterial infec- form a slime that is deposited on the inside of the tions and the observed increase in notifications catheter, providing a good nidus for infection. both in England and Wales and in Scotland in 1989 Infection is often due to Staph. epidermidis and is and 1990 may be due to this but it is likely that other thought often to be derived from the skin flora. factors are also responsible. Infection with M. Blood cultures are frequently positive in these tuberculosis is a feature ofthe relatively early stages patients. In a recent review, the importance of of HIV infection and, although tuberculosis may prevention of catheter-associated sepsis by careful present abnormally in these patients (as a general- http://pmj.bmj.com/ attention to aseptic procedure was stressed. Other ized infection with fairly non-specific lung signs) it preventive measures include intravenous heparin is amenable to treatment with standard therapy. In therapy, protection ofcatheterjunctions, attention the later stages of the disease when the patient has to details ofprocedure and tunnelling of catheters. developed AIDS, infections with other mycobact- Once established, catheter-associated infections eria, notably Mycobacterium avium, are a feature. may require removal ofthe catheter (often this is all These infections are often difficult to treat and may that is required) or the use of a systemic antibiotic prove to be terminal events. It is difficult to know on September 30, 2021 by guest. Protected such as vancomycin. Balakrishnan and colleagues whether such an infection is merely a marker of a pointed out'04 that these infections may have very severely depleted immune system or whether it important cost implications that include increased precipitates further deterioration in immunity. stay in hospital (usually in Intensive Care Units) There are no recognized protocols for treating and the use of expensive antibiotics such as vanco- these infections and individual clinicians use mycin. different drug combinations that often include Organisms infecting catheters or other implant- amikacin, rifampicin (or rifabutin). Much work ed devices may grow as a biofilm and create a local needs to be done to establish the best treatment for microenvironment.'05 The features of the popula- these mycobacterial infections. tion may be different from those of single Many of the 4-quinolones possess antimycobac- organisms, making them for example more resis- terial activity. Some of the more recent ones still tant to antibiotics and, by production of exopoly- under development, for example, sparfloxacin, saccharide glycocalices, more resistant to host show considerable promise.56 To date there have defence mechanisms. It has been suggested that the been no formal clinical trials, but studies are to adherence of coagulase-negative staphylococci to commence in some European countries in the near polystyrene or rubber is influenced both by anti- future. Quinolone compounds may well prove to be Postgrad Med J: first published as 10.1136/pgmj.68.795.6 on 1 January 1992. Downloaded from 18 B. WATT & J.G. COLLEE a useful addition to the therapeutic armamen- The oral cephalosporins have only moderate tarium of anti-mycobacterial drugs. activity against H. influenzae, and 1-4% of strains in the UK and Eire were reported to be resistant to chloramphenicol. "14, '5 Injectable cephalosporins Bacterial drug resistance such as cefotaxime, aztreonam, the penems or the 4-quinolones are all suggested by Powell as useful This problem is unrelenting. In the last decade, we drugs in the treatment of serious infections caused have seen penicillin resistance extending into a wide by ampicillin-resistant strains of H. influenzae. range of organisms that include Haemophilus By 1988, bacterial strains resistant to third- influenzae and Neisseria gonorrhoeae. ' It has been generation cephalosporins were being encountered known for years that genetic information endow- across the world and many observers expressed ing bacteria with antibiotic resistance can be alarm."6 As these drugs were increasingly used, transferred by various mechanisms that include various opportunist pathogens acquired resistance transduction by phage, and by conjugation which and added significantly to the gene pool of resis- has some parallels with sexual forms of transmis- tance information. Bergogne-Berezin and Joly- sion. The transfer of plasmids between related Guillon'" drew special attention to acinetobacter bacteria allows packets ofresistance information to organisms and their potential danger in hospital. be exchanged, and the potential harm of plasmid- We were already aware of the problems posed by mediated resistance is well recognized. There are klebsiellae and enterobacters and many other now examples of exchanges of resistance inform- opportunists in this context. Reports from various ation between coliform bacteria that cross taxono- countries provided strangely conflicting evidence mic boundaries and qualify for the description of of bacterial drug resistance."16 It is essential to promiscuous behaviour. These interlinked systems develop better surveillance and reporting systems if account for the daunting speed ofthe transmission we are to control or moderate the threat to all of of bacterial drug resistance information so that our antimicrobial drugs. The staphylococcus pro- resistant strains are encountered rapidly across the vides a frightening illustrative example. world."0 This has been assisted by transposons which are small bits of DNA that are able to jump copyright. between plasmids in the same cell."' To add further Methicillin-resistant Staph. aureus (MRSA) to the complexity of the scenario, it is now becom- ing clear that a mechanism of genetic exchange The first reports of resistance to methicillin in resembling transformation may account for the staphylococci appeared soon after the introduction exchange of plasmid-borne information in coli- of the drug in 1959. Although sporadic outbreaks form bacteria, while conjugation systems may ofinfection due to these organisms occurred, it was operate in Gram-positive bacteria that we pre- not until the 1980s that they posed significant viously thought were unable to exchange DNA in problems in the UK and elsewhere"8 in relation to http://pmj.bmj.com/ this way. hospital infection control. We have had to extend our understanding ofthe Some strains are more transmissible than others range of pathogens that readily acquire resis- ('epidemic methicillin-resistant Staph. aureus' tance."2 In recent years we have recognized that EMRSA)."19 Such strains often belong to a single Moraxella (Branhamella) catarrhalis is not merely phage group although many are untypable by a respiratory commensal but can be an important standard phages. Most MRSA strains have a respiratory tract pathogen."3 M. catarrhalis is special ability to colonize skin and anterior nares on September 30, 2021 by guest. Protected resistant to some ofthe antibiotics commonly used and to spread from person to person, though they for the treatment of respiratory tract infection, are not more virulent than methicillin-sensitive especially ampicillin/amoxycillin, due to beta-lact- strains. The problems that they pose relate to amase production. Over 70% ofclinical isolates are control of spread of infection and to treatment of beta-lactamase producing, in our experience at the established infections, when methicillin and City Hospital Bacteriology Laboratory, Edinburgh. flucloxacillin are inactive. Another pathogen that may be resistant to Spread of infection has to be controlled or penicillins because of beta-lactamase production is prevented by rigorous control of infection Haemophilus influenzae. A recent revieweri5 indic- measures such as those laid down by the Joint ated that 10% ofnon-capsulate and 25% of type b Working Party of the Hospital Infection Society strains from blood and CSF in the UK were and British Society for Antimicrobial beta-lactamase positive. Some non-capsulate strains Chemotherapy.'20 In addition, the development of resistant to ampicillin (MIC > 1 mg/l) are beta- mupirocin (a pseudomonic acid) as a topical lactamase negative, the mechanism of resistance specific anti-staphylococcal agent has enabled being chromosomal in nature. Such strains are efforts to be made to eradicate nasal and skin often resistant to several beta-lactams. carriage by applying mupirocin ointment and Postgrad Med J: first published as 10.1136/pgmj.68.795.6 on 1 January 1992. Downloaded from BACTERIAL CHALLENGES AND ANTIBACTERIAL DRUGS 19 mupirocin in a polyethylene glycol base respec- vancomycin) and ciprofloxacin offer promise'2' tively. though strains of MRSA that are resistant to Treatment ofestablished infections may be diffi- ciprofloxacin have been described and therapeutic cult, as strains of MRSA are usually resistant to failures reported. It has become clear that the gentamicin and chloramphenicol as well as to presence of an implanted prosthesis or venous line methicillin and flucloxacillin. Many authorities may provide a nidus for continuing infection and suggest vancomycin, alone or in combination with that removal of the device may be necessary to rifampicin."8-'20 Newer agents such as teicoplanin eradicate the infection. a glycopeptide antibiotic with similar activity to

References The basic armament 1. Williams, J.D. Antimicrobial substances used in the treat- 18. Levey, S.B. Evolution and spread of tetracycline resistance ment of infections. In: Linton, A.H. & Dick, H.M. (eds) determinants. Leading article. J Antimicrob Chemother Topley & Wilson's Bacteriology, Virology and Immunity, 8th 1989, 24: 1-7. ed, Vol.1, chapter 5. Edward Arnold, London, 1990, 19. Anonymous. Tetracyclines after 25 years. Br Med J 1974, 2: pp. 105-152. 400-401. 2. Anonymous. Current practice: Today's drugs. Penicillins, 20. Garrod, L.P., Lambert, H.P. & O'Grady, F. Tetracyclines. Benzylpenicillin. Br Med J 1963, 1: 1137-1140. In: Antibiotic and Chemotherapy, 5th ed. Churchill Living- 3. Bush, K., Beta-lactamase inhibitors from laboratory to stone, Edinburgh, 1981, pp. 169-172. clinic. Clin Microb Rev 1988, 1: 109-123. 21. Smyth, E.G. & Pallett, A.P. Clinician's guide to antibiotics. 4. Kuk, N.A., Jacobus, N.V., Petersen, P.J. et al. Comparative Br J Hosp Med 1988, 39: 424-428. in vitro and in vivo activities of piperacillin combined with 22. Stevens, J.D. & Mission, G.P. Ophthalmic use of chloram- beta-lactamase inhibitors tazobactam, clavulanic acid and phenicol. Lancet 1987, ii: 1456. sulbactam. Antimicrob Agents Chemother 1989, 33: 23. Collee, J.G. & Amyes, S.G.B. Relevance of bacterial resis- 1964-1969. tance for clinical and community medicine: point of view of 5. Williams, J.D. The cephalosporin antibiotics. Drugs 1987, the bacteriologist. In: Michel, M.F. & van der Meer, J.W.M.

34 (Suppl 2): 1-258. (eds), Proceedings of the BRL Kurhaus Workshop on Anti- copyright. 6. Rubinstein, E. & Isturiz, R. Aztreonam: the expanding biotics. Beecham Research Laboratories, Amstelveen, Nether- clinical profile. Rev Infect Dis 1991, 13 (Suppl 7): S581 -S654. lands, 1985, pp. 67-77. 7. Clissold, S.P., Todd, P.A. & Campoli-Richards, D.M. 24. Mandal, B.K. Modem treatment of typhoid fever. J Infect Imipenem/Cilastatin: A review of its antibacterial activity, 1991, 22: 1-4. pharmacokinetic properties and therapeutic efficacy. Drugs 25. Powell, M. Chemotherapy for infections caused by Haemo- 1987, 33: 183-241. philus influenzae: Current problems and future prospects. J 8. Davey, P., Davies, A., Livermore, D. & Speller, D. Mero- Antimicrob Chemother 1991, 1: 3-7. penem (SM 7338) - a new carbapenen. J Antimicrob Chemo- 26. Martin, J.R., Johnson, P. & Miller, M.F. Uptake accumula- ther 1989, Suppl. A, 9-29. tion and egress of erythromycin by tissue culture cells of

9. Rolinson, G.L. Beta-lactam antibiotics. J Antimicrob human origin. Antimicrob Agents and Chemother 1985, 27: http://pmj.bmj.com/ Chemother 1986, 17: 5-36. 314-319. 10. Livermore, D.M. & Wood, M.J. Mechanisms and clinical 27. Miller, M.F., Martin, J.R., Johnson, P. et al. Erythromycin significance ofresistance to new beta-lactam antibiotics. Br J uptake and accumulation by human polymorphonuclear Hosp Med 1990, 44: 252-263. leukocytes and efficacy of erythromycin in killing ingested 11. Davey, P. Clinical use of the aminoglycosides in the 1990s. Legionella pneumophila. J Infect Dis 1984, 149: 714-718. Rev Med Microbiol 1991, 2: 22-30. 28. Baskerville, A., Fitzgeorge, R.B., Gibson, D.H. et al. 12. Mattie, H., Craig, W.A. & Pechere, J.C. Determinants of Pathological and bacteriological findings after aerosol efficacy and toxicity of aminoglycosides. J Antimicrob Legionella pneumophila infection of susceptible, convales- Chemother 1989, 24: 281-293. cent and antibiotic-treated animals. In: Thornsberry, C., 13. Lovering, A.M., Bywater, M.J., Holt, H.A. et al. Resistance Balows, A., Feeley, J.C. & Jakubowski, W. (eds) Legionella. on September 30, 2021 by guest. Protected ofbacterial pathogens to four aminoglycosides and six other Proceedings of the Second International Symposium. antibacterials and prevalence of aminoglycoside modifying American Society for Microbiology, Washington, DC, enzymes, in 20 UK centres. J Antimicrob Chemother 1988, 1984, pp. 131-132. 22: 823-839. 29. Malmborg, A.S. The renaissance of erythromycin. J Anti- 14. European Study Group on Antibiotic Resistance. In-vitro microb Chemother 1986, 18: 293-299. susceptibility to aminoglycoside antibiotics in blood and 30. Anders, B.J., Lauer, B.A., Paisley, J.W. & Reller, L.B. urine isolates consecutively collected in 29 European labora- Double-blind placebo controlled trial of erythromycin for tories. Eur J Clin Microbiol 1987, 6: 378-385. treatment of campylobacter enteritis. Lancet 1982, i: 15. Muscato, J.J., Wilbur, D.W., Stout, J.J. & Fahrlender, R.A. 131- 132. An evaluation of the susceptibility patterns of Gram- 31. Hardy, D.J., Hensey, D.M., Beyer, J.M. et al. Comparative negative organisms isolated in cancer centres with amino- in vitro activities of new 14-, 15-, and 16-membered macro- glycoside usage. In: Davey, P.G., Finch, R.G. & Wood, M.J. lides. Antimicrob Agents Chemother 1988, 32: 1710-1719. (eds) Once Daily Amikacin. J Antimicrob Chemother 1991, 32. Bernstein, N., Roudier, C. & Fleurette, J. Determination of 27 (Suppl. C): 1-7. the activity against Legionella of eight macrolides and 16. Hathorn, J.W. & Pizzo, P.A. Is there a role for monotherapy related agents by comparative testing on three media. J with beta-lactam antibiotics in the initial empirical manage- Antimicrob Chemother 1985, 13: 17-22. ment of febrile neutropenic cancer patients? J Antimicrob Chemother 1986, 17 (Suppl. A): 41-54. 17. Greenwood, D. Antimicrobial Chemotherapy, 2nd ed. Oxford Medical Publications, Oxford. 1989, p. 45. Postgrad Med J: first published as 10.1136/pgmj.68.795.6 on 1 January 1992. Downloaded from 20 B. WATT & J.G. COLLEE

33. Hardy, D.J., Swanson, R.N., Rode, R.A. et al. Enhance- 54. Cooper, M.A., Andrews, J.M., Ashby, J.P. et al. In vitro ment of the in vitro and in vivo activities of clarithromycin activity ofsparfloxacin, a new quinolone agent. JAntimicrob against Haemophilus influenzae by 14-hydroxy-clarithro- Chemother 1990, 26: 667-676. mycin, its major metabolite in humans. Antimicrob Agents 55. King, A., Boothman, C. & Phillips, I. The in vitro activity of Chemother 1990, 34: 1407-1413. PD127,391, a new quinolone. JAntimicrob Chemother 1988, 34. Phillips, I. & Spellar, D. (eds). Fusidic acid: a reappraisal. J 22: 135-141. Antimicrob Chemother 1990, 25 (Suppl B): 1-60. 56. Yajko, D.M., Sanders, C.A., Bassos, P.S. & Hadley, W.K. 35. Fleming, D.W., Cochi, S.L., Hull, H.F. et al. Prevention of In-vitro susceptibility of Mycobacterium avium complex to Haemophilus influenzae type b infections in day care: a public the new fluoroquinolone sparfloxacin (CI-978; AT-4140) health perspective. Rev Infect Dis 1986, 8: 568-572. and comparison with ciprofloxacin. Antimicrob Agents 36. Dickinson, J.M. & Mitchison, D.A. In vitro activity of new Chemother 1990, 34: 2442-2444. rifamycins against rifampicin-resistant Mycobacterium 57. Leigh, D.A., Tait, S. & Walsh, B. Antibacterial activity of tuberculosis and MAIS-complex mycobacteria. Tubercle lomefloxacin. J Antimicrob Chemother 1991, 27: 589-598. 1987, 68: 177- 182. 37. Saito, H., Sato, K. & Tonicoka, H. Comparable in vitro and New challenges and changes In concept and practice in vivo activity of rifabutin and rifampicin against Myco- 58. Oakley, C.M. Treatment of infective endocarditis. Pre- bacterium avium complex. Tubercle 1988, 69: 187-192. scribers'J 1990, 30: 152-165. 38. Heifets, L.B., Lindholm-Levy, P.J. & Iseman, M.D. Rifa- 59. Brumfitt, W. & Hamilton-Miller, J.M.T. Prophylactic anti- butine: minimal inhibitory and bactericidal concentrations biotics for recurrent urinary tract infections. J Antimicrob for Mycobacterium tuberculosis. Am Rev Resp Dis 1988,137: Chemother 1990, 25: 505-512. 719-721. 60. Smellie, J.M. & Prescod, N. Natural history ofovert urinary 39. Heifets, L.B., Iseman, M.D. & Lindholm-Levy, P.J. Com- infection in childhood. In: Asscher, A.W. & Brumfitt, W. binations ofrifampicin or rifabutin plus ethambutol against (eds) Microbiological Diseases in Nephrology. John Wiley, Mycobacterium avium complex. Am Rev Resp Dis 1988, 137: Chichester, 1986, pp. 243-254. 711-715. 61. Willis, A.T. Rationale for antimicrobial prophylaxis at 40. Young, L.S. Mycobacterium avium complex infection. J surgery. Eur J Chemother Antibio 1982, 2: 87-93. Infect Dis 1988, 157: 863-867. 62. Goldman, L.A. (ed) A Contemporary View of Hospital 41. Cavalleri, B., Turconi, M., Tamboini, G. etal. Synthesis and Antibiotic Prophylaxis. Update Sibert Publications, London, biological activity ofsome derivatives ofrifamycin P. J Med 1987. Chem 1990, 33: 1470-1476. 63. Pollock, A.V. Surgical prophylaxis - the emerging picture. 42. Wise, R. & Logan, M.N. Anaerobic infections and their Lancet 1988, i: 225-229. treatment. In: Gruneberg, R.N. (ed.) Antibiotics and Chemo- 64. Taylor, E.W. Failed antibiotic prophylaxis in elective therapy. Current Status of Modern Therapy. MTP Press, surgery. Signed editorial. Hosp Update 1991, 17: 455-456. Lancaster, 1980, vol. 4, chapter 4, pp. 113-137. 65. Clyde, W.A. Mycoplasma pneumonia Respiratory Diseasecopyright. 43. Greenwood, D., Watt, B. & Duerden, B.I. Antibiotics and Symposium: summation and significance. Yale J Biol Med Anaerobes. In: Duerden, B.I. & Drasar, B.S. (eds) 1983, 56: 523-527. Anaerobes in Human Disease. Edward Arnold, London, 66. Sanford, J.P. Legionnaires' disease: the first thousand days. 1991, chapter 25, pp. 415-429. N Engl J Med 1979, 300: 654-656. 44. Skirrow, M.B. Campylobacter, Helicobacter and other 67. MacFarlane, J.T., Finch, R.G., Ward, M.J. & Macrae, A.D. curved Gram-negative rods. In: Parker, M.T. & Duerden, Hospital study of adult community-acquired pneumonia. B.I. (eds) Topley & Wilson's Bacteriology, Virology and Lancet 1982, ii: 255-282. Immunity, 8th ed, vol. 2, chapter 27. Edward Arnold, 68. Woodhead, M.A. & Macfarlane, J.T. Legionnaire's disease: London, 1990, pp. 531-549. a review of 79 community-acquired cases in Nottingham. 45. Wolfson, J.S. & Hooper, D.C. The fluoroquinolones: struc- Thorax 1986, 41: 635-640. http://pmj.bmj.com/ ture, mechanisms of action and resistance, and spectra of 69. Palmer, S.R. Psittacosis in man - recent developments in the activity in vitro. Antimicrob Agents Chemother 1985, 28: UK: A review. J R Soc Med 1982, 75: 262-267. 581-586. 70. Grayston, J.T., Kuo, C.-C., Campbell, L.A. & Wang, S.-P. 46. Sanders, C.C., Sanders, W.E. & Grering, R.V. Overview of Chiamydia pneumoniae sp. nov. for Chlamydia sp. strain preclinical studies with ciprofloxacin. Am J Med 1987, TWAR. Int J Syst Bact 1989, 39: 88-90. Suppl. 4A: 2-11. 71. Marmion, B.P. Rickettsial diseases of man and animals. In: 47. King, A., Shannon, K. & Phillips, I. The in vitro activity of Smith, G.R. & Easmon, C.S.F. (eds) Topley & Wilson's ciprofloxacin compared with that of norfloxacin and nali- Bacteriology, Virology and Immunity, 8th ed, vol.3, chapter dixic acid. J Antimicrob Chemother 13: 35. Edward Arnold, London, 1990, pp. 673-689. 1984, 325-331. on September 30, 2021 by guest. Protected 48. Young, L.S., Berlin, O.G.W. & Inderlied, C.B. Activity of 72. Parker, M.T. Enteric infections: typhoid and paratyphoid ciprofloxacin and other fluorinated quinolones against fever. In: Smith, G.R. & Easmon, C.S.F. (eds) Topley & mycobacteria. Am J Med 1987, 82 (Suppl. 4A): 23-26. Wilson's Bacteriology, Virology andImmunity, 8th ed, vol. 3, 49. Watt, B. & Brown, F.V. Is ciprofloxacin active against chapter 22. Edward Arnold, London, 1990, pp. 423-446. clinically important anaerobes? J Antimicrob Chemother 73. Gross, R.J. Escherichia coli diarrhoea. In: Smith, G.R. & 1986, 17: 605-613. Easmon, C.S.F. (eds) Topley & Wilson's Bacteriology, 50. Kucsers, A. & Bennett, N.M. Norfloxacin. In: Kucsers, A. & Virology and Immunity, 8th ed, vol. 3, chapter 25. Edward Bennett, N.M. (eds) The Use of Antibiotics. Heinemann Arnold, London, 1990, pp. 469-487. Medical Books, London, 1987, pp. 1234-1241. 74. Attridge, S.R. & Rowley, D. Cholera. In: Smith, G.R. & 51. Cozzarelli, N.R. DNA gyrase and the supercoiling ofDNA. Easmon, C.S.F. (eds) Topley & Wilson's Bacteriology, Science 1980, 207: 953-960. Virology and Immunity, 8th ed, vol. 3, chapter 24. Edward 52. Lewin, C.S., Allen, R.B. & Amyes, S.G.B. Potential mecha- Arnold, London, 1990, pp. 459-468. nisms of resistance to the modern 4-quinolones. J Med 75. Goodwin, C.S., Marshall, B.J., Blincow, E.D. et al. Preven- Microbiol 1990, 31: 153-161. tion of nitroimidazole resistance in Campylobacter pylori by 53. Kaatz, G.W. & Seo, S.M. WIN 57273, a new fluoro- coadministration of colloidal bismuth subcitrate: clinical quinolone with enhanced in vitro activity versus Gram- and in vitro studies. J Clin Path 1988, 41: 207-210. positive pathogens. Antimicrob Agents Chemother 1990, 34: 1376-1380. Postgrad Med J: first published as 10.1136/pgmj.68.795.6 on 1 January 1992. Downloaded from BACTERIAL CHALLENGES AND ANTIBACTERIAL DRUGS 21

76. Turnberg, L.A. Traveller's diarrhoea. In: Turnberg, L.A. 99. Anonymous. Microbial selective decontamination in inten- (ed) Clinical Gastroenterology, chapter 10. Blackwell Scienti- sive care patients. Lancet 1988, i: 803-804. fic Publications, Oxford, 1989, pp. 201-210. 100. Van der Waaij, D. Selective decontamination for prevention 77. Collee, J.G. Virulence factors ofanaerobes: An overview. In: of infection in ICU patients. J Hosp Infect 1988, 11 (Suppl. Borriello, S.P. (ed) Clinical and Molecular Aspects of A): 303-308. Anaerobes. Wrightson Biomedical Publishing Ltd, London, 101. Van der Waaij, D. The digestive tract in immunocompro- 1990, pp. 127-136. mised patients: importance of maintaining its resistance to 78. De Louvois, J., Gortvai, P. & Hurley, R. Bacteriology of colonization, especially in hospital in-patients and those abscesses of the central nervous system. A multi-centre taking antibiotics. In: Sabbath, L.D. (ed.) Action of Anti- prospective study. Br Med J 1977, 2: 981-984. biotics in Patients. Huber, Bern, 1982, pp. 104-118. 79. De Louvois, J., Gortvai, P. & Hurley, R. Antibiotic 102. Borriello, S.P. Anaerobic bacteria in diarrhoea and colitis. treatment ofabscesses ofthe central nervous system. Br Med In: Duerden, B. & Drasar, B.S. (eds) Anaerobes in Human J 1977, 2: 985-987. Disease. Edward Arnold, London, 1991, chapter 21, 80. Ingham, H.R., Selkon, J.B. & Roxby, C.M. Bacteriological pp. 351-353. study of otogenic cerebral abscesses: chemotherapeutic role 103. Speller, D.C.E. Hospital-associated infections. In: Smith, of metronidazole. Br Med J 1977, 2: 991-993. G.R. & Easmon, C.S.F. (eds) Topley & Wilson's Principles of 81. Ingham, H.R., High, A.S., Kalbag, R.M. et al. Abscesses of Bacteriology, Virology and Immunity, 8th ed, vol. 3, chapter the frontal lobe of the brain secondary to covert dental 9. Edward Arnold, London, 1990, pp. 155-157. sepsis. Lancet 1978, if: 497-499. 104. Balakrishnan, G., Simpkins, C., Greig, M. & Hallworth, D. 82. Anonymous. Chemotherapy of brain abscess. Lancet 1978, Catheter-related sepsis. Br J Intensive Care 1991, 1: 17-23. ii: 1081-1082. 105. Brown, M.R.W., Costerton, J.W. & Gilbert, P. Extra- 83. Alderston, D., Strong, A.J., Ingham, H.R. et al. Fifteen-year polating to bacterial life outside the test tube. Leading review of the mortality ofbrain abscess. Neurosurgery 1981, article. J Antimicrob Chemother 1991, 27: 565-567. 8: 1-6. 106. Wilcox, M.H., Finch, R.G., Smith, D.G.E. et al. Effects of 84. Ispahani, P. The therapeutic use of antimicrobial agents: carbon dioxide and sub-lethal levels of antibiotics on meningitis and brain abscess. In: Greenwood, D. (ed.) adherence of coagulase-negative staphylococci to polysty- Antimicrobial Chemotherapy 2nd ed. Oxford Medical Pub- rene and silicone rubber. J Antimicrob Chemother 1991, 27: lications, Oxford, 1989, pp. 289-301. 577-587. 85. Welsby, P.D. & Golledge, C.L. Meningococcal meningitis. 107. Wosornu, D., Maclntyre, D. & Watt, B. An outbreak of Br Med J 1990, 300: 1150-1151. isoniazid-resistant tuberculosis in Glasgow, 1981-1988. 86. Wall, R.A. The chemoprophylaxis of meningococcal infec- Resp Med 1990, 84: 361-364. tion. J Antimicrob Chemother 1988, 21: 698-699. 108. Chemotherapy of tuberculosis: Recommendations of Joint 87. Finch, R. Bacterial meningitis. Prescribers'J 1989, 29: 2-11. Tuberculosis Committee of the British Thoracic Society. 88. Pearce, J.M. Pelvic inflammatory disease. Br Med J 1990, Thorax 1990, 45: 403-408. copyright. 300: 1090-1091. 89. Mitchell, R.G. Miscellaneous bacteria: Capnocytophaga. Bacterial drug resistance In: Parker, M.T. & Duerden, B.I. (eds) Topley & Wilson's 109. Levy, S.B. Microbial resistance to antibiotics. In: Good Bacteriology, Virology and Immunity, 8th ed, vol. 2, chapter Antimicrobial Prescribing. Lancet, London, 1982, pp. 4-19. 29. Edward Arnold, London, 1990, pp. 585-587. 110. Amyes, S.G.B. The success of plasmid-encoded resistance 90. Rogers, T.R.F. Infections associated with immunodefi- genes in clinical bacteria. J Med Microbiol 1989, 28: 73-83. ciency. In: Smith, G.R. & Easmon, C.S.F. (eds) Topley & 111. Hedges, R.W. & Jacob, A.E. Transposition of ampicillin Wilson's Bacteriology, Virology andImmunity, 8th ed, vol. 3, resistance from RP4 to other replicons. Molec Gen Genet chapter 10, Edward Arnold, London, 1990, pp. 174-196. 1974, 132: 31-40. 91. British National Formulary. Immunological products and 112. Collee, J.G. The surveillance and control of bacterial and http://pmj.bmj.com/ vaccines: pneumococcal vaccine. Chapter 14.4. No. 20. viral infections. MIRCEN J 1986, 2: 61-73. British Medical Association and Royal Pharmaceutical 113. Vaneechoutte, M., Verschraegen, G., Claeys, G. et al. Society of Great Britain, London, 1990, p. 410. Respiratory tract carrier rates of Moraxella (Branhamella) 92. Pizzo, P.A. After empiric therapy: what to do until the catarrhalis in adults and children and interpretation of the granulocyte comes back. Rev Infect Dis 1987, 9: 214-219. isolation of M. catarrhalis from sputum. J Clin Microbiol 93. Klastersky, J., Glauser, M.P., Schimpff, S.C. et al. Prospec- 1990, 28: 2674-2680. tive randomised comparison ofthree antibiotic regimens for 114. Powell, M., Koutsia-Carouzou, C., Voutsinas, D. et al. empirical therapy of suspected bacteremic infection in Resistance of clinical isolates of Haemophilus influenzae in Antimicrob febrile granulocytopenic patients. Agents United Kingdom 1986. Br Med J 1987, 295: 1765-179. on September 30, 2021 by guest. Protected Chemother 1986, 29: 263-270. 115. Howard, A.J. & Williams, H.M. The prevalence of anti- 94. The EORTC International Antimicrobial Therapy Co- biotic resistance in Haemophilus influenzae in Ireland. J operative Group. Ceftazidime combined with a short or long Antimicrob Chemother 1989, 24: 963-971. course of amikacin for empirical therapy of Gram-negative 116. Collee, J.G. Current trends in antimicrobial therapy: the bacteremia in cancer patients with granulocytopenia. NEngl Lister Lecture. Proc R Coll Phys Edinburgh 1988, 18:16-30. J Med 1987, 317: 1692-1698. 117. Bergogne-Berezin, E., Joly-Guillou, M.L. & Vieu, J.F. 95. Chan, C.K., Oppenheim, B.A., Anderson, H. et al. Ran- Epidemiology ofnosocomial infections due to Acinetobacter domised trial comparing ciprofloxacin plus netilmicin versus calcoaceticus. J Hosp Infect 1987, 10: 105-113. piperacillin plus netilmicin for empiric treatment of fever in 118. Casewell, M.W. Epidemiology and control of the 'modern' neutropenic patients. Antimicrob Agents Chemother 1989, methicillin-resistant Staphylococcus aureus. J Hosp Infect 33: 87-91. 1986, (Suppl. A): 1-11. 96. Hughes, W.T., Armstrong, D., Bodey, G.P. et al. Guidelines 119. Orange, G. Methicillin-resistant Staphylococcus aureus in for the use of antimicrobial agents in neutropenic patients intensive care units. Intensive Ther Clin Monitoring 1990, 11: with unexplained fever. J Infect Dis 1990, 161: 381-396. 20-23. 97. Ledingham, I.McA., Alcock, S.R., Eastaway, A.T. et al. 120. Working Party Report. Revised guidelines for the control of Triple regimen of selective decontamination of the digestive epidemic methicillin-resistant Staphylococcus aureus. JHosp tract, systemic cefotaxime and microbiological surveillance Infect 1990, 16: 351-377. for prevention ofacquired infection in intensive care. Lancet 121. Piercy, E.A., Barbour, D., Luby, J.P. & Mackowiak, P.A. 1988, 1: 785-790. Ciprofloxacin for methicillin-resistant Staphylococcus aureus 98. Stoutenbeek, C.P., Van Saene, H.K.F., Miranda, D.R. et al. infection. Antinicrob Agents Chemother 1989, 33: 128-130. The prevention ofsuperinfection in multiple trauma patients. J Antimicrob Chemother 1984, 14 (Suppl. B): 203-21 1.