Abstract & Commentary

Anti-staphylococcal β-lactam Antibiotics Potentiate Daptomycin Activity vs. MRSA

By Dean L. Winslow, MD, FACP, FIDSA, Chief, Division of AIDS Medicine, Santa Clara Valley Medical Center; Clinical Professor, Stanford University School of Medicine, is Associate Editor for Infectious Disease Alert.

Dr. Winslow is a speaker for GSK and is a consultant for Siemens Diagnostics.

Synopsis: Daptomycin (DAP) plus anti-staphylococcal β-lactam antibiotics (ASBLs) were used to clear refractory MRSA bacteremia. These β-lactam antibiotics produced in vitro enhancement of DAP bactericidal activity, increased cell membrane daptomycin binding, and decreased positive surface charge in DAP-nonsusceptible MRSA.

Sources: Dhand A, et al. Use of antistaphylococcal β-lactams to increase daptomycin activity in eradicating persistent bacteremia due to methicillin-resistant Staphylococcus aureus: Role of enhanced daptomycin binding. Clin Infect Dis 2011;53:158-163.

Seven patients were identified when DAP-ASBL therapy was used to eradicate persistent MRSA bacteremia. Isolates from 3 patients were available for in vitro study. Standard minimum inhibitory concentrations (MICs) were determined and time-kill curves in Mueller-Hinton broth media were performed on the three isolates using DAP (10 µg/mL) alone and in combination with oxacillin 20 µg/mL. A DAP-resistant strain isolated from 1 patient was studied using fluorescein-labeled DAP.

Of the three well-characterized isolates of MRSA studied, all received initial therapy with vancomycin for 4-11 days and experienced an increase in vancomycin MICs from 1-2 to 2-4 µg/mL. Second-line therapy of these 3 patients consisted of DAP given for an additional 4-6 days and DAP MIC rose from 0.5-0.75 to 0.75-4 µg/mL with this treatment. Third-line therapy consisted of DAP + gentamicin for 3-5 days followed by DAP + nafcillin for an additional 9-55 days. With fourth-line therapy (DAP + nafcillin), all patients cleared their MRSA bacteremia within 24 hours.

Time-kill curves showed no inhibition of growth with oxacillin by itself, delayed/partial killing of the isolates by DAP alone at 10 µg/mL, and marked enhancement of bactericidal activity of DAP (approximately 6 log10 reduction in viable bacteria at 13 hours) by the addition of oxacillin 20 µg/mL to DAP 10 mg/mL.

One DAP-resistant isolate demonstrated poor binding of DAP in the absence of ASBLs. However, in the presence of nafcillin 40 µg/mL, significant DAP binding was detected, focally and on the organism's surface. This same isolate demonstrated reduction in net-positive surface charge during growth in the presence of ASBLs.

Commentary

MRSA has emerged in many regions of the world to be the predominant isolate of Staphylococcus aureus. The usual treatment for life-threatening bacteremic infections due to MRSA is IV vancomycin. Unfortunately, treatment failure manifested by persistent bacteremia is seen with increasing regularity and is commonly associated with the development of increasing vancomycin MICs while on therapy. While daptomycin often is effective in treating infections due to vancomycin-insensitive strains of MRSA, development of DAP resistance on treatment with daptomycin also is seen in some cases and treatment options are often quite limited since bacteriostatic antibiotics like clindamycin and linezolid are seldom effective in the treatment of infective endocarditis and other intravascular infections.

This paper presents preliminary data on the successful treatment of 7 patients with bacteremic infection due to DAP-resistant MRSA using DAP + ASBLs. In addition, the in vitro studies on three isolates demonstrated enhanced bactericidal activity, increased cellular binding of DAP, and reduced net-positive surface charge in the presence of ASBLs. These are important observations, which suggest a mechanism for this clinically useful antibiotic interaction. We eagerly anticipate additional studies that will shed further light on the mechanisms of DAP resistance and the useful interaction between ASBLs and DAP in these difficult-to-treat bacteremic MRSA infections.