Comparative analysis of neutropenia in patients receiving prolonged treatment with ceftaroline

Inverse probability-weighted estimation is a powerful tool for use with observational data. In this article, we describe how this propensity score-based method can be used to compare the effectiveness of 2 or more treatments. First, we discuss the inherent problems in using observational data to assess comparative effectiveness. Next, we provide a conceptual explanation of inverse probability-weighted estimation and point readers to sources that address the method in more formal, technical terms. Finally, we offer detailed guidance about how to implement the estimators in comparative effectiveness analyses.

To assess whether methicillin-resistant Staphylococcus aureus (MRSA) vancomycin MIC shifts (MIC creep) at a tertiary care institution occurred that may have gone undetected using traditional susceptibility markers (percentage susceptible, MIC(50), MIC(90)) over a 5 year period. Additionally, MIC trends were evaluated for oxacillin, linezolid and daptomycin. Etest MICs were performed on MRSA blood culture isolates (January 2001-December 2005). Only one isolate per patient was studied. The reported Etest MIC result was used and not rounded upward. MIC(50), MIC(90), median and geometric mean MIC, percentage susceptible and percentage resistant were calculated for each drug in each year. Non-parametric methods (linear correlation and Mantel-Haenszel chi(2)) were used to assess MIC trends over time and the association of vancomycin, linezolid and daptomycin MICs with oxacillin MICs. All isolates were susceptible to vancomycin, linezolid and daptomycin and resistant to oxacillin. MICs increased for vancomycin, linezolid and oxacillin (P < 0.0001); however, daptomycin MICs decreased slightly (P = 0.0386). For vancomycin, linezolid and oxacillin, there were significant increases (P < 0.0001) in the percentage of isolates with MICs that were higher than the respective 2001 median MIC, but not for daptomycin (P = 0.1361). Oxacillin MICs were associated with MICs of linezolid (r = 0.364, P < 0.0001), vancomycin (r = 0.353, P < 0.0001) and daptomycin (r = 0.106, P = 0.0063). Oxacillin, vancomycin and linezolid MICs increased over time. For vancomycin and linezolid, these MIC increases were not reliably detected by percentage susceptibility as they occurred below the susceptibility breakpoint. Although the MICs of all agents appeared to be associated with increasing oxacillin MICs, the strongest associations were noted for vancomycin and linezolid.

Ceftaroline (active form of the prodrug ceftaroline fosamil) is a novel cephalosporin with activity against pathogens commonly associated with community-acquired pneumonia (CAP), including Streptococcus pneumoniae and Gram-negative pathogens. This randomized, double-blind, Phase III study evaluated the efficacy and safety of ceftaroline fosamil in treating patients with CAP. The primary objective was to determine non-inferiority [lower limit of 95% confidence interval (CI) ≥ -10%] of clinical cure rates achieved with ceftaroline fosamil compared with those achieved with ceftriaxone in the clinically evaluable (CE) and modified intent-to-treat efficacy (MITTE) populations. Patients hospitalized in a non-intensive care unit setting with CAP of Pneumonia Outcomes Research Team (PORT) risk class III or IV requiring intravenous (iv) therapy were randomized (1:1) to receive 600 mg of ceftaroline fosamil iv every 12 h or 1 g of ceftriaxone iv every 24 h. Clinical cure, microbiological response, adverse events (AEs) and laboratory tests were assessed. FOCUS 2 registration number NCT00509106 (http://clinicaltrials.gov/ct2/show/NCT00509106). The study enrolled 627 patients, 315 of whom received ceftaroline fosamil and 307 of whom received ceftriaxone. Patients in both treatment groups had comparable baseline characteristics. Clinical cure rates were as follows: CE population, 82.1% (193/235) for ceftaroline fosamil and 77.2% (166/215) for ceftriaxone [difference (95% CI), 4.9% (-2.5, 12.5)]; and MITTE population, 81.3% (235/289) for ceftaroline fosamil and 75.5% (206/273) for ceftriaxone [difference (95% CI), 5.9% (-1.0, 12.7)]. Clinical cure rates for CAP caused by S. pneumoniae in the microbiological MITTE (mMITTE) population were 83.3% (35/42) and 70.0% (28/40) for ceftaroline fosamil and ceftriaxone, respectively. Ceftaroline fosamil and ceftriaxone were well tolerated, with similar rates of AEs, serious AEs, deaths and discontinuations due to an AE. The most common AEs for ceftaroline fosamil-treated patients were diarrhoea, headache, hypokalaemia, insomnia and phlebitis, and the most common AEs for ceftriaxone-treated patients were diarrhoea, insomnia, phlebitis and hypertension. Ceftaroline fosamil achieved high clinical cure and microbiological response rates in patients hospitalized with CAP of PORT risk class III or IV. Ceftaroline fosamil was well tolerated, with a safety profile that is similar to that of ceftriaxone and other cephalosporins. Ceftaroline fosamil is a promising agent for the treatment of CAP.