Synergy of Daptomycin with Oxacillin and Other β-Lactams against Methicillin-Resistant Staphylococcus aureus

Abstract

We previously observed marked synergy between daptomycin and both rifampin and ampicillin against vancomycin-resistant enterococci (VRE). Because the synergy between daptomycin and ampicillin was observed for 100% of VRE strains with high-level ampicillin resistance (ampicillin MIC of >128 g/ml), we looked for synergy between daptomycin and other ␤-lactams against 18 strains of methicillin-resistant Staphylococcus aureus (MRSA) by employing a time-kill method using Mueller-Hinton broth supplemented to 50 mg of Ca 2؉ /liter. All strains were resistant to oxacillin (16 of 18 strains were resistant at drug concentrations of >256 g/ml), and all strains were susceptible to daptomycin (the MIC at which 90% of the tested isolates were inhibited was 1 g/ml). Daptomycin was tested at concentrations of 2, 1, 0.5, 0.25, 0.125, and 0.0625 g/ml alone or in combination with oxacillin at a fixed concentration of 32 g/ml. Synergy was found for all 18 strains with daptomycin at one-half the MIC in combination with 32 g of oxacillin/ml, and synergy was found for 11 of 18 strains (61%) with daptomycin at one-fourth the MIC or less in combination with oxacillin. At 24 h, the daptomycin-oxacillin combination with daptomycin at one-half the MIC showed bactericidal activity against all 18 strains, and the combination with one-fourth the daptomycin MIC showed bactericidal activity against 9 of 18 strains. We also used a novel screening method to look for synergy between daptomycin and other ␤-lactams. In this approach, daptomycin was incorporated into Ca Daptomycin is a novel lipopeptide antibiotic with bactericidal activity against a wide range of clinically important grampositive bacteria, including vancomycin-resistant enterococci (VRE) and methicillin-resistant Staphylococcus aureus (MRSA). In a recent study, we found synergy between daptomycin and both rifampin and ampicillin against VRE (12a). In that work, a screening technique was used to test daptomycin with 18 other antibiotics, and promising combinations were further tested by time-kill studies. In brief, daptomycin was added to Ca 2ϩ -supplemented Mueller-Hinton broth at subinhibitory concentrations, and the Etest-determined MIC of individual antibiotics on agar containing daptomycin was compared with the MIC on agar without daptomycin. When MRSA strains were studied with this method, combinations of daptomycin and ␤-lactams were found to warrant further study. In this report, we present comparative results for several daptomycin-␤-lactam combinations by the screening method and confirmative time-kill studies using combinations of daptomycin and oxacillin or ampicillin-sulbactam for 18 strains of MRSA. MATERIALS AND METHODSEighteen randomly selected strains of MRSA were obtained from the clinical microbiology laboratory at Shands Hospital at the University of Florida, Gainesville, between January and March 2002. All isolates were tested for relatedness by pulsed-field gel electrophoresis at the Mayo Medical Laboratories, Rochester, Minn. Five isolates were different from ea...

Treatment options for methicillin-resistant Staphylococcus aureus (MRSA) infection: Where are we now?

“…Most available data exist on combination therapy with daptomycin and b-lactam antibiotics [95,96]. Oxacillin, in particular, appears to be very efficacious [97,98]. bLactams improve the binding of daptomycin by increasing the net negative charge of the cell membrane [96].…”

“…Combination therapy should therefore have potential in patients with endocarditis, undrainable abscesses and other high-inoculum infections. Knowing that daptomycin with oxacillin increases bactericidal activity and decreases the development of resistance [97] leads to speculation regarding potential advantages in empirical combination therapy.…”

Penicillin Binding Protein 1 Is Important in the Compensatory Response of Staphylococcus aureus to Daptomycin-Induced Membrane Damage and Is a Potential Target for β-Lactam–Daptomycin Synergy

“…he presence of subinhibitory concentrations of ␤-lactam antibiotics increases daptomycin (DAP) activity against both DAP-susceptible and -nonsusceptible (DNS) methicillin-resistant Staphylococcus aureus (MRSA) (1,2). The mechanisms for this are not fully understood, but some ␤-lactams have been observed to increase binding of DAP to bacterial cell membranes (3,4) or to target binding to membrane regions where DAP is most effective (5).…”

Solubilization of Dipropofol, an Antibacterial Agent, Using Saccharide and Ascorbic Acid

“…Combinational administration could be an alternative to the development of new classes of agents [11][12][13][14] and we have studied the combined effect between dipropofol and other classes of antibiotics. The synergy against VRE was only confirmed with the combination between dipropofol and rifampicin.…”