Improving the ability of antimicrobial susceptibility tests to predict clinical outcome accurately: Adding metabolic evasion to the equation.

Antimicrobial susceptibility tests (AST) are based on the minimal inhibitory concentration (MIC), the method used worldwide to guide antimicrobial therapy. Despite its relevance in correctly predicting clinical outcome for most acute infections, this approach is misleading for multiple clinical cases in which pathogens do not grow rapidly, uniformly or with physical protection. This behaviour, named 'metabolic evasion' (ME), enables bacteria to survive antimicrobials. ME can result from different, and sometimes combined, bacterial mechanisms such as biofilms, intracellular growth, persisters or dormancy. We discuss how ME can influence the MIC-based probability of target attainment. We identify clinical cases in which this approach is undermined by ME and propose a new approach that takes ME into account in order to improve patient management and the evaluation of innovative drugs.

Ceftaroline-Fosamil efficacy against methicillin-resistant Staphylococcus aureus in a rabbit prosthetic joint infection model.

Ceftaroline (CPT), the active metabolite of the prodrug ceftaroline-fosamil (CPT-F), demonstrates in vitro bactericidal activity against methicillin-resistant Staphylococcus aureus (MRSA) and is effective in rabbit models of difficult-to-treat MRSA endocarditis and acute osteomyelitis. However, its in vivo efficacy in a prosthetic joint infection (PJI) model is unknown. Using a MRSA-infected knee PJI model in rabbits, the efficacies of CPT-F or vancomycin (VAN) alone and combined with rifampin (RIF) were compared. After each partial knee replacement with a silicone implant that fit into the tibial intramedullary canal was performed, 5 × 10(7) MRSA CFU (MICs of 0.38, 0.006, and 1 mg/liter for CPT, RIF, and VAN, respectively) was injected into the knee. Infected animals were randomly assigned to receive no treatment (controls) or CPT-F (60 mg/kg of body weight intramuscularly [i.m.]), VAN (60 mg/kg i.m.), CPT-F plus RIF (10 mg/kg i.m.), or VAN plus RIF starting 7 days postinoculation and lasting for 7 days. Surviving bacteria in crushed tibias were counted 3 days after ending treatment. Although the in vivo mean log10 CFU/g of CPT-treated (3.0 ± 0.9, n = 12) and VAN-treated (3.5 ± 1.1, n = 12) crushed bones was significantly lower than those of controls (5.6 ± 1.1, n = 14) (P < 0.001), neither treatment fully sterilized the bones (3/12 were sterile with each treatment). The mean log10 CFU/g values for the antibiotics in combination with RIF were 1.9 ± 0.5 (12/14 were sterile) for CPT-F and 1.9 ± 0.5 (12/14 were sterile) for VAN. In this MRSA PJI model, the efficacies of CPT-F and VAN did not differ; thus, CPT appears to be a promising antimicrobial agent for the treatment of MRSA PJIs.