In vitro activity of faropenem and 21 other compounds against 385 different genetically characterized isolates of antibiotic-resistant Streptococcus pneumoniae

F.-J. Schmitza,b,*, M. Boosa, S. Mayera, J. Verhoefb, D. Milatovicb and A. C. Fluitb

a Institute for Medical Microbiology and Virology, Heinrich-Heine-Universität Düsseldorf, Universitätsstraße 1, Geb. 22.21, D-40225 Düsseldorf, Germany; b Eijkman-Winkler-Institute for Medical Microbiology, Utrecht, The Netherlands

Sir,

Not only are isolates of Streptococcus pneumoniae showing resistance to ß-lactams, but strains resistant to macrolides, tetracycline, quinolones and trimethoprim–sulphamethoxazole, either alone or in combination, are now being detected. This growing worldwide incidence of multidrug-resistant S. pneumoniae has created the need for new, effective oral agents that can be used to treat adult and paediatric pneumococcal infections. Faropenem is a novel penem antimicrobial agent intended for oral administration. Penems share structural similarities with both penicillins and cephalosporins. Preliminary reports indicate that faropenem's activity is not only broad spectrum (Gram-negative, Gram-positive and some anaerobic bacteria), but also bactericidal.1,2 Previous studies have shown that target modifications via altered penicillin-binding proteins cause a significant increase in the MICs of faropenem compared with wild-type strains.3 The purpose of the present study was to evaluate the in vitro activity of faropenem against genetically characterized S. pneumoniae isolates resistant to classes of antibiotics other than ß-lactams.

This in vitro study compared the activities of faropenem and 21 other oral and/or parenteral antimicrobial agents against 385 different recent European clinical isolates, with some of the isolates tested displaying cross-resistance to several of the antibiotics studied, i.e. erythromycin, tetracycline, levofloxacin and trimethoprim–sulphamethoxazole. NCCLS broth microdilution methodology was used.4 The isolates comprised five groups of genetically characterized pneumococci: (i) those resistant to erythromycin and clindamycin [erm(B) genotype]; (ii) those resistant to erythromycin, but susceptible to clindamycin [mef(A) genotype]; (iii) those resistant to tetracycline [tet(M) genotype]; (iv) those with decreased susceptibility to levofloxacin [mutations in gyr(A) and par(C), combined with efflux activity]; and (v) those resistant to trimethoprim–sulphamethoxazole [mutations in the dihydrofolate reductase (DHFR) gene as well as modifications within sul(A), which encodes dihydropteroate synthase (DHPS)]. They were collected from patients with bacteraemia, community-acquired respiratory tract infections or nosocomial pneumonia during international surveillance studies between 1997 and 1999.5 Only one isolate, which was considered clinically significant according to local criteria, per patient was studied.

A total of 215 S. pneumoniae isolates were selected that were resistant to erythromycin: 157 carried the erm(B) gene and 58 the mef(A) gene. All isolates with erm(B) displayed the MLSB phenotype, while all of those with mef(A) had the M phenotype.

All 240 tetracycline-resistant S. pneumoniae isolates studied carried the tet(M) gene and none the tet(O) gene.

Twenty-five S. pneumoniae isolates were selected that had a decreased susceptibility to levofloxacin (MIC >= 2 mg/L).5 Ten of 16 isolates with a levofloxacin MIC of 4 mg/L demonstrated mutations within par(C) encoding Ser-79->Phe, while six of 16 demonstrated mutations encoding Asp-83->Asn. All 16 isolates demonstrated mutations within gyr(A) encoding either a Ser-81->Phe or a Ser-81->Tyr amino acid change. None of these mutations was found in any of the nine isolates with levofloxacin MICs of 2 mg/L and ciprofloxacin MICs of 4 mg/L. A mutation in par(E) was found to result in the amino acid change Ile-460->Val in 18 of the 25 isolates tested. No alteration was found in GyrB. Reserpine lowered ciprofloxacin MICs by between one and four doubling dilutions in 20 of 25 isolates tested with a ciprofloxacin MIC >= 4 mg/L. Therefore, an efflux system probably contributed to the decreased ciprofloxacin susceptibility in most of the isolates tested.

All 50 S. pneumoniae isolates that were resistant to trimethoprim–sulphamethoxazole were also resistant to the two drugs separately. The DHFR genes were sequenced and all isolates displayed the amino acid change Ile-100->Leu, as described previously.6 With regard to sulphonamide resistance, sequence comparisons of the chromosomal DHPS gene of resistant and susceptible clinical pneumococcal isolates revealed duplications of either three or six bases, resulting in the repetition of one or two amino acids in the region from Arg-58 to Tyr-63 of the DHPS of resistant isolates, as described previously.6

The comparative activities of the 22 compounds tested are listed in the TableGo. These data show that faropenem was one of the most potent agents with an MIC90 <= 0.25 mg/L. The highest MIC observed was 0.5 mg/L, indicating that all isolates tested, including those with a decreased susceptibility to penicillin, were susceptible to the drug, based on a provisional breakpoint of <1 mg/L. Furthermore, faropenem also showed significant activity against the genetically characterized S. pneumoniae isolates that were not susceptible to antibiotics commonly used in antipneumococcal therapy, i.e. macrolides, tetracyclines, quinolones and co-trimoxazole. In addition, Boswell and colleagues2 have shown that faropenem exhibits significant bactericidal activity and has a good post-antibiotic effect on S. pneumoniae isolates. Based on all of the data collected to date, faropenem appears to be a promising new antimicrobial agent and warrants further clinical investigation.


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Table. Susceptibility of S. pneumoniae to 22 selected antimicrobial agents
 

Notes

* Corresponding author. Tel/Fax: +49-2132-72040; E-mail: schmitfj{at}uni-duesseldorf.de Back

References

1 . Woodcock, J. M., Andrews, J. M., Brenwald, N. P., Ashby, J. P. & Wise, R. (1997). The in-vitro activity of faropenem, a novel penem. Journal of Antimicrobial Chemotherapy 39, 35–43.[Abstract]

2 . Boswell, F. J., Andrews, J. M. & Wise, R. (1997). Pharmacodynamic properties of faropenem demonstrated by studies of time–kill kinetics and postantibotic effect. Journal of Antimicrobial Chemotherapy 39, 415–8.[Abstract]

3 . Marchese, A., Debbia, E. A., Bryskier, A. & Schito, G. C. (1999). Antimicrobial activity of faropenem, a new oral penem, against lower respiratory tract pathogens. Clinical Microbiology and Infection 5, 282–7.[Medline]

4 . National Committee for Clinical Laboratory Standards. (1997). Methods for Dilution Antimicrobial Tests for Bacteria that Grow Aerobically: Approved Standard M7-A4. NCCLS, Wayne, PA.

5 . Milatovic, D., Schmitz, F. J., Brisse, S., Verhoef, J. & Fluit, A. C. (2000). In vitro activities of sitafloxacin (DU-6859a) and six other fluoroquinolones against 8,796 clinical bacterial isolates. Antimicrobial Agents and Chemotherapy 44, 1102–7.[Abstract/Free Full Text]

6 . Widdowson, C. A. & Klugman, K. P. (1999). Molecular mechanisms of resistance to commonly used non-betalactam drugs in Streptococcus pneumoniae. Seminars in Respiratory Infections 14, 255–68.[Medline]