Handling Time-dependent Variables: Antibiotics and Antibiotic Resistance

Munoz-Price, L. Silvia; Frencken, Jos F.; Tarima, Sergey; Bonten, Marc J. M.

doi:10.1093/cid/ciw191

Cited by 45 publications

(41 citation statements)

References 29 publications

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“…To our knowledge, this is the largest population‐based retrospective study evaluating the association of antipseudomonal β‐lactam exposure with the development of new resistance in the critically ill population. This study is also unique in that antibiotic exposures were not defined in a binary fashion, but rather as a time‐dependent variable, which is a concept highlighted previously . The duration of antibiotic exposures varies greatly in the critically ill population and should, therefore, be evaluated as a time‐dependent variable when assessing its association on new resistance development.…”

Section: Discussionmentioning

confidence: 99%

“…This study is also unique in that antibiotic exposures were not defined in a binary fashion, but rather as a timedependent variable, which is a concept highlighted previously. 12 The duration of antibiotic exposures varies greatly in the critically ill population and should, therefore, be evaluated as a time-dependent variable when assessing its association on new resistance development.…”

Section: Discussionmentioning

confidence: 99%

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Duration of Exposure to Antipseudomonal β‐Lactam Antibiotics in the Critically Ill and Development of New Resistance

et al. 2019

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Study Objective Minimizing the duration of broad‐spectrum antimicrobial exposure in the critically ill is a commonly used strategy aimed at preventing resistance. Our objective was to correlate the duration of exposure to antipseudomonal β‐lactam antibiotics with the development of new resistance in critically ill patients. Design Single‐center, retrospective cohort study. Setting A large, academic, tertiary care hospital. Patients A total of 7118 adults with a discharge diagnosis of severe sepsis or septic shock who received at least one dose of cefepime, meropenem, or piperacillin‐tazobactam during their hospitalization between 2010 and 2015. Measurements and Main Results Cohort entry was defined as the first day of any antipseudomonal β‐lactam initiation, and exposure was defined as the cumulative days of any antipseudomonal β‐lactam exposure during the 60‐day follow‐up period. The primary outcome was development of new resistance to any antipseudomonal β‐lactam > 3 days after cohort entry. New resistance was defined as detection of resistance to any antipseudomonal β‐lactam not identified within 180 days before cohort entry. Patients without an outcome (i.e., did not develop new resistance) or who died by day 60 were censored. Cox proportional hazards models were performed to assess the risk of development of new resistance to any antipseudomonal β‐lactam with each additional day of exposure. Analyses of each individual antipseudomonal β‐lactam were evaluated as secondary outcomes. Each additional day of exposure to any antipseudomonal β‐lactam resulted in an adjusted hazard ratio (aHR) of 1.04 (95% confidence interval [CI] 1.04–1.05) for new resistance development. The risk of developing new resistance to cefepime, meropenem, and piperacillin‐tazobactam for each additional day of exposure resulted in an aHR of 1.08 (95% CI 1.07–1.09), 1.02 (95% CI 1.01–1.03), and 1.08 (95% CI 1.06–1.09), respectively. Conclusion Among critically ill patients who receive antipseudomonal β‐lactam antibiotics, each additional day of exposure to cefepime, meropenem, and piperacillin‐tazobactam is associated with an increased risk of new resistance development.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Duration of Exposure to Antipseudomonal β‐Lactam Antibiotics in the Critically Ill and Development of New Resistance

et al. 2019

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“…This supports prior work demonstrating that characterization of time-varying antibiotic exposures has important implications for interpreting antimicrobial-associated infection risk. 29 …”

Section: Discussionmentioning

confidence: 99%

Bacterial Infections in Neonates Following Mupirocin-Based MRSA Decolonization: A Multicenter Cohort Study

Pierce

Bryant

Elward

et al. 2017

Infect. Control Hosp. Epidemiol.

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Objective To characterize the risk of infection after Staphylococcus aureus decolonization with intranasal mupirocin. Design Multicenter, retrospective cohort study. Setting Tertiary care neonatal intensive care units (NICUs) from three urban hospitals in US. Bed size range: 45–100. Methods MRSA-colonized neonates were identified from NICU admissions occurring from January 2007–December 2014, during which a targeted decolonization strategy was used for MRSA control. In two time-to-event analyses, MRSA-colonized neonates were observed from date of first MRSA positive surveillance screen until 1) first occurrence of novel gram-positive cocci in sterile culture or discharge and 2) first occurrence of novel gram-negative bacilli in sterile culture or discharge. Mupirocin exposure was treated as time varying. Results A total of 522 MRSA-colonized neonates were identified from 16,144 neonates admitted to site NICUs. Of the MRSA-colonized neonates, 384 (74%) received mupirocin. Average time from positive culture to mupirocin treatment was 3.5 days (sd=7.2 days). The adjusted hazard of gram-positive cocci infection was 64% less among mupirocin-exposed versus mupirocin-unexposed neonates (HR=0.36, 95% CI: 0.17–0.76), while the adjusted hazard ratio of gram-negative bacilli infection comparing mupirocin-exposed and -unexposed neonates was 1.05 (95% CI: 0.42–2.62). Conclusions In this multi-centered cohort of MRSA-colonized neonates, mupirocin-based decolonization treatment appeared to decrease the risk of infection with select gram-positive organisms, as intended, and was not significantly associated with risk of subsequent infections with organisms not covered by mupirocin’s spectrum of activity.

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“…The proposed methodology has great potential in other fields of medical research, whenever statistical inference for transition probabilities or functionals thereof is required. Current examples include the clinical course of liver diseases (Jepsen et al., ), joint replacements in orthopaedic patients (Gillam et al., ), different stages of illicit drug use (Mayet et al., ), pregnancy outcome data (Di Termini et al., ), investigations of longitudinal individual disability and mortality (Willekens, ), and infection control trials in healthcare epidemiology (e.g., Munoz‐Price et al., ; Sommer et al., , and references therein).…”

Section: Discussionmentioning

confidence: 99%

A Wild Bootstrap Approach for the Aalen–Johansen Estimator

Bluhmki¹,

Schmoor

Dobler³

et al. 2018

Biometrics

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We suggest a wild bootstrap resampling technique for nonparametric inference on transition probabilities in a general time-inhomogeneous Markov multistate model. We first approximate the limiting distribution of the Nelson-Aalen estimator by repeatedly generating standard normal wild bootstrap variates, while the data is kept fixed. Next, a transformation using a functional delta method argument is applied. The approach is conceptually easier than direct resampling for the transition probabilities. It is used to investigate a non-standard time-to-event outcome, currently being alive without immunosuppressive treatment, with data from a recent study of prophylactic treatment in allogeneic transplanted leukemia patients. Due to non-monotonic outcome probabilities in time, neither standard survival nor competing risks techniques apply, which highlights the need for the present methodology. Finite sample performance of time-simultaneous confidence bands for the outcome probabilities is assessed in an extensive simulation study motivated by the clinical trial data. Example code is provided in the web-based Supplementary Materials.

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Handling Time-dependent Variables: Antibiotics and Antibiotic Resistance

Cited by 45 publications

References 29 publications

Duration of Exposure to Antipseudomonal β‐Lactam Antibiotics in the Critically Ill and Development of New Resistance

Duration of Exposure to Antipseudomonal β‐Lactam Antibiotics in the Critically Ill and Development of New Resistance

Bacterial Infections in Neonates Following Mupirocin-Based MRSA Decolonization: A Multicenter Cohort Study

A Wild Bootstrap Approach for the Aalen–Johansen Estimator

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