Clostridium difficile treatment in neutropenic patients: Clinical outcomes of metronidazole, vancomycin, combinations, and switch therapy.

BACKGROUND: Clostridium difficile infection treatment guidelines exist for immunocompetent patients; however, there is a paucity of data evaluating clinical outcomes and time to C. difficile-associated diarrhea resolution in neutropenic patients. OBJECTIVE: To assess clinical outcomes in neutropenic patients treated with metronidazole, oral vancomycin, the combination of metronidazole plus oral vancomycin, and switch of metronidazole to oral vancomycin. METHODS: This retrospective, observational cohort study assessed adult neutropenic inpatients with C. difficile-associated diarrhea treated with metronidazole, oral vancomycin, combination (metronidazole and oral vancomycin), or switch therapy (metronidazole to oral vancomycin). The primary outcome was time to diarrhea resolution based on treatment regimen. Secondary outcomes included C. difficile-associated diarrhea resolution of diarrhea by day 14, recurrence, and occurrence of major complications. RESULTS: Overall, 44 patients met full inclusion criteria (52.2% metronidazole monotherapy, 22.7% combination, and 25.0% switch therapy). Two patients on oral vancomycin monotherapy were excluded due to insufficient sample size. Overall time to C. difficile-associated diarrhea resolution was 9.1 ± 10.7 days. The Cox regression results suggested both switch and combination therapy were associated with 65.5% (p = 0.002) and 65.9% (p = 0.046) longer time to C. difficile-associated diarrhea resolution compared to metronidazole monotherapy, respectively. An increasing absolute neutrophil count was associated with an increase in C. difficile-associated diarrhea resolution (p = 0.007). CONCLUSION: Switch or combination therapy was associated with a prolonged time to C. difficile-associated diarrhea resolution. The decision to use switch or combination therapy may represent a surrogate marker for more severe disease and need for therapy escalation. It is unknown if initial therapy with oral vancomycin would provide better outcomes as this could not be assessed.

Clinical outcomes of fidaxomicin vs oral vancomycin in recurrent Clostridium difficile infection.

WHAT IS KNOWN AND OBJECTIVE: Recurrent Clostridium difficile infection (CDI) occurs after initial treatment in approximately 20%-30% of patients, regardless of therapy chosen. The objective of this study was to assess clinical outcomes of recurrent CDI treated with fidaxomicin or oral vancomycin. METHODS: This study was a retrospective, propensity score-matched nationwide analysis of adult patients with first or second CDI recurrence prescribed fidaxomicin or oral vancomycin from any Veterans Affairs Medical Center between June 2011 and December 2015. The primary outcome was evidence of clinical failure or 90-day recurrence. RESULTS AND DISCUSSION: Univariate variables associated with failure or recurrence were identified among 65 fidaxomicin-treated episodes and 1065 vancomycin-treated episodes and placed into a multivariable logistic regression model. Propensity scores were calculated from this model; 195 vancomycin-treated episodes were matched by the next-nearest propensity score to 65 fidaxomicin-treated episodes. CDI failure or recurrence was similar between the two groups (18 of 65 [27.7%] fidaxomicin-treated episodes vs 42 of 195 [21.5%] vancomycin-treated episodes [P = 0.31]). Multivariate analysis demonstrated only baseline second recurrence episode, not choice of drug, as independently associated with failure or recurrence. WHAT IS NEW AND CONCLUSION: There was no difference in the combined outcome of clinical failure or 90-day recurrence between fidaxomicin and oral vancomycin in the treatment of first or second recurrent CDI.

Maximized quantitative phosphoproteomics allows high confidence dissection of the DNA damage signaling network.

The maintenance of genomic stability relies on DNA damage sensor kinases that detect DNA lesions and phosphorylate an extensive network of substrates. The Mec1/ATR kinase is one of the primary sensor kinases responsible for orchestrating DNA damage responses. Despite the importance of Mec1/ATR, the current network of its identified substrates remains incomplete due, in part, to limitations in mass spectrometry-based quantitative phosphoproteomics. Phosphoproteomics suffers from lack of redundancy and statistical power for generating high confidence datasets, since information about phosphopeptide identity, site-localization, and quantitation must often be gleaned from a single peptide-spectrum match (PSM). Here we carefully analyzed the isotope label swapping strategy for phosphoproteomics, using data consistency among reciprocal labeling experiments as a central filtering rule for maximizing phosphopeptide identification and quantitation. We demonstrate that the approach allows drastic reduction of false positive quantitations and identifications even from phosphopeptides with a low number of spectral matches. Application of this approach identifies new Mec1/ATR-dependent signaling events, expanding our understanding of the DNA damage signaling network. Overall, the proposed quantitative phosphoproteomic approach should be generally applicable for investigating kinase signaling networks with high confidence and depth.