The effect of combinations of cefotiam and other antibiotics on methicillin-resistant Staphylococcus aureus in vitro

Several studies have previously reported synergistic effects between vancomycin and a given ␤-lactam or a given aminoglycoside against methicillin-resistant Staphylococcus aureus (MRSA) strains. The aim of our study was to exhaustively compare the effects of different combinations of a ␤-lactam, vancomycin, and/or an aminoglycoside against 32 clinical MRSA strains with different aminoglycoside susceptibility patterns. The effects of 26 different ␤-lactam-vancomycin and 8 different aminoglycoside-vancomycin combinations were first studied using a disk diffusion screening method. The best interactions with vancomycin were observed with either imipenem, cefazolin, or netilmicin. By checkerboard studies, imipenem-vancomycin and cefazolinvancomycin each provided a synergistic bacteriostatic effect against 22 strains; the mean fractional inhibitory concentration (FIC) indexes were 0.35 and 0.46 for imipenem-vancomycin and cefazolin-vancomycin, respectively. The vancomycin-netilmicin combination provided an indifferent effect against all of the 32 strains tested; the mean of FIC index was 1.096. The mean concentrations of imipenem, cefazolin, netilmicin, and vancomycin at which FIC indexes were calculated were clinically achievable. Killing experiments were then performed using imipenem, cefazolin, netilmicin, and vancomycin at one-half of the MIC, alone and in different combinations, against 10 strains. The vancomycin-netilmicin regimen was rarely bactericidal, even against strains susceptible to netilmicin. The imipenem-vancomycin and cefazolin-vancomycin combinations were strongly bactericidal against six and five strains, respectively. The addition of netilmicin markedly enhanced the killing activity of the combination of cefazolin or imipenem plus vancomycin, but only for the MRSA strains against which the ␤-lactam-vancomycin combinations had no bactericidal effect. It is noteworthy that the latter strains were both susceptible to netilmicin and heterogeneously resistant to methicillin.

Section: Discussionsupporting

confidence: 75%

Section: Discussionmentioning

confidence: 99%

In Vitro Synergistic Effects of Double and Triple Combinations of β-Lactams, Vancomycin, and Netilmicin against Methicillin-Resistant Staphylococcus aureus Strains

Rochon-Edouard¹,

Pestel-Caron²,

Lemeland³

et al. 2000

“…There have been many contradictory observations with regard to the combination effect of vancomycin and ␤-lactam against S. aureus clinical isolates, including additive and/or synergistic effects (2,4,15,18,19,20,21) and antagonistic effects (7, 9, 14; H. Hanaki, S. Ohkawa, Y. Inaba, T. Hashimoto, and K. Hiramatsu, Abstr. 38th Intersci.…”

mentioning

confidence: 99%

Combination Effect of Vancomycin and β-Lactams against a Staphylococcus aureus Strain, Mu3, with Heterogeneous Resistance to Vancomycin

Aritaka

Hanaki

Cui

et al. 2001

We tested the combined activity of vancomycin and seven ␤-lactam antibiotics against Staphylococcus aureus clinical strain Mu3, which displays heterogeneous resistance to vancomycin. When combined with vancomycin, four of the seven tested ␤-lactams exhibited an additive effect at or near their MICs, while all showed an antagonistic effect at lower, sub-MIC levels. This study implicated the unpredictable nature of combination therapy of ␤-lactams and vancomycin against S. aureus with reduced susceptibility to vancomycin.

“…Several recent studies from Japan have shown that combinations of carbapenems with ␤-lactams and cephalosporins with penicillins exhibit synergy against MRSA (13)(14)(15). As far as is known, MRSA is resistant to ␤-lactams because of the presence of an altered penicillin-binding protein (PBP 2a) with reduced affinity for methicillin and other ␤-lactam antibiotics (4,9).…”

mentioning

confidence: 99%

Concentration-dependent synergy and antagonism between cefoperazone and imipenem against methicillin-resistant Staphylococcus aureus

Rand

Brown

1995

By the agar dilution checkerboard method, striking synergy between cefoperazone and imipenem was observed with 32 strains of methicillin-resistant Staphylococcus aureus (fractional inhibitory concentration indices, Յ0.03 to 0.34; mean, 0.12 ؎ 0.08). By the double-disk diffusion method, the synergy was confirmed, but about 60% of strains showed antagonism manifest by truncation of the zone of inhibition around cefoperazone. The mechanism may involve auxiliary factors distinct from those essential for the expression of methicillin resistance.Methicillin-resistant Staphylococcus aureus (MRSA) have become major nosocomial pathogens over the past 15 years. Several recent studies from Japan have shown that combinations of carbapenems with ␤-lactams and cephalosporins with penicillins exhibit synergy against MRSA (13-15). As far as is known, MRSA is resistant to ␤-lactams because of the presence of an altered penicillin-binding protein (PBP 2a) with reduced affinity for methicillin and other ␤-lactam antibiotics (4, 9). We explored the synergy between imipenem and cefoperazone and confirmed the striking degree of synergy noted by others. However, our studies also show that there is a simultaneous concentration-dependent antagonism between these two antibiotics in vitro against MRSA.Antibiotics. Cefoperazone (Roerig Division, Pfizer, Inc., New York, N.Y.) and imipenem (Merck Sharpe & Dohme, West Point, Pa.) powders for in vitro use were generously supplied by their manufacturers. Kirby-Bauer disks were obtained from BBL (Becton Dickinson Microbiology Systems, Cockeysville, Md.). Thirty-two strains of MRSA were obtained from the microbiology laboratories of the Shands Hospital and the Department of Veterans Affairs Medical Center, Gainesville, Fla. The MRSA isolates grew on medium containing 6 g of oxacillin per ml and were identified by coagulase testing and other conventional methods (Microscan and Vitek). A quality control strain of MRSA from the Shands Hospital Microbiology Laboratory was included in every test run.Synergy testing. The agar dilution checkerboard procedure was performed as described previously (7). Briefly, cefoperazone (2 to 256 g/ml) and imipenem (0.5 to 64 g/ml) were prepared in Ca 2ϩ -and Mg 2ϩ -supplemented Mueller-Hinton agar and were dispensed into 9-cm agar plates. Each plate contained a fixed concentration of each antibiotic alone or in combination. A non-antibiotic-containing control plate was always included. Plates were used within 24 h of preparation. The inoculum was delivered with a Cathra replicate plater and was adjusted to provide approximately 10 4 CFU per spot. The inoculated plates were incubated at 36ЊC for 24 h in a non-CO 2 -containing incubator and were read by one of us (P.B.). A spot was considered positive according to the criteria given in document M7-A2 of the National Committee for Clinical Laboratory Standards (16). Double-disk diffusion was performed as described previously (7), except that the imipenem disk was placed in the middle and the cefoperazone disks were plac...