Observed Antagonistic Effect of Linezolid on Daptomycin or Vancomycin Activity against Biofilm-Forming Methicillin-Resistant Staphylococcus aureus in an In Vitro Pharmacodynamic Model

Abstract

c Pharmacodynamic activity in antibiotic combinations of daptomycin, vancomycin, and linezolid was investigated in a 48-h in vitro pharmacodynamic model. Using human-simulated free drug concentrations, activity against clinical biofilm-forming methicillin-resistant Staphylococcus aureus isolates was evaluated. Linezolid antagonized vancomycin activity at 24 and 48 h. Linezolid antagonized daptomycin at 24 and 48 h depending on dose and strain. Adding daptomycin increased vancomycin activity at 48 h (P < 0.03). These results may be strain dependent and require further clinical investigation. There is recent increased interest in the activity of protein synthesis inhibitors in combination with cell wall-active agents. Some combination regimens are being used clinically but lack data to support their combined use (1). High-dose daptomycin and linezolid were recommended for use as a combination therapy in the Infectious Diseases Society of America 2011 methicillinresistant Staphylococcus aureus (MRSA) treatment guidelines for persistent bacteremia or vancomycin failure (2). However, other in vitro studies have demonstrated antagonism with combinations of linezolid and vancomycin (3, 4). To date, there have been limited investigations of daptomycin and linezolid in combination (5, 6). The combined use of these agents prompted an investigation into pharmacokinetic and pharmacodynamic activity and possible interactions when using combinations of bactericidal and bacteriostatic antimicrobials as previously described (7,8).(A portion of these results were presented as a poster at the 53rd annual Interscience Conference on Antimicrobial Agents and Chemotherapy [ICAAC], Denver, CO, 10 September 2013.) Two randomly selected clinical MRSA blood isolates (L31 and L328) from the LaPlante Laboratory at the Providence Veterans Affairs Medical Center were selected for analysis. The two isolates are known biofilm-producing strains, previously isolated from patients with catheter-related bloodstream infections (9). Biofilm formation was determined as previously described (9, 10). Daptomycin (lot CDC271; Cubist Pharmaceuticals, Inc., Lexington, MA), linezolid (lot 11C10U10, 13F05U09; Pfizer, New York, NY), and vancomycin (lot 12070DD, 382553A; Hospira, Lake Forest, IL) were tested. Mueller-Hinton broth (MHB) (Becton Dickinson, Sparks, MD, USA) supplemented with calcium and adjusted to 25 mg/liter calcium chloride (for daptomycin studies, 50 mg/ml of calcium chloride, ionized Ca, and 1.03 to 1.23 mmol/liter) and 12.5 mg/liter magnesium was used for all assays for MICs, minimum bactericidal concentrations (MBCs), and in vitro pharmacodynamic (IVPD) infection models (11-13). Colony counts were determined using tryptic soy agar (TSA) (BD Difco).A previously described IVPD model was used to evaluate several antibiotic regimens against MRSA (7). Briefly, a 0.5 McFarland standard of planktonic bacteria from overnight growth on TSA was diluted in a one-compartment model (250-ml working volume) to a starting inoculum of ϳ10 6 CFU/ml. (14); ...

Combination of Tedizolid and Daptomycin against Methicillin-Resistant Staphylococcus aureus in an In Vitro Model of Simulated Endocardial Vegetations

“…Therefore, we caution the reader that LZD, although not antagonistic at 192 h, appears to substantially inhibit the initial bactericidal activity of DAP over the first 32 h. Previously, LZD has demonstrated antagonism to vancomycin in a rabbit model of endocarditis, perhaps suggesting that LZD is antagonistic to cell wall-active agents, similar to what we demonstrated with TZD and DAP here (16). This potential antagonism has been further demonstrated in an in vitro model evaluating LZD in combination with either vancomycin or DAP (20). Both DAP and vancomycin were found to be antagonized by LZD in that study.…”

Community-Acquired MRSA Pericarditis and Mediastinitis in a Previously Healthy Infant

“…7 We favored a bactericidal agent that has potential synergy with vancomycin based on in vitro studies. 18 Although there are limited reports of daptomycin use in infants, a dose of 6 mg/kg daily was chosen based on one pharmacokinetic study of 20 infants, demonstrating more rapid drug clearance in infants compared with adults. 19 In children, daptomycin is generally not considered as the first-line therapy due to limited data on efficacy, pharmacokinetics, and adverse events.…”

Treatment strategies for persistent methicillin‐resistantStaphylococcus aureusbacteraemia

“…In vitro data assessing the combinations with linezolid and daptomycin and vancomycin have shown mixed results with some studies observing antagonism whereas others showing indifference . Smith et al evaluated daptomycin combined with tedizolid, a novel oxazolidinone antibiotic, in an in vitro simulated endocardial vegetation model using two clinical strains of MRSA.…”

“…In vitro data assessing the combinations with linezolid and daptomycin and vancomycin have shown mixed results with some studies observing antagonism whereas others showing indifference. [84][85][86][87] Smith et al 88 and animal models of both endocarditis and osteomyelitis also demonstrating no benefit with combination. [89][90][91] Daptomycin plus vancomycin combination has not demonstrated synergy in vitro, but has been shown, in combination with rifampin to be effective in two cases of MRSA orthopaedic infections that relapsed after initial vancomycin and rifampin therapy.…”