Antimicrobial agents and chemotherapy
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Antimicrob. Agents Chemother. · May 2012
Comparative StudyComparative in vivo efficacies of epithelial lining fluid exposures of tedizolid, linezolid, and vancomycin for methicillin-resistant Staphylococcus aureus in a mouse pneumonia model.
The antibacterial efficacies of tedizolid phosphate (TZD), linezolid, and vancomycin regimens simulating human exposures at the infection site against methicillin-resistant Staphylococcus aureus (MRSA) were compared in an in vivo mouse pneumonia model. Immunocompetent BALB/c mice were orally inoculated with one of three strains of MRSA and subsequently administered 20 mg/kg TZD every 24 hours (q24h), 120 mg/kg linezolid q12h, or 25 mg/kg vancomycin q12h over 24 h. These regimens produced epithelial lining fluid exposures comparable to human exposures observed following intravenous regimens of 200 mg TZD q24h, 600 mg linezolid q12h, and 1 g vancomycin q12h. ⋯ The vancomycin regimen was less protective than either the TZD or linezolid regimens, with overall survival of 61.1% versus 94.7% or 89.5%, respectively. At human simulated exposures to epithelial lining fluid, vancomycin resulted in minimal reductions in bacterial counts and higher mortality compared to those of either TZD or linezolid. TZD and linezolid showed similar efficacies in this MRSA pneumonia model.
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Antimicrob. Agents Chemother. · May 2012
Incidence and predictors of nephrotoxicity associated with intravenous colistin in overweight and obese patients.
Intravenous colistin is used to treat resistant Gram-negative infections and is associated with nephrotoxicity. In overweight and obese adults, a paucity of data exists regarding the incidence and predictors of such toxicity. A retrospective nested case-control study was performed over 35 months for patients receiving intravenous colistin for ≥ 72 h with a body mass index (BMI) of ≥ 25 kg/m(2). ⋯ The 30-day all-cause in-hospital mortality rate was 40% in the toxicity group and 14% in the nontoxicity group (P = 0.14). Patients receiving intravenous colistin should be monitored for nephrotoxicity, especially when the BMI exceeds 31.5 kg/m(2). Prospective, randomized, controlled trials are warranted to further examine nephrotoxicity incidence and predictors and appropriate dosing strategies in this population.
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Antimicrob. Agents Chemother. · May 2012
Therapeutic equivalence requires pharmaceutical, pharmacokinetic, and pharmacodynamic identities: true bioequivalence of a generic product of intravenous metronidazole.
Animal models of infection have been used to demonstrate the therapeutic failure of "bioequivalent" generic products, but their applicability for this purpose requires the accurate identification of those products that are truly bioequivalent. Here, we present data comparing one intravenous generic product of metronidazole with the innovator product in a neutropenic mouse thigh anaerobic infection model. Simultaneous experiments allowed comparisons (generic versus innovator) of potency and the concentration of the active pharmaceutical ingredient (API), analytical chemistry (liquid chromatography/mass spectrometry [LC/MS]), in vitro susceptibility testing, single-dose serum pharmacokinetics (PK) in infected mice, and in vivo pharmacodynamics (PD) against Bacteroides fragilis ATCC 25825 in synergy with Escherichia coli SIG-1 in the neutropenic mouse thigh anaerobic infection model. ⋯ We found no differences between products in bacteriostatic doses (BD) (15 to 22 mg/kg of body weight per day) or the doses needed to kill 1 log (1LKD) (21 to 29 mg/kg per day) or 2 logs (2LKD) (28 to 54 mg/kg per day) of B. fragilis under dosing schedules of every 12 h (q12h), q8h, or q6h. The area under the concentration-time curve over 24 h in the steady state divided by the MIC (AUC/MIC ratio) was the best PD index to predict the antibacterial efficacy of metronidazole (adjusted coefficient of determination [AdjR(2)] = 84.6%), and its magnitude to reach bacteriostasis in vivo (56.6 ± 5.17 h) or to kill the first (90.8 ± 9.78 h) and second (155.5 ± 22.2 h) logs was the same for both products. Animal models of infection allow a thorough demonstration of the therapeutic equivalence of generic antimicrobials.
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Antimicrob. Agents Chemother. · May 2012
Randomized Controlled Trial Multicenter StudyCANVAS 1 and 2: analysis of clinical response at day 3 in two phase 3 trials of ceftaroline fosamil versus vancomycin plus aztreonam in treatment of acute bacterial skin and skin structure infections.
Scientific and regulatory interest in assessing clinical endpoints after 48 to 72 h of treatment for acute bacterial skin and skin structure infections (ABSSSI) has increased. Historical, pre-antibiotic-era data suggest that a treatment effect relative to untreated controls can be discerned in this time interval. Ceftaroline fosamil, a broad-spectrum bactericidal cephalosporin with activity against Gram-positive organisms, including methicillin-resistant Staphylococcus aureus (MRSA), and Gram-negative organisms was efficacious in two phase 3 trials of complicated skin infections (CANVAS 1 and 2) using clinical cure rates at the test-of-cure visit. ⋯ In the individual studies, absolute treatment differences of 9.4% (CANVAS 1) and 5.9% (CANVAS 2) favoring ceftaroline were observed. For ABSSSI due to MRSA, response rates were 81.7% and 77.4% in the ceftaroline and V/A groups, respectively. In this retrospective analysis, ceftaroline fosamil monotherapy had a numerically higher clinical response than V/A at day 3 in the treatment of ABSSSI.
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Antimicrob. Agents Chemother. · May 2012
Multicenter StudyMicrobiological aetiology, epidemiology, and clinical profile of prosthetic joint infections: are current antibiotic prophylaxis guidelines effective?
Prosthetic joint infections remain a major complication of arthroplasty. At present, local and international guidelines recommend cefazolin as a surgical antibiotic prophylaxis at the time of arthroplasty. This retrospective cohort study conducted across 10 hospitals over a 3-year period (January 2006 to December 2008) investigated the epidemiology and microbiological etiology of prosthetic joint infections. ⋯ The results of this study highlight the importance of ongoing reviews of the local ecology of prosthetic joint infection, demonstrating that the spectrum of pathogens involved is broad. The results should inform empirical antibiotic therapy. This report also provokes discussion about infection control strategies, including changing surgical antibiotic prophylaxis to a combination of glycopeptide and cefazolin, to reduce the incidence of infections due to methicillin-resistant staphylococci.