Ceftolozane-Tazobactam in the Treatment of Experimental Pseudomonas aeruginosa Pneumonia in Persistently Neutropenic Rabbits: Impact on Strains with Genetically Defined Mechanisms of Resistance.

Ceftolozane-tazobactam (C/T) is a novel cephalosporin with in vitro activity against Pseudomonas aeruginosa that is resistant to extended-spectrum penicillins and antipseudomonal cephalosporins. In order to assess the antimicrobial effect of C/T in treatment of Pseudomonas pneumonia, we investigated the pharmacokinetics and efficacy of C/T in persistently neutropenic rabbits. Pseudomonas pneumonia was established by direct endotracheal inoculation. Treatment groups consisted of C/T, ceftazidime (CAZ), piperacillin-tazobactam (TZP), and untreated controls (UC). Rabbits received a dosage of C/T of 80 mg/kg every 4 h (q4h) intravenously (i.v.) (53 mg/kg ceftolozane/26 mg/kg tazobactam) to match the free drug time above the MIC as well as a comparable plasma area under the concentration-time curve (AUC) (humanized doses of ceftolozane-tazobactam of 3 g [2 g/1 g]) q8h, due to the more rapid elimination of ceftolozane in rabbits (0.75 h) than in humans (2.5 h). Four molecularly characterized clinical P. aeruginosa isolates from patients with pneumonia were studied, including one isolate from each classification group: pan-susceptible (PS), outer membrane porin D (OPRD) porin loss (OPRDPL), efflux pump expression (EPE), and AmpC hyperexpression (ACHE). Treatment was continued for 12 days. Treatment with ceftolozane-tazobactam resulted in a ≥105 reduction in residual pulmonary and bronchoalveolar lavage (BAL) fluid bacterial burdens caused by all 4 strains (P ≤ 0.01). This antibacterial activity coincided with reduction of lung weight (an organism-mediated pulmonary injury marker) (P < 0.05). CAZ was less active in ACHE-infected rabbits, and TZP had less activity against EPE, ACHE, and OPRDPL strains. Survival was prolonged in the C/T and CAZ treatment groups in comparison to the TZP and UC groups (P < 0.001). Ceftolozane-tazobactam is highly active in treatment of experimental P. aeruginosa pneumonia in persistently neutropenic rabbits, including infections caused by strains with the most common resistance mechanisms.

Comparative Effectiveness of Vancomycin Versus Daptomycin for MRSA Bacteremia With Vancomycin MIC >1 mg/L: A Multicenter Evaluation.

PURPOSE: Clinical studies comparing vancomycin with alternative therapy for methicillin-resistant Staphylococcus aureus (MRSA) bacteremia are limited. The objective of this study was to compare outcomes of early daptomycin versus vancomycin treatment for MRSA bacteremia with high vancomycin MICs in a geographically diverse multicenter evaluation. METHODS: This nationwide, retrospective, multicenter (N = 11), matched, cohort study compared outcomes of early daptomycin with vancomycin for MRSA bloodstream infection (BSI) with vancomycin MICs 1.5 to 2 µg/mL. Matching variables, based on propensity regression analysis, included age, intensive care unit (ICU), and type of BSI. Outcomes were as follows: (1) composite failure (60-day all-cause mortality, 7-day clinical or microbiologic failure, 30-day BSI relapse, or end-of-treatment failure (EOT; discontinue/change daptomycin or vancomycin because of treatment failure or adverse event]); (2) nephrotoxicity; and (2) day 4 BSI clearance. FINDINGS: A total of 170 patients were included. The median (interquartile range) age was 60 years (50-74); the median (range) Acute Physiology and Chronic Health Evaluation II score was 15 (10-18); 31% were in an ICU; and 92% had an infectious disease consultation. BSI types included endocarditis/endovascular (39%), extravascular (55%), and central catheter (6%). The median daptomycin dose was 6 mg/kg, and the vancomycin trough level was 17 mg/L. Overall composite failure was 35% (59 of 170): 15% due to 60-day all-cause mortality, 14% for lack of clinical or microbiologic response by 7 days, and 17% due to failure at end of therapy (discontinue/change because of treatment failure or adverse event). Predictors of composite failure according to multivariate analysis were age >60 years (odds ratio, 3.7; P < 0.01) and ICU stay (odds ratio, 2.64; P = 0.03). Notable differences between treatment groups were seen with: (1) end of therapy failure rates (11% vs 24% for daptomycin vs vancomycin; P = 0.025); (2) acute kidney injury rates (9% vs 23% for daptomycin vs vancomycin; P = 0.043); and (3) day 4 bacteremia clearance rates for immunocompromised patients (n = 26) (94% vs 56% for daptomycin vs vancomycin; P = 0.035). IMPLICATIONS: Results from this multicenter study provide, for the first time, a geographically diverse evaluation of daptomycin versus vancomycin for patients with vancomycin-susceptible MRSA bacteremia with vancomycin MIC values >1 µg/mL. Although the overall composite failure rates did not differ between the vancomycin and daptomycin groups when intensively matched according to risks for failure, the rates of acute kidney injury were significantly lower in the daptomycin group. These findings suggest that daptomycin is a useful therapy for clinicians treating patients who have MRSA bacteremia. Prospective, randomized trials should be conducted to better assess the potential significance of elevated vancomycin MIC.

Daptomycin for the treatment of surgical site infections.

BACKGROUND: The increasing frequency of methicillin-resistant Staphylococcus aureus (MRSA) as a cause of surgical site infections, and decreased susceptibility to vancomycin, highlight the need for alternative therapies. METHODS: All patients with a surgical site infection enrolled in the Cubicin Outcomes Registry and Experience (CORE 2007 retrospective multicenter registry were studied. Outcome was assessed at the end of daptomycin therapy using protocol-defined criteria. Success was defined as cured or improved. Non-evaluable patients were excluded from the efficacy analysis but were included in the safety analysis. RESULTS: Of 962 patients in the CORE registry in 2007, 104 (11%) had a surgical infection and met the criteria for the efficacy analysis. The overall success rate was 91% (95/104). The distribution of surgical site infections by depth was 36% (38/104) superficial incisional, 36% (38/104) deep incisional, and 27% (28/104) organ/space. Success rates by infection depth were 92% for superficial incisional, 92% deep incisional, and 89% organ/space (P = .9). Success in patients with and without surgery was 89% (49/55) and 94% (46/49) (P = .5). The median final daptomycin dose was 5.5 mg/kg. The median duration of daptomycin therapy was 14 days. Prior antibiotic therapy was given to 79% of patients; 35% failed. Prior vancomycin was used in 45% of patients; 24% failed. Among vancomycin failures, the daptomycin success rate was 91% (10/11). Of those with a positive culture, common pathogens were S. aureus (68%; MRSA 61%) and enterococci (26%; vancomycin-resistant 36%). There were 9 possible treatment-related adverse events (AEs) in 8 of 118 (7%) patients; 2 serious AEs were reported in 1 patient. CONCLUSION: Success rates for patients with a surgical site infection treated with daptomycin were high and did not differ based on the need for surgical intervention. High success rates were achieved in patients with infection caused by MRSA as well as in patients who had failed to respond to previous antibiotic therapies, including vancomycin, regardless of the depth of the infection.