Journal of Antimicrobial Chemotherapy (1997) 40, 105 108 Brief reports JAC Decreased susceptibility to imipenem among penicillin-resistant Streptococcus pneumoniae Andreas Pikis a *, Jacob A. Donkersloot b, Shama Akram c, Jerry M. Keith b, Joseph M. Campos d and William J. Rodriguez a a Department of Infectious Diseases, Children s National Medical Center, Washington, DC; b Laboratory of Microbial Ecology, National Institute of Dental Research, National Institutes of Health, Bethesda MD; c Microbiology Research, The Research Foundation, Children s National Medical Center, Washington, DC; d Department of Laboratory Medicine, Children s National Medical Center, and the Departments of Paediatrics, Pathology and Microbiology/Immunology, George Washington University Medical Center, Washington, DC, USA We assessed the antimicrobial susceptibilities of 59 penicillin-intermediate or penicillinresistant pneumococci. All strains were susceptible to vancomycin and rifampicin. The frequency of strains with decreased susceptibility to cefotaxime, chloramphenicol, imipenem and meropenem was 15, 31, 47 and 49% respectively. The high percentage of penicillinintermediate or penicillin-resistant Streptococcus pneumoniae with decreased susceptibility to third-generation cephalosporins, chloramphenicol and carbapenems limits the therapeutic options for the treatment of invasive pneumococcal infections and particularly of meningitis. Introduction Streptococcus pneumoniae remains a significant cause of morbidity and mortality in all age groups. It is a major cause of otitis media, sinusitis, pneumonia, bacteraemia and meningitis. The increasing frequency of pneumococcal strains resistant to penicillin and other antibiotics has raised significant concerns regarding the management of patients with pneumococcal infections, particularly meningitis. 1 In areas with a high prevalence of penicillin- and cephalosporin-resistant pneumococci the combination of vancomycin and a third-generation cephalosporin is currently recommended as the initial empirical antibiotic therapy in children with suspected pneumococcal meningitis. 1 Imipenem has been shown to be very effective in vitro and in experimental meningitis against penicillinresistant pneumococci. 2 Consequently in areas with a high prevalence of penicillin- and cephalosporin-resistant pneumococci some investigators have proposed imipenem as an alternative for the empirical treatment of patients with suspected pneumococcal meningitis. After testing a small number of penicillin-resistant pneumococci, we found that several strains also had decreased susceptibility to various antibiotics including third-generation cephalosporins and the carbapenem imipenem. These findings prompted us to investigate the susceptibility of a larger number of penicillin-resistant pneumococci to imipenem and other antibiotics. Materials and methods This study included 59 S. pneumoniae strains with decreased susceptibility to penicillin (52 were penicillinintermediate and seven penicillin-resistant) recovered from usually sterile body sites. Strains were either isolated by the Clinical Microbiology Laboratory at Children s National Medical Center, Washington, DC, USA, or referred from other hospitals or clinics in the Washington metropolitan area to the Laboratory of Microbiology Research at the same hospital. The identification of S. pneumoniae was based on optochin sensitivity and bile *Corresponding author. Department of Infectious Diseases, Children s National Medical Center, W 3.5, Suite 100, 111 Michigan Avenue, NW, Washington, DC 20010-2970, USA. Tel: 1-202-884-5051; Fax: 1-202-884-5989. 1997 The British Society for Antimicrobial Chemotherapy 105
A. Pikis et al. solubility. MICs of penicillin and other antimicrobial agents were determined by an agar dilution method with a final inoculum of 10 4 cfu delivered by a Steers Foltz replicator on to Mueller Hinton agar enriched with 3% lysed horse blood and incubated for 20 24 h at 37 C in a 7% CO 2 atmosphere. The MIC was defined as the lowest concentration of the antibiotic that inhibited visible growth. Strains were defined as susceptible to penicillin when the MIC was 0.06 mg/l, intermediate when the MIC was between 0.1 and 1 mg/l, and resistant when the MIC was 2 mg/l. The following antimicrobial agents were tested: imipenem (Merck Sharp and Dohme, Rahway, NJ, USA), meropenem (Zeneca Pharmaceutical Group, Wilmington, DE, USA), cefotaxime, chloramphenicol, penicillin G, rifampicin and vancomycin (US Pharmacopeial Convention, Inc., Rockville, MD, USA). Serotyping was performed on the basis of capsular swelling (Quellung reaction) with type-specific pneumococcal antisera. The Danish system of nomenclature was used. Thirteen randomly selected pneumococcal strains were submitted to Merck Research Laboratories (Rahway, NJ, USA) for independent imipenem MIC determination. Susceptibility testing for these isolates was performed with the microtitre broth dilution method using cation-adjusted Mueller Hinton broth with 3% lysed horse blood. Results The susceptibilities of the 59 S. pneumoniae strains to selected antimicrobial agents were determined (Table). As judged by recommended susceptibility breakpoints, all strains were susceptible to vancomycin and rifampicin. On the other hand, 15, 31, 47 and 49% of penicillin-intermediate or penicillin-resistant strains had decreased susceptibility to cefotaxime, chloramphenicol, imipenem and meropenem, respectively. Five of the nine strains with decreased susceptibility to cefotaxime were cefotaximeintermediate and the other four were cefotaxime-resistant. Twenty-eight of the 59 strains exhibited decreased susceptibility to imipenem (all were imipenem-intermediate). MICs of imipenem determined by Merck Research Laboratories for the 13 randomly selected strains confirmed our results. Meropenem MICs ranged from 0.015 to 1 mg/l (MIC 50 and MIC 90 were 0.25 and 0.5 mg/l, respectively). According to the manufacturer s recommendations for the meropenem MIC susceptibility breakpoint, 29 of our strains had decreased susceptibility. There are at present, no NCCLS or manufacturer s recommendations for further categorizing such strains as intermediate or resistant to meropenem. Twenty-six of the 28 strains with decreased susceptibility to imipenem were serotyped. The serotype distribution was as follows: 23F (eight strains), 6B (seven), 14 (six), 6A (three) and 19F (two). Discussion Until recently, cefotaxime or ceftriaxone alone have been the drugs of choice for the treatment of suspected bacterial meningitis in children and infants beyond the neonatal period. However, resistance and clinical failure of these antimicrobial agents in the treatment of pneumococcal meningitis have been noted during the last few years. 3,4 Of great concern are clinical failures with third-generation cephalosporins not only for infections caused by cephalosporin-resistant strains (MICs 2 mg/l), 3 but also for those caused by cephalosporin-intermediate strains (MICs 1 mg/l). 4 Consequently, in areas in which penicillinresistant strains have been identified, the addition of vancomycin to a third-generation cephalosporin has become the standard treatment of suspected pneumococcal meningitis. Vancomycin is presently the only antibiotic for which no resistant strains have been reported in vitro. Clinical failures with vancomycin have been described in four adult patients from Spain (two of them had penicillin-susceptible Table. Susceptibilities to selected antibiotics of 59 S. pneumoniae isolates with decreased susceptibility to penicillin a Antimicrobial MIC breakpoint agent (mg/l) b MIC range MIC 50 MIC 90 % Susceptible Cefotaxime 0.5 0.03 4 0.25 1 85 Chloramphenicol 4 2 32 4. 16 69 Imipenem 0.125 0.015 0.5 0.25 0.5 53 Meropenem 0.125 c 0.015 1.0 0.25 0.5 51 Rifampicin 1 0.015 0.06 0.06 0.06 100 Vancomycin 1 0.125 0.25 0.25 0.25 100 a Fifty-two strains were penicillin-intermediate and seven were penicillin-resistant. b As recommended by the National Committee for Clinical Laboratory Standards. 11 c As recommended by the manufacturer. 106
S. pneumoniae with decreased susceptibility to imipenem and the other two penicillin-resistant pneumococcal meningitis). 5 In this study vancomycin was used as monotherapy, and the dosages were suboptimal (30 mg/kg/day). Additionally, the concomitant administration of dexamethasone in these patients may have contributed to the poor outcome, although a recent report demonstrated that vancomycin penetrates reliably into the CSF of children with bacterial meningitis despite the concomitant administration of dexamethasone. 6 Other potentially useful drugs in the treatment of pneumococcal meningitis due to strains resistant to penicillin and cefotaxime or ceftriaxone include chloramphenicol, rifampicin and imipenem. The incidence of chloramphenicol resistance noted in this study was 31%. In addition, the bactericidal activity of chloramphenicol against strains which are resistant to penicillin is poor, and clinical failures of pneumococcal meningitis caused by penicillin-resistant strains after treatment with chloramphenicol have been reported. 7 Therefore, chloramphenicol should not be used in suspected or proven penicillin-resistant pneumococcal meningitis. Although the clinical role of rifampicin in the treatment of penicillin-resistant pneumococcal meningitis is not clear, it has often been used as part of therapy. 1 It is very effective i n v i t r o against penicillin-resistant pneumococci. However, the results of in-vitro studies vary when rifampicin is used in combination with other antibiotics. In one study, killing activity by -lactam antibiotics and vancomycin was reduced by the addition of rifampicin. Furthermore, resistance to rifampicin may increase rapidly if widespread use occurs. Previous in-vitro studies of imipenem showed that it is the most effective -lactam antibiotic against penicillinresistant pneumococci and has the best bactericidal activity measured by the time killing curve method. 2 It is noteworthy that in the USA a recent survey involving 13 hospitals from 12 states revealed that only one of 544 S. pneumoniae strains isolated during the period 1 October 1991, to 30 September 1992, was resistant to imipenem. 8 Clinical experience with imipenem is limited because of its propensity to cause seizures. Nevertheless, imipenem has been used successfully in two cases of pneumococcal meningitis caused by penicillin-resistant strains that had failed treatment with other antibiotics including thirdgeneration cephalosporins. 9 We noted that 28 of the 59 (47%) penicillin-intermediate or penicillin-resistant strains had also decreased susceptibility to imipenem. The imipenem-intermediate strains were of seven different serotypes suggesting that resistance to this antibiotic is not limited to a single clone. The high incidence of elevated imipenem MICs is not unique for the Washington, DC, area: similar findings have recently been reported from Canada and Switzerland. Meropenem, a new carbapenem which seems not to have epileptogenic side-effects, has been reported to be very effective in vivo and in experimental meningitis against penicillin-resistant S. pneumoniae. Recent clinical trials showed that meropenem is comparable to cefotaxime in the treatment of bacterial meningitis. 10 But there are no data regarding the clinical use of meropenem against pneumococcal strains with decreased susceptibility to penicillin and third-generation cephalosporins. Several of our strains had meropenem MICs higher than the suggested susceptibility breakpoint. The results of this study indicate that a high percentage of our penicillin-intermediate and penicillin-resistant strains also had decreased susceptibility to carbapenems. The higher in-vitro efficacy we noted with cefotaxime compared with that of carbapenems may be a reflection of the MIC breakpoints selected and the limited clinical experience with the latter. Further knowledge of the pharmacokinetics of meropenem as well as additional clinical experience should help resolve this issue. Until further information is available we believe that in areas in which penicillin-intermediate or penicillin-resistant pneumococci have been identified, suspected cases of pneumococcal meningitis should be treated empirically with vancomycin plus cefotaxime or ceftriaxone with or without rifampicin. Subsequent modification of the treatment should be according to the antibiotic susceptibility of the infecting microorganism. References 1. Schreiber, J. R. & Jacobs, M. R. (1995). Antibiotic-resistant pneumococci. Pediatric Clinics of North America 42, 519 37. 2. Doit, C. P., Bonacorsi, S. P., Fremaux, A. J., Sissia, G., Cohen, R., Geslin, P. L. et al. (1994). In vitro killing activities of antibiotics at clinically achievable concentrations in cerebrospinal fluid against penicillin-resistant Streptococcus pneumoniae isolated from children with meningitis. Journal of Antimicrobial Chemotherapy 38, 2655 9. 3. Bradley, J. S. & Connor, J. D. (1991). Ceftriaxone failure in meningitis caused by Streptococcus pneumoniae with reduced susceptibility to beta-lactam antibiotics. Pediatric Infectious Disease Journal 10, 871 3. 4. Catalán, M. J., Fernández, J. M., Vasquez, A., Varela de Seijas, E., Suárez, A. & Bernaldo de Quirós, J. C. (1994). Failure of cefotaxime in the treatment of meningitis due to relatively resistant Streptococcus pneumoniae. Clinical Infectious Diseases 18, 766 9. 5. Viladrich, P. F., Gudiol, F., Línares, J., Pallarés, R., Sabaté, I., Rufí, G. et al. (1991). Evaluation of vancomycin for therapy of adult pneumococcal meningitis. Antimicrobial Agents and Chemotherapy 35, 2467 72. 6. Klugman, K. P., Friedland, I. R. & Bradley, J. S. (1995). Bactericidal activity against cephalosporin-resistant Streptococcus pneu - moniae in cerebrospinal fluid of children with acute bacterial meningitis. Antimicrobial Agents and Chemotherapy 39, 1988 92. 7. Friedland, I. R. & Klugman, K. P. (1992). Failure of chloramphenicol therapy in penicillin-resistant pneumococcal meningitis. Lancet 339, 405 8. 8. Breiman, R. F., Butler, J. C., Tenover, F. C., Elliott, J. A. & 107
A. Pikis et al. Facklam, R. R. (1994). Emergence of drug-resistant pneumococcal infections in the United States. Journal of the American Medical Association 271, 1831 5. 9. Asensi, F., Otero, M. C., Pérez-Tamarit, D., Rodríguez-Escribano, I., Cabedo, J. L., Gresa, S. et al. (1993). Risk/benefit in the treatment of children with imipenem-cilastatin for meningitis caused by penicillin-resistant pneumococcus. Journal of Chemotherapy 5, 133 4. 10. Klugman, K. P., Dagan, R. & the Meropenem Meningitis Study Group. (1995). Randomized comparison of meropenem with cefotaxime for treatment of bacterial meningitis. Antimicrobial Agents and Chemotherapy 39, 1140 6. 11. National Committee for Clinical Laboratory Standards. (1995). Performance Standards for Antimicrobial Susceptibility Testing: Sixth Informational Supplement. Document M100-S6. NCCLS, Villanova, PA. Received 5 August 1996; returned 21 October 1996; revised 13 November 1996; accepted 6 February 1997 108
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