Antimicrobial Agents Research Group, Division of Immunity and Infection, University of Birmingham, Birmingham B15 2TT, UK
Received 28 March 2003; returned 22 April 2003; revised 13 June 2003; accepted 18 June 2003
![]() |
Abstract |
---|
![]() ![]() ![]() ![]() ![]() ![]() |
---|
Methods: The MICs were determined for 150 fluoroquinolone-resistant bacteria, plus 20 nalidixic acid-resistant strains of Salmonella enterica serovar Typhimurium.
Results: Faropenem was very active against Escherichia coli and Streptococcus pneumoniae, but 5/31 Staphylococcus aureus and 2/26 Bacteroides fragilis required 16 mg/L for inhibition. Of 30 multiply drug-resistant isolates with a phenotype suggestive of enhanced efflux, only for one strain (a Bacteroides fragilis) was the faropenem MIC higher than that associated with the other isolates of the same species.
Conclusions: Faropenem was in general as active as imipenem. There was no association between resistance to ciprofloxacin and faropenem or imipenem resistance.
Keywords: carbapenem, fluoroquinolone, MIC
![]() |
Introduction |
---|
![]() ![]() ![]() ![]() ![]() ![]() |
---|
Faropenem, a novel broad-spectrum ß-lactam (penem) has been shown to have good activity for pathogens of the respiratory tract.25 Faropenem has also been shown to have good activity for Enterobacteriaceae2,6,7 and anaerobes.7,8 Therefore the aim of this study was to determine the activity of faropenem, compared with those of ciprofloxacin and imipenem, for fluoroquinolone-resistant bacteria (ciprofloxacin MIC 2 mg/L) of species commonly isolated from the respiratory and digestive tracts and from the skin. This set of isolates was chosen to compare in vitro activities of different drug classes against selected clinical isolates or laboratory-generated strains. The overall objective of this study was to determine whether there was any association between fluoroquinolone resistance and carbapenem resistance.
![]() |
Materials and methods |
---|
![]() ![]() ![]() ![]() ![]() ![]() |
---|
![]() |
Results and discussion |
---|
![]() ![]() ![]() ![]() ![]() ![]() |
---|
For the 21 laboratory mutants and clinical isolates of S. pneumoniae, the MICs of ciprofloxacin were 4>32 mg/L (Table 1). The control strains were NCTC 7466, R6 and its pmrA mutant R6N. Nine strains had at least one of seven substitutions in ParC: Ser-16 to Gly (n = 1), Asp-78 to Asn (n = 1), Ser-79 to Phe (n = 5), Ser-80 to Pro (n = 1), Asp-83 to Tyr (n = 1) Arg-95 to Cys (n = 1) and Lys-137 to Asn (n = 3). Five of the strains had two of these mutations. Thirteen strains had substitutions at Ser-79 or Ser-81 in GyrA. Irrespective of susceptibility to fluoroquinolones or resistance mechanism, including over-expression of the efflux pump gene pmrA, both faropenem and imipenem had good activity.
|
The vancomycin-resistant (MICs 2 mg/L) enterococci (17 Enterococcus faecium, three Enterococcus faecalis) comprised laboratory mutants and human clinical isolates. Eighteen of these strains were also ciprofloxacin-resistant (MIC
2 mg/L). The control strains were E. faecalis NCTC 775 and E. faecium NCTC 7171. We were unable to determine the DNA sequences of the QRDRs of the topoisomerase genes for these strains as there was insufficient sequence information in the EMBL database to design primers. Faropenem inhibited 10/22 of the enterococci at
4 mg/L. Imipenem was less active than faropenem.
For the 27 laboratory mutants and clinical isolates of E. coli, the MICs of ciprofloxacin were 2>32 mg/L. The control strain was E. coli NCTC 10418. All of the E. coli had a substitution in GyrA of Ser-83 to Leu. Twenty-five strains also had substitutions at Asp-87, the most common being with Asn (n = 16). Twenty-three strains also had substitutions within the QRDR of ParC, the most common being at Ser-80 (n = 21; two at Glu-84). Faropenem and imipenem were active against all the ciprofloxacin-resistant E. coli including 11 strains that over-expressed acrB, six strains that over-expressed soxS and four strains that over-expressed marA.
For the 20 laboratory mutants and clinical isolates of S. enterica serovar Typhimurium, the MIC of nalidixic acid was 128 mg/L and for ciprofloxacin 0.060.5 mg/L. The control strain was S. Typhimurium NCTC 74. Eight S. Typhimurium contained substitutions in GyrA at Ser-83 to Phe or Asp-87 to Gly. Faropenem was active against the nalidixic acid-resistant S. Typhimurium including three strains that over-expressed acrB. Imipenem was also active but MICs were generally one-fold higher than those for faropenem.
For the 12 clinical isolates of Pseudomonas aeruginosa, the MIC of ciprofloxacin was 264 mg/L. The control strain was NCTC 10662. One isolate had a substitution in GyrA at Thr-83 to Ile, and two had substitutions at Arg-87 to Ile. The remaining nine isolates had a wild-type gyrA, and mutation in parC was not investigated. Only 6/12 of the P. aeruginosa were inhibited by 8 mg/L faropenem, however 11/12 were inhibited by the same concentration of imipenem. The one strain that over-expressed both mexABoprM and mexEFoprN was susceptible to faropenem.
For the 26 laboratory mutants and clinical isolates of B. fragilis strains, the MIC of ciprofloxacin was 4>32 mg/L. The control strain was NCTC 9343. None of the B. fragilis had mutations in gyrA or gyrB. Twenty-five of the 26 B. fragilis were inhibited by 8 mg/L faropenem and imipenem (Table 1). One multiply antibiotic-resistant strain (mechanism unknown) was resistant to faropenem.
For the 13 clinical isolates of Campylobacter jejuni, the MIC of ciprofloxacin was 1664 mg/L. The control strain was C. jejuni ATCC 33560. All 13 isolates had substitutions in GyrA at Thr-86 to Ile, and 4/13 also had a silent mutation at His-81. Despite repeated attempts, no PCR amplimers for parC were obtained. Faropenem and imipenem had good activity against the ciprofloxacin-resistant campylobacteria (Table 1).
In summary, faropenem shows excellent activity against ciprofloxacin-resistant bacteria, and was as potent as imipenem in this study. The MICs of faropenem were similar for strains with different mutations in the topoisomerase genes encoding ciprofloxacin resistance, suggesting that there was no effect upon faropenem activity. There was no relationship between ciprofloxacin resistance and faropenem resistance regardless of the level of ciprofloxacin resistance. As may have been anticipated, these data indicate that the mechanisms of fluoroquinolone and faropenem resistance are distinct. Finally, faropenem activity was unaffected by over-expression of efflux genes.
![]() |
Acknowledgements |
---|
![]() |
Footnotes |
---|
![]() |
References |
---|
![]() ![]() ![]() ![]() ![]() ![]() |
---|
2 . Cormican, M. G. & Jones, R. N. (1995). Evaluation of the in-vitro activity of faropenem (SY 5555 or SUN 5555) against respiratory tract pathogens and ß-lactamase producing bacteria. Journal of Antimicrobial Chemotherapy 35, 5359.[Abstract]
3 . Inoue, E. & Mitsuhashi, S. (1994). In vitro antibacterial activity and ß-lactamase stability of ST5555, a new oral penem antibiotic. Antimicrobial Agents and Chemotherapy 38, 19749.[Abstract]
4 . Mortensen, J. E. & Egleton, J. H. (1995). Comparative activity of faropenem against aerobic bacteria isolated from pediatric patients. Diagnostic Microbiology and Infectious Disease 22, 3016.[CrossRef][ISI][Medline]
5
.
Woodcock, J. M., Andrews, J. M., Brenwald, N. P. et al. (1997). The in-vitro activity of faropenem, a novel oral penem. Journal of Antimicrobial Chemotherapy 39, 3543.
6 . Sewell, D., Barry, S., Allen, S. et al. (1995). Comparative antimicrobial activities of the penem WY-49605 (SUN 5555) against recent clinical isolates from five US centers. Antimicrobial Agents and Chemotherapy 39, 1591.
7 . Spangler, S. K., Jacobs, M. R. & Appelbaum, P. C. (1994). In vitro susceptibilities of 185 penicillin susceptible and -resistant pneumococci to WY-49605 (SUN/SY 5555), a new oral penem, compared with those of penicillin G, amoxicillin, amoxicillin-clavulanate, cefixime, cefaclor, cefpodoxime, cefuroxime and cefdinir. Antimicrobial Agents and Chemotherapy 38, 29024.[Abstract]
8 . Fuchs, P. C., Barry, A. L. & Sewell, D. L. (1995). Antibacterial activity of WY-49605 compared with those of six other oral agents and selection of disk content for disk diffusion susceptibility testing. Antimicrobial Agents and Chemotherapy 39, 14729.[Abstract]
9 . Andrews, J. M. (2000). Determination of minimum inhibitory concentrations. Journal of Antimicrobial Chemotherapy 48, Suppl. S1, 516.[CrossRef][ISI]
10
.
Eaves, D. J. & Piddock, L. J. V. (2002). Denaturing HPLC, a rapid method to detect novel and multiple mutations in bacterial genes: detection of gyrA mutations in quinolone-resistant Salmonella enterica. Journal of Clinical Microbiology 40, 41215.
|