Antimicrobial agents and chemotherapy
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Antimicrob. Agents Chemother. · Feb 2015
Randomized Controlled TrialAssessment of time to clinical response, a proxy for discharge readiness, among hospitalized patients with community-acquired pneumonia who received either ceftaroline fosamil or ceftriaxone in two phase III FOCUS trials.
The primary driver of health care costs for patients with community-acquired pneumonia (CAP) is the hospital length of stay (LOS). Unfortunately, hospital LOS comparisons are difficult to make from phase III CAP trials because of their structured designs and prespecified treatment durations. However, an opportunity still exists to draw inferences about potential LOS differences between treatments through the use of surrogates for hospital discharge. ⋯ In the Cox regression, ceftaroline was associated with a shorter time to a clinical response (HR, 1.16, P=0.02). The methodology employed here provides a framework to draw comparative effectiveness inferences from phase III CAP efficacy trials. (The FOCUS trials whose data were analyzed in this study have been registered at ClinicalTrials.gov under registration no. NCT00621504 and NCT00509106.).
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Antimicrob. Agents Chemother. · Feb 2015
Broad coverage of genetically diverse strains of Clostridium difficile by actoxumab and bezlotoxumab predicted by in vitro neutralization and epitope modeling.
Clostridium difficile infections (CDIs) are the leading cause of hospital-acquired infectious diarrhea and primarily involve two exotoxins, TcdA and TcdB. Actoxumab and bezlotoxumab are human monoclonal antibodies that neutralize the cytotoxic/cytopathic effects of TcdA and TcdB, respectively. In a phase II clinical study, the actoxumab-bezlotoxumab combination reduced the rate of CDI recurrence in patients who were also treated with standard-of-care antibiotics. ⋯ Actoxumab and bezlotoxumab neutralized toxins from culture supernatants of all clinical isolates tested, including multiple isolates of the BI/NAP1/027 and BK/NAP7/078 strains, at antibody concentrations well below plasma levels observed in humans. We compared the bezlotoxumab epitopes in the TcdB receptor binding domain across known TcdB sequences and found that key substitutions within the bezlotoxumab epitopes correlated with the relative differences in potencies of bezlotoxumab against TcdB of some strains, including ribotypes 027 and 078. Combined with in vitro neutralization data, epitope modeling will enhance our ability to predict the coverage of new and emerging strains by actoxumab-bezlotoxumab in the clinic.
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Antimicrob. Agents Chemother. · Jan 2015
Randomized Controlled TrialImpact of nonlinear interactions of pharmacokinetics and MICs on sputum bacillary kill rates as a marker of sterilizing effect in tuberculosis.
The relationships between antituberculosis drug exposure and treatment effects on humans receiving multidrug therapy are complex and nonlinear. In patients on treatment, an analysis of the rate of decline in the sputum bacillary burden reveals two slopes. The first is the α-slope, which is thought to reflect bactericidal effect, followed by a β-slope, which is thought to reflect sterilizing activity. ⋯ However, isoniazid and ethambutol exposures may only be of importance when rifampin exposure is low. These findings need confirmation in larger studies. (This study has been registered at controlled-trials.com under registration no. ISRCTN80852505.).
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Antimicrob. Agents Chemother. · Jan 2015
Multicenter StudyNovel dosing strategies increase exposures of the potent antituberculosis drug rifapentine but are poorly tolerated in healthy volunteers.
Rifapentine is a potent antituberculosis drug currently in phase III trials. Bioavailability decreases with increasing dose, yet high daily exposures are likely needed to improve efficacy and shorten the tuberculosis treatment duration. Further, the limits of tolerability are poorly defined. ⋯ In conclusion, two strategies to increase rifapentine exposures, dividing the dose or giving it with a high-fat breakfast, successfully increased exposures, but toxicity was common in healthy adults. The limits of tolerability in patients with tuberculosis remain to be defined. (AIDS Clinical Trials Group study A5311 has been registered at ClinicalTrials.gov under registration no. NCT01574638.).
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Antimicrob. Agents Chemother. · Jan 2015
Multicenter StudyStratification of the impact of inappropriate empirical antimicrobial therapy for Gram-negative bloodstream infections by predicted prognosis.
The bloodstream infection mortality risk score (BSIMRS) predicts the outcome of patients with Gram-negative bloodstream infections (BSI) with high discrimination. This retrospective cohort study examined the impact of inappropriate antimicrobial therapy on mortality in adult patients with Gram-negative BSI admitted to Palmetto Health Hospitals in Columbia, SC, USA, from 1 January 2011 to 31 December 2012 after stratification by predicted prognosis at initial presentation using BSIMRS. A multivariate Cox regression model was used to identify independent risk factors for 28-day mortality overall and within each predefined BSIMRS category (<5, 5 to 9, and ≥ 10). ⋯ RRR, ARR, and NNT were 0.25, 0.02, and 63 for BSIMRS of <5; 0.56, 0.32, and 3 for BSIMRS of 5 to 9; and 0.39, 0.39, and 3 for BSIMRS of ≥ 10, respectively. There is a significant benefit from appropriate antimicrobial therapy in patients with Gram-negative BSI with guarded (BSIMRS of 5 to 9) and poor (BSIMRS of ≥ 10) predicted prognosis. Survival difference remains unclear among those with good predicted prognosis (BSIMRS of <5) at initial presentation.