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,