Novel Daptomycin Combinations against Daptomycin-Nonsusceptible Methicillin-Resistant Staphylococcus aureus in an In Vitro Model of Simulated Endocardial Vegetations

Abstract

Reduced susceptibility to daptomycin has been reported in patients with infections due to methicillinresistant Staphylococcus aureus (MRSA). Although infections with daptomycin-nonsusceptible (DNS) MRSA are infrequent, optimal therapy of these strains has not been determined. We investigated the killing effects of novel antibiotic combinations with daptomycin (DAP) against two clinical DNS MRSA isolates (SA-684 and R6003) in a 72-h in vitro pharmacokinetic/pharmacodynamic (PK/PD) model with simulated endocardial vegetations (SEV). Simulated regimens included DAP at 6 mg/kg every 24 h (q24h) alone or in combination with trimethoprim-sulfamethoxazole (TMP/SMX) at 160/800 mg q12h, linezolid (LIN) at 600 mg q12h, cefepime (CEF) at 2 g q12h, and nafcillin (NAF) at 4 g q4h. Bactericidal activity was defined as a >3-log 10 CFU/g kill. Differences in CFU/g were evaluated between 4 and 72 h by analysis of variance with the Bonferroni post hoc test. DAP MICs were 4 and 2 mg/liter for SA-684 and R6003, respectively. In the PK/PD model, DAP alone was slowly bactericidal, achieving a 3-log 10 kill at 24 and 50 h for SA-684 and R6003, respectively. Against SA-684, DAP plus TMP/SMX, CEF, LIN, or NAF was bactericidal at 4, 4, 8, and 8 h, respectively, and maintained this activity for the 72-h study duration. DAP plus TMP/SMX or CEF exhibited superior killing than DAP alone against SA-684 between 4 and 72 h, and overall this was significant (P < 0.05). Against R6003, DAP plus TMP/SMX was bactericidal (8 h) and superior to DAP alone between 8 and 72 h (P < 0.001). The unique combination of DAP plus TMP/SMX was the most effective and rapidly bactericidal regimen against the two isolates tested and may provide a clinical option to treat DNS S. aureus infections.

Relationship of In Vitro Synergy and Treatment Outcome with Daptomycin plus Rifampin in Patients with Invasive Methicillin-Resistant Staphylococcus aureus Infections

“…Daptomycin in combination with adjunctive antibiotics, such as rifampin, aminoglycosides, or co-trimoxazole, may improve antimicrobial killing or inhibit the emergence of resistance compared to daptomycin alone (5,14). New Infectious Diseases Society of America (IDSA) guidelines for the treatment of prosthetic joint infections recommend combining rifampin with primary therapy (15), but published clinical experiences with daptomycin combined with rifampin have been very limited.…”

Daptomycin in Combination with Ceftolozane-Tazobactam or Cefazolin against Daptomycin-Susceptible and -Nonsusceptible Staphylococcus aureus in an In Vitro , Hollow-Fiber Model

“…Samples from each model were collected at 0, 4,8,24,32,48,72, and 96 h in duplicate. Colony counts were determined by spiral plating of appropriate dilutions using an automatic spiral plater (Wasp; DW Scientific, West Yorkshire, England).…”

“…The ceftolozane concentration against R8846 was used based on the MIC obtained for ceftolozane of 16 g/ml in the presence of 23.8 g/ml tazobactam. Samples were collected at 0, 4,8,24, and 48 h, and colony counts (log 10 CFU per milliliter) were compared among the regimens at 48 h. Synergy was defined as a combination regimen possessing a Ͼ100-fold increase in bacterial killing compared to the most active single constituent, with one of the single constituents demonstrating no important effect on organism growth (18).…”

“…Daptomycin nonsusceptibility has been reported, however, and creative therapies are needed to combat this problem (5-10). Recent data have demonstrated that beta-lactam antibiotics in combination with daptomycin are efficacious in both preventing daptomycin nonsusceptibility and providing bactericidal activity (6,8,(10)(11)(12)(13).Because antibiotic resistance among Gram-negative bacteria is as much, if not more, of a problem as resistance among Grampositive bacteria, several agents are under development or have recently been approved to combat Gram-negative infections. Ceftolozane (TOL) is a novel cephalosporin with activity against a broad range of Gram-negative pathogens, including excellent activity against Pseudomonas aeruginosa (14).…”

“…Daptomycin nonsusceptibility has been reported, however, and creative therapies are needed to combat this problem (5-10). Recent data have demonstrated that beta-lactam antibiotics in combination with daptomycin are efficacious in both preventing daptomycin nonsusceptibility and providing bactericidal activity (6,8,(10)(11)(12)(13).…”