1 Department of Pathology, Hershey Medical Center, P.O. Box 850, Hershey, PA 17033; 2 Case Western Reserve University, Cleveland, OH 44106, USA
Keywords: faropenem, cidality
Sir,
Faropenem is a novel oral ß-lactam antimicrobial (no longer under development) for therapy of community-acquired respiratory tract and other infections. Previous studies have highlighted the broad spectrum of activity of this compound (also known as SUN/SY 5555, ALP-201 and WY-49605) against Gram-negative, Gram-positive and also anaerobic bacteria. In addition, faropenem MICs have been shown to be unaffected by ß-lactamase production in common respiratory tract and other pathogens.14
In this study, broth microdilution and timekill methodology were used to examine the in vitro activity of faropenem compared with a variety of antimicrobials against 14 Gram-negative and -positive pathogens, including four staphylococci, four streptococci and six Enterobacteriaceae. Faropenem was compared with levofloxacin, cefuroxime, co-amoxiclav and ceftriaxone (all strains); with linezolid and azithromycin (staphylococci and streptococci) and with linezolid, vancomycin and azithromycin (staphylococci).
All organisms were recent cultures isolated from clinical specimens within the past year identified by standard methodology. All had faropenem MICs in the range described by other authors.14 Strains included two each of Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Streptococcus pyogenes, methicillin-susceptible Staphylococcus aureus, methicillin-susceptible Staphylococcus saprophyticus and Streptococcus intermedius (S. milleri: UK classification).
Faropenem susceptibility powder was obtained from Bayer Pharmaceuticals (West Haven, CT, USA) and other antimicrobials were obtained from their respective manufacturers. Microdilution MICs were carried out according to NCCLS recommendations5 using cation-adjusted MuellerHinton broth with 5% lysed defibrinated horse blood for streptococci. Standard quality control strains were included in each run. Faropenem MICs for quality control strains were: E. coli ATCC 25922, 0.51 mg/L; S. aureus ATCC 29213, 0.060.125 mg/L. Quality control values for other organism/drug combinations were all within acceptable ranges according to NCCLS recommendations.5
Timekill activities were as described previously6 using cation-adjusted MuellerHinton broth (Difco) + 5% lysed horse blood for streptococci. Antibiotic concentrations were chosen to comprise the MIC and two doubling dilutions above the MIC. Growth controls with inoculum but no antibiotic were included with each experiment. The original inoculum was determined using the untreated growth control. Only tubes containing an initial inoculum within the range of 5 x 105 to 5 x 106 cfu/mL were acceptable.6 Viability counts of antibiotic-containing suspensions were carried out at 0, 3, 6, 12 and 24 h as described previously6 using blood agar plates for all species except P. mirabilis where MacConkey agar was used to prevent swarming. Colony counts were carried out on plates yielding 30300 colonies. The lower limit of sensitivity of colony counts was 300 cfu/mL.6
Timekill assays were analysed by determining the number of strains which yielded a log10 cfu/mL of 1, 2 and 3 at 3, 6, 12 and 24 h, compared with counts at 0 h. Antimicrobials were considered bactericidal at the lowest concentration that reduced the original inoculum by
3 log10 cfu/mL (99.9%) at each of the time periods, and bacteriostatic if the inoculum was reduced by 0<3 log10 cfu/mL. The problem of bacterial carryover was addressed by dilution as described previously.6 For levofloxacin, the one strain with levofloxacin MIC > 32.0 mg/L, and for azithromycin, the one strain with azithromycin MIC > 256.0 mg/L, were excluded from timekill analysis.
Results of microdilution MICs are presented in Table 1. As can be seen, faropenem MICs ranged between 0.03 and 8.0 mg/L with the highest MICs being found for Gram-negative bacteria especially P. mirabilis strains. In comparison, MICs of cefuroxime ranged between 0.016 and 32.0 mg/L; those of co-amoxiclav ranged between 0.016 and 16.0 mg/L, and those of ceftriaxone ranged between 0.016 and 32.0 mg/L. Levofloxacin MICs ranged between 0.06 and >32.0 mg/L. For Gram-positive organisms tested, MICs were as follows: linezolid, 2.04.0 mg/L; vancomycin, 1.04.0 mg/L; azithromycin, 0.125>256.0 mg/L.
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Our results confirm findings by other authors. Lower MICs of faropenem as well as other ß-lactams for Gram-positive compared with Gram-negative organisms have also been described before.14 Additionally, faropenem yielded favourable kill kinetics relative to the MIC against all organisms tested, compared with other ß-lactams and levofloxacin. Vancomycin and linezolid, agents active against Gram-positive organisms only, were predominantly bacteriostatic.
Results of the current MIC and timekill studies must be integrated with pharmacokinetic/pharmacodynamic findings before conclusions can be reached as to clinical validity.
Acknowledgements
This study was supported by a grant from Bayer AG, Leverkusen, Germany.
Footnotes
* Corresponding author. Tel: +1-717-531-5113; Fax: +1-717-531-7953; E-mail: pappelbaum{at}psu.edu
References
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