In vitro and in vivo activities of linezolid alone and combined with vancomycin and imipenem against Staphylococcus aureus with reduced susceptibility to glycopeptides

Abstract

The objective of this study was to evaluate the in vitro and in vivo efficacies of linezolid (35 mg/kg/5 h), vancomycin (60 mg/kg/5 h), imipenem (30 mg/kg/5 h), linezolid+imipenem, linezolid+vancomycin and vancomycin+imipenem against two clinical Staphylococcus aureus isolates with reduced susceptibility to glycopeptides using time–kill curves and the murine peritonitis model. Time–kill curves were performed over 24 h. For the murine peritonitis model, peritonitis was induced by the intraperitoneal inoculation of 108 CFU/ml of each bacterial strain. Four hours later (0 h), the mice were randomly assigned to a control group or to therapeutic groups receiving subcutaneous treatment for 25 h. Bacterial counts in peritoneal fluid, bacteraemia and mortality rates were determined. The time–kill curves showed that the addition of linezolid to imipenem yielded synergistic results after 24 h. The addition of linezolid decreased vancomycin activity. In the animal model, vancomycin and linezolid monotherapies produced comparable bacterial decreases in mice infected with each strain but linezolid achieved higher rates of blood sterilisation. Linezolid tested either in monotherapy or in combination showed similar efficacy against both strains in terms of bacterial killing, number of negative blood cultures and survival. Linezolid and vancomycin were moderately bactericidal and similar in efficacy against glycopeptide-intermediate or -resistant S. aureus. Linezolid combinations, as effective as linezolid tested alone, could be considered as alternative options for the treatment of glycopeptide-intermediate S. aureus (GISA) infections.

Combination Antibiotic Treatment of Serious Methicillin-Resistant Staphylococcus aureus Infections

“…At least 16 in vitro studies have explored synergy between vancomycin and β-lactams against MRSA isolates, [54][55][56][57][58][59][60][61][62][63][64][65][66][67][68][69] all but one of which found evidence of synergy in some or all of the tested strains (►Table 1). These studies varied in their methodology (checkerboard synergy testing or time-kill curves), types of strains tested (MRSA vs. hVISA vs. VISA) and the β-lactams used, but a consistent finding across nearly all the studies was synergistic bacterial killing in most but not all strains tested.…”

“…The few studies that have assessed combinations of vancomycin with β-lactams in animal models have all found evidence of synergy. 56,61,65 Climo et al found faster sterilization of infection with vancomycin plus nafcillin in MRSA rabbit endocarditis and renal abscess models. 56 Ribes et al tested various combinations of linezolid, vancomycin, and imipenem in a murine peritonitis VISA model using time-kill curves, and found faster bacterial killing with vancomycin plus imipenem compared with vancomycin alone, in both strains tested.…”

Detection of Synergistic Antimicrobial Activities of Ceftaroline, Telavancin, Daptomycin, and Vancomycin Against Methicillin-Resistant Staphylococcus aureus Strains in Intensive Care Units

“…The combination of antibiotics acting by different mechanisms is recommended for the treatment of MRSA infections in order to ensure a synergistic action, reduce the occurrence of side-effects, and decrease the risk of resistance. These different antibiotic combinations offer a potential option in the management of the infections caused by MRSA (9)(10)(11)(12)(13)(14). In our study, the E test method was used to evaluate the synergistic effects of the antibiotics against MRSA strains isolated from patients in intensive care units.…”

“…Alternative therapies including novel combinations are essential to treat MRSA infections. Different antibiotic combinations are frequently used for the treatment of infections caused by MRSA strains (9)(10)(11)(12)(13)(14).…”

Effect of Linezolid Alone and in Combination with Other Antibiotics , on Methicillin-Resistant Staphylococcus Aureus

“…Linezolid has unique mechanism of action by inhibiting ribosomal protein synthesis at an early stage of bacterial replication which leads to the absence of cross resistance with other antimicrobials (Rubinstein et al, 2010). Although linezolid unsusceptible strains are unusual, long courses of oxazolidinone therapy could select resistant mutants (Wilson et al, 2003) hence, the use of a combined strategy might be considered in clinical practice (Ribes et al, 2010). Combination therapy, with the goal to enhance the antibacterial activity of known and effective antibiotics, cannot only enhance the activity of known antibiotics but can possibly support the clinical development of agents previously found to be very effective but too toxic for the host.…”