β-LACTAMS AND IMIPENEM

802 This is not to say that enzyme induction is a negligible event. One consequence is that the inducing 3-lactam may itself be inactivated more rapidly than would otherwise be the case, leading to the emergence of resistance during therapy. Another consequence is that a /3-lactamase-labile antibiotic present in a mixture of two (3-lactams may be inactivated more rapidly than if the inducing P-lactam had not been present, leading to antagonism. However, such phenomena should not be confused with those that result in the stable derepression now described in many in-vitro and clinical studies, which may affect subsequent therapy with a wide variety of /3-lactams both of the patient initially treated and potentially others to whom the organism may be transmitted. Ureidopenicillins (mezlocillin, azlocillin, and piperacillin) require the same "judicious and restricted use" advocated by Sanders8as do "the newer cephalosporins" in this respect, until we know more about the differential ability of /3-lactams to select derepressed mutants. The recent letters from Dr Livermore and Mr Hewinson and others (Feb 22, p 450) suggest that they have no advantage or even a theoretical disadvantage in this context. Department of Microbiology, Hospital Ramon y Cajal, Madrid, Spain

The table shows the MICs (at an inoculum of 104 colony forming units) of seven (3-lactams to the parent strain and their respective derepressed mutant. With cefamandole, cefotaxime, and cefoxitin there was either an 8-fold decrease in susceptibility to the agent in the mutant compared with the parent strain or it was already nonsusceptible. A less striking effect was seen with mezlocillin (which accords with Livermore’s observation on Pseudomonas aeruginosa) and carbenicillin. With imipenem no decrease in susceptibility was ’

found. These results suggest that although imipenem will induce resistance to other &bgr;-lactams, as does cefoxitin, it remains active itself and it will not select derepressed mutants and will also be active against such mutants if selected by other &bgr;-lactams. These properties suggest that imipenem may have an important role both in treatment failures with other p-lactams and, more importantly, in the initial therapy of severe infections caused by Enterobacteriaceae. Department of Medical Microbiology, Dudley Road Hospital, Birmingham B18 7QH

B. KIRKPATRICK

J. ASHBY R. WISE

IAN PHILLIPS

1. Wembren MJ, Perinpanayagam RM. Test for &bgr;-lactamase production. Lancet 1985; ii: 673. 2. Shannon KP, King A, Eykyn SJ. Which antibiotic for bacteria with inducible class I &bgr;-lactamase? Lancet 1985; ii: 1016. 3. Weinbren MJ, Perinpanayagam RM. Which antibiotic for bacteria with inducible class 1 &bgr;-lactamase? Lancet 1986; i: 102. 4. Minami S, Yotsuji A, Inoue M, Mitsuhashi S. Induction of &bgr;-lactamase by various &bgr;-lactam antibiotics in Enterobacter cloacae Antimicrob Agents Chemother 1980; 18: 382. 5. Shannon KP, King A, Phillips I. Development of resistance to beta-lactam antibiotics during therapy of Ps aeruginosa. Lancet 1982; i: 1466. 6. Marier RL, Marinaccio AT, Sanders CV, Aldridge KE, Mitchell JW. Susceptibility Chemother patterns of bacteria following therapy with piperacillin. Antimicrob J 1982; 9 (suppl B): 85. 7. Gwynn MN, Rolinson G. Selection of variants of gram-negative bacteria with elevated production of type 1 &bgr;-lactamase. J Antimicrob Chemother 1983; 11: 577. 8. Sanders C. Emerging problems of resistance to the new cephalosporins: Clinical significance. Intern Med 1984; 5: 37.

&bgr;-LACTAMS AND IMIPENEM SiR,-Recent correspondence has highlighted confusion about mechanisms of resistance of gram-negative bacilli to the newer &bgr;-Iactams. Dr Livermore (Feb 22, p 450) succinctly pointed out the difference between (3-lactamase induction and the selection of stably derepressed mutant. Both mechanisms may lead to failure of treatment. We have been investigating the ability of the carbapenem P-lactam imipenem to induce class I (3-lactamases and its activity against stably derepressed mutants and ability to select strains expressing derepressed &bgr;-Iactamase. Eight strains of Enterobacteriaceae (3 Enterobacter cloacae, 2 Citrobacter freundii, I Serratia marcescens, 1 Morganella morganii, and 1 Providencia stuartiz) were studied. Using a disc diffusion technique with 30 g of antibiotic (10 qg for imipenem) to show antagonism between imipenem or cefoxitin and other (3-lactams (cefamandole, cefotaxime, latamoxef, and carbenicillin) and an exaggerated nitrocefin reaction, we found that both imipenem and cefoxitin antagonise, by zone blunting (ie, enzyme induction), the

NEONATAL SCREENING FOR CYSTIC FIBROSIS

SIR,-The apparent contradiction between the result reported by

Chalmers and the results found in the Netherlands is not resolved by their reply (Feb 22, p 439) to our Feb 8 letter or by Professor Dodge’s (March 15, p 615). They seem to suggest that the Dutch experience is not typical for up-to-date management of cystic fibrosis (CF) but there are few data to support this opinion. We are happy to be able to present some new findings. Dr Wilcken and Ms

-

action of cefamandole, cefotaxime, latamoxef, and carbenicillin. Five of the eight strains (2 E cloacae, 2 C freundii, and 1 M morganii) yielded stably derepressed mutants after culture in media containing subinhibitory concentrations of cefoxitin; but in a parallel experiment no such mutants were selected by imipenem. These experiments were repeated three times with essentially consistent results. ACTIVITY

Survival

rates

of CF

patients.

NED = Netherlands.

The survival

rate in the Dutch CF population, including the population studied, is similar to that for Victoria, Australia, reported by Phelan and Hey2 (see figure). The reference, to our contribution to a 1982 meeting in Brussels, that Wilcken and Chalmers provide does not support a CF

prevalence rate at birth of 1 in 5500 in the Netherlands; nor does any other publication of ours. The best available estimate is 1 in 3600.3

(mg/1) OF SEVEN (3-LACTAMS AGAINST PARENT STRAINS (AND DEREPRESSED MUTANTS)