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ment techniques suggests that a clinical director drawn from solutions, including more computerisation and more day case the ranks of the surgeons or anaesthetists might provide more surgery. The possibility that overall there might not be direct and effective support. For the foreseeable future the enough surgical beds in the NHS at present was not most intransigent problem that the new managers will face, addressed. however, will be shortage of staff. This report properly Operating theatres-like the whole of the NHS after the pointed out that operation department assistants and nurses white paper-will need to be heavily managed. Whether should be interchangeable, as should theatre and anaesthetic history will show that the huge injection of cash, technology, BMJ: first published as 10.1136/bmj.300.6735.1289 on 19 May 1990. Downloaded from work-and that with parity of work should come parity of human effort, and angst will be worth while in clinical, pay. financial, and human terms remains to be seen. The problems of operating theatres are neatly quantifiable ANTHONY YOUNG and thus may be soluble; but theatres and beds are almost Consultant Surgeon, totally interdependent, and if the problems of providing beds St Thomas's Hospital, are not solved reforms in the theatre suite will be wasted. London SEI 7EH Ensuring a steady flow of patients is a much more taxing problem than improving the usage of theatres, and it depends I National Audit Officc. The usc of oiperating theatres in the Natio'onal Healih Service, report hbv thei on factors such as waiting lists, admissions, case mix, and ComptrollerandAuditorGeneral. London: HMtSO, 1987. 2 NHS Management Exccutive. The management and utilisation of operatitng departmentis. Lsondon: staffing. The Bevan report made a stab at suggesting some HMSO, 1989. (Chairman P ( Bevan.)

The today Use is now well defined by clinical trials

Pneumococci, streptococci, gonococci, and meningococci infections, and the increase in the number of strains of have been the major targets for for half a century. H influenzae and Branhamella catarrhalis producing P-lacta- Resistance has long excluded from this mase raises questions concerning the continuing efficacy of list of pyogenic cocci with predictable susceptibility to these drugs to treat such infections. penicillin. The extent of penicillin resistance in gonococci The discovery that resistance to penicillin is caused by reached a peak in 1983 and has since declined.' Pneumococci enzymatic hydrolysis of the f-lactam ring by Staph aureus are still generally susceptible, despite the worrying identi- stimulated the development of the penicillinase-resistant fication of strains with either reduced susceptibility penicillins such as , , and the isoxazolyl (minimum inhibitory concentration >0 1-2 mg/l), or, less penicillins-, , , and flucloxa- common still, overt resistance (minimum inhibitory concen- cillin. These compounds are the mainstay of antistaphylo- coccal treatment, with popular in Europe and tration >2 mg/1).2 The highest incidence of these resistant http://www.bmj.com/ pneumococci is in the Iberian peninsula -a popular holiday nafcillin, oxacillin, and dicloxacillin in North America. These destination for many Britons.3 Penicillin resistance among have generally been assumed to be of comparable clinical meningococci has been identified in Spain, South Africa, and efficacy. Recent experimental data suggest, however, that Britain.46 dicloxacillin and (especially) methicillin are more stable to Despite these concerns the indications for penicillin G Staph aureus [3-lactamase." Strains of Staph aureus with remain infections caused by pneumococci, meningococci, reduced affinity ofthe binding protein 2' are resistant to these Streptococcus pyogenes and other non-enterococcal strepto- and all other penicillins.'2 And coagulase negative staphylo- cocci, microaerophilic streptococci such as Streptococcus cocci, which are now a major cause of hospital sepsis, are also on 26 September 2021 by guest. Protected copyright. milleri, and gonorrhoea when susceptibility can be confirmed. often resistant to these penicillins. 13 The continued susceptibility of Treponema pallidum is re- Penicillinase is one of a large and expanding family of assuring, though when syphilis complicates HIV infection 1-lactamases that has eroded the therapeutic efficacy of the more prolonged treatment is necessary.7 Acute leptospirosis' penicillins.'4 Resistance is now recognised in about 40% of and established Lyme borreliosis9 are other indications. Most Escherichia coli, " 6% of H influenzae (8% among type b oral and anaerobic bacteria, including both the actinomycetes isolates),'6 some 5% of gonococci,' and up to 70% of B and the clostridia, remain susceptible to penicillin.'0 catarrhalis,'7 while Staph aureus that are sensitive to penicillin The isolation of the 6-aminopenicillanic acid nucleus in are collectors' items. Recognition that antistaphylococcal 1957 was an important milestone in the development of the penicillins such as cloxacillin and bind penicillinase suggested penicillins. The first fruit of this discovery was . a chemotherapeutic solution to the protection of the 1-lactam Other , analogues, esters, and prodrugs ring, and this has been realised in ,B-lactamase inhibitors such followed: amoxycillin, , , and as , , and . While lacking to name but a few. The extensive indications for useful antibacterial activity they confer broad spectrum, the aminopenicillins include infections of the middle ear, yet individually variable, resistance to Gram negative paranasal sinuses, and lower respiratory tract; meningitis 3-lactamases.'8 Where resistance is the result of impaired cell caused by meningococci, pneumococci, Haemophilus wall penetration, however, these j-lactamase inhibitors are of influenzae, susceptible Gram negative enteric bacilli, Strep no therapeutic benefit. Clavulanate is licensed in combination agalactiae, and Listena monocytogenes; systemic salmonelloses, with both an , co-amoxiclav (augmentin), and including enteric fever; and serious enterococcal sepsis and . Sulbactam is licensed in other countries as the urinary tract infections. Despite their established safety, mutual prodrug . Co-amoxiclav is available in a including for use in pregnancy, drug resistance has relegated fixed ratio of amoxycillin and clavulanate of 2:1 for oral the aminopenicillins to second line treatment for urinary tract administration and as a 5: 1 ratio for parenteral use; ticarcillin-

BMJ VOLUME 300 19 MAY 1990 1289 clavulanate is available only in the ratio 15: 1. The pharmaco- are highly resistant to many common plasmid and chromo- kinetic features of the component drugs must be matched to somally mediated P-lactamases. Such compounds include maintain adequate tissue concentrations. many of the extended spectrum (third generation) cephalo- Gram negative enteric pathogens dominated hospital infec- sporins, the ,27 and, among the peni- tions from the 1960s to the 1980s. The antipseudomonal cillins, .28 Temocillin is now marketed and has a penicillins , ticarcillin, and met this spectrum of activity limited to most medically important challenge and extended the spectrum of the penicillins. Their Gram negative bacteria but excluding P aeruginosa. Its half BMJ: first published as 10.1136/bmj.300.6735.1289 on 19 May 1990. Downloaded from activity against Klebsiella species, however, is poor and is only life is 4-5 hours; thus it can be given twice daily.29 Its place in modest against . The well established treatment has yet to be established, but it is unlikely to be safety of the penicillins, however, permitted dosages of up to used alone except in infections known to be due to susceptible 30 g a day-though this may result in excessive sodium pathogens. loading'9 and interference with platelet aggregation.20 Efficacy Research has also led to an appreciation that certain in the febrile patient with neutropenia is a stringent test of 1-lactam drugs have the ability to induce production of the "therapeutic muscle" of any anti-infective drug; the a P3-lactamase in selected pathogens such as Enterobacter have been successful when combined with species, Serratia species, and Pseudomonas species.30 This an aminoglycoside and provide broad spectrum cover and varies by organism and f-lactam; it is most pronounced for activity that is often synergic against selected pathogens such drugs such as and certain third generation cephalo- as P aeruginosa.21 When used in combination, however, they sporins and lower for drugs such as temocillin.3' The clinical must be given at separate times and sites to avoid inactivation impact of inducible resistance varies widely and depends on ofthe aminoglycoside by the penicillin-an action that is most the selection of derepressed mutants.32 pronounced for carbenicillin and gentamicin.22 In summary, the interaction between a penicillin and its The -, , and pipera- target pathogen is complex. The final outcome depends on cillin-are active against many Gram negative and Gram several phenomena, including pharmacokinetic behaviour, positive bacteria including enterococci but excluding many penetration, and binding to specific target proteins, staphylococci. This activity is unfortunately dependent on the which may be neutralised by 1B-lactamase activity. Though inoculum23 and is not compensated for by relatively poor many of these features have been defined in vitro, the clinical resistance to ,B-lactamase hydrolysis.24 Only azlocillin and use of the penicillins has been established through carefully show definite activity against P aeruginosa, but designed and executed trials. Such trials are essential to again large doses are necessary. The poor results reported establish the efficacy and safety of a drug and to define its when these agents were given as monotherapy in febrile, place in chemotherapy.33 neutropenic patients require them to be given in combination ROGER FINCH with an aminoglycoside.2526 As such they have proved a popular regimen. Senior Lecturer in Microbial Diseases, As our understanding of structure-activity determinants City Hospital and University of Nottingham, has improved j3-lactam compounds have been designed that Nottingham NG5 1PB

1 Ison CA, Easmon CSF. Changes in penicillinase-producing Neisseria gonorrhoeae isolated in 19 Cabizuca SV, Desser KG. Carbenicillin-associated hypokalemic alkalosis. JAMA 1976;236:956-7. http://www.bmj.com/ London.J MedMicrobiol 1989;30:239-44. 20 Anonymous. Antimicrobials and haemostasis [Editorial]. Lancei 1983;i:5101. 2 Appelbaum PC. World-wide development of resistance in pneumococci. Eur j Clin 21 Bodey GP, Bolivar R, Fainstein V, Jadeja L. Infections caused by Pseudomonas aeruginosa. Microbiol 1987;6:367-77. Rev Infecs Dis 1983;5:279-313. 3 Finch RG. Is pneumococcal infection a preventable disease?J Inject 1988;17:95-8. 22 Thompson MIB, Russo ME, Saxon BJ, Atkinthor M, Mlatsen JM. Gentamicin inactivation by 4 Saez-Nieto JA, Campos J. Penicillin-resistant strains of Neisseria meningitidis in Spain. Lancet piperacillin or carbenicillin in patients with end-stage renal disease. Anri'nicrob Agents Chemother 1988;i: 1452-3. 1982;21:268-73. 5 Botha P. Penicillin-resistant Neisseria meningitidis in Southern Africa. Lancet 1988;i:54. 23 Greenwood D, Eley A. A turbidimetric study of the responses of selected strains of Pseudomonas 6 Sutcliffe EM, Jones DM, El-Sheikh S, Percival A. Penicillin-insensitive meningococci in the UK. aeruginosa to eight antipseudomonal B-lactam . J Infect Dis 1982;145:110-7. Lancet 1988;i:657. 24 Eliopoulos GM, Moellering RG Jr. Azlocillin, mezlocillin, and piperacillin: new broad-spectrum 7 Anonymous. Recommendations for diagnosing and treating syphilis in HIV-infected patients. penicillins. Ann Intern Med 1982;97:755-60.

MMWR 1988;37:600-8. 25 Gribblc MJ, Chow AW, Naiman SC, et al. Prospective randomized trial of piperacillin on 26 September 2021 by guest. Protected copyright. 8 Watt G, Tuazon MAL, Santiago E, et al. Placebo-controlled trial of intravenous penicillin for monotherapy versus -aminoglycoside combination regimens in the empirical severe and late leptospirosis. Lancet 1988;i:433-5. treatment of serious bacterial infections. Antimicrob Agents Chemother 1983;24:388-93. 9 Steere AC. Lvme disease. N EnglJ7 Med 1989;321:586-96. 26 Issell BF, Bodey GP. Mezlocillin for treatment of infections in cancer patients. Antimicrob Agents 10 Rosenblatt JE. Antimicrobic susceptibility of anaerobic bacteria. In: Finegold SM, George WL, Chemother 1980;17:1008-13. eds. Anaerobic infections in humans. San Diego, California: Academic Press, 1989:731-3. 27 Neu HC, Labthavikul P. Comparative in vitro activity of N-formimidoyl against 11 Rennenberg J, Forsgren A. The activity of isoxazolvl penicdlins in experimental staphylococcal Gram-positive and Gram-negative aerobic and anaerobic species and its beta-lactamase stability. infection.J Intfect I)is 1989;159:1128-35. Antimicrob Agents Chemother 1982;21:180-7. 12 Lyon BR, Skurry R. Antimicrobial resistance of Staphylococcus aureus: genetic basis. Microbiol 28 Jules K, Neu HC. Antibacterial activity and beta-lactamase stability of temocillin. Antimicrob Rev 1987;51:88-134. Agents Chemother 1982;22:453-60. 13 Nafziger DA, Wenzel RP. Coagulase-negative staphylococci: epidemiology, esaluation and 29 Brown RM, Wise R, Andrews JM. Temocillin, in-vitro activity and the pharmacokinetics and therapy. Infectious D)iseases Clinics of North America 1989;3:915-29. tissue penetration in healthy volunteers. J Antimicrob Chemother 1982;10:295-302. 14 Williams RJ. Antibiotic resistance. Current Opinion in Infectious Diseases 1988;1:350-5. 30 Rolinson GN. Beta-lactamase induction and resistance to beta-lactam antibiotics. J Antimicrob 15 Lovering AM, Bywater MJ, Holt HA, Champion HM, Reeves DS. Resistance of bacterial Chemother 1989;23: 1-5. pathogens to four aminoglycosides and six other antibacterials and prevalence of aminoglycoside 31 Farmer TH, Reading C. Induction of the beta-lactamases of a strain of Pseudomonas aeruginosa, modifying enzymes, in 20 UK centres. J Antimicrob Chemother 1988;22:823-39. Morganella morganii and Enterobacter cloacae.J Antimicrob Chemnother 1987;19:401-8. 16 Powell M. Antimicrobial resistance in Haemophilus influenzae. JMed Microbtol 1988;27:81-7. 32 Livermore DM. Clinical significance of beta-lactarnase induction and stable depression in Gram- 17 McLeod DTF, Ahmad F, Capewell S, Croughan MJ, Calder MA, Seaton A. Increase in negative rods. Eurj Clin Microbiol 1987;6:439-45. bronchopulmonary infection due to Branhamella catarrhalis. Br Medj 1986;292:1103-5. 33 Finch RG. The clinical evaluation ofantibacterial drugs. Report of the Working Party of the British 18 Bush K. jI-lactamase inhibitors from laboratorv to clinic. Clinical Microbiology Reviews 1988;1: Society of Antimicrobial Chemotherapy. J Antimicrob Chemother 1989;23(suppl): 1-42. 109-23.

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