Synergy between gemifloxacin and trimethoprim/sulfamethoxazole against community-associated methicillin-resistant Staphylococcus aureus.
OBJECTIVE
The rapid emergence of methicillin-resistant Staphylococcus aureus from the community (CA-MRSA) presents difficulties in making treatment choices. We evaluated whether combining another orally available agent commonly used to treat CA-MRSA with gemifloxacin would enhance gemifloxacin activity against CA-MRSA.


METHODS
Fifty strains of SCCmec IV, agr group 1, Panton-Valentine leucocidin-positive CA-MRSA were evaluated for susceptibilities to gemifloxacin, trimethoprim/sulfamethoxazole, doxycycline, levofloxacin, rifampicin, clindamycin and erythromycin. Twenty of these strains were evaluated for the potential for synergy between gemifloxacin and trimethoprim/sulfamethoxazole, clindamycin and rifampicin by time-kill analysis. Two strains were further evaluated in an in vitro pharmacokinetic/pharmacodynamic (PK/PD) model.


RESULTS
In time-kill analyses, gemifloxacin combined with trimethoprim/sulfamethoxazole produced additivity (6/20) or synergy (11/20) in 85% of the isolates tested. The addition of clindamycin to gemifloxacin showed additivity (3/20) or synergy (2/20) in 25% of the isolates. All isolates displayed indifference to the combination of gemifloxacin and rifampicin. In the PK/PD model, combining gemifloxacin and trimethoprim/sulfamethoxazole provided potent and sustained bactericidal activity to detection limits of 2 log(10) cfu/mL by 48 h; gemifloxacin combined with clindamycin or with rifampicin killed to detection limits by 56 h or later. One isolate developed efflux-mediated resistance to gemifloxacin at 96 h with gemifloxacin monotherapy. All combinations prevented the emergence of this resistance.


CONCLUSIONS
Synergy or additivity was demonstrated by time-kill analysis between gemifloxacin and trimethoprim/sulfamethoxazole in most isolates tested. In the PK/PD model, the addition of trimethoprim/sulfamethoxazole, clindamycin and rifampicin enhanced the activity of gemifloxacin against CA-MRSA and suppressed the emergence of resistance to gemifloxacin.
Leonard
Steven N
SN
Anti-Infective Research Laboratory, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, 259 Mack Avenue, Detroit, MI 48201, USA.
Kaatz
Glenn W
GW
Rucker
Latoyia R
LR
Rybak
Michael J
MJ
D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000096:biosynthesis; D001427:Bacterial Toxins / Q000096:biosynthesis; D017714:Community-Acquired Infections / Q000382:microbiology*; D024881:Drug Resistance, Bacterial; D004357:Drug Synergism; D005098:Exotoxins / Q000096:biosynthesis; D024841:Fluoroquinolones / Q000494:pharmacology*; D000077735:Gemifloxacin; D006801:Humans; D007956:Leukocidins / Q000096:biosynthesis; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects* / Q000302:isolation & purification; D008826:Microbial Sensitivity Tests; D050296:Microbial Viability; D009287:Naphthyridines / Q000494:pharmacology*; D013203:Staphylococcal Infections / Q000382:microbiology; D013997:Time Factors; D015534:Trans-Activators / Q000096:biosynthesis; D015662:Trimethoprim, Sulfamethoxazole Drug Combination / Q000494:pharmacology*
C095698:Agr protein, Staphylococcus aureus; D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D001427:Bacterial Toxins; D005098:Exotoxins; D024841:Fluoroquinolones; D007956:Leukocidins; D009287:Naphthyridines; C078284:Panton-Valentine leukocidin; D015534:Trans-Activators; D015662:Trimethoprim, Sulfamethoxazole Drug Combination; D000077735:Gemifloxacin