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

Abstract

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.

Evaluation of a ceiling effect on the association of new resistance development to antipseudomonal beta-lactam exposure in the critically ill

“…The demographic and clinical characteristics of this cohort have been described previously. 4 Briefly, 7,118 patients met the criteria for inclusion into the cohort. The median age was 61 years old (interquartile range [IQR], 51-71 years old).…”

“…To the Editor-Infections and gut colonization with vancomycinresistant enterococci (VRE) have been increasingly reported in hospitalized patients from different regions of Brazil, where difficulties in controlling VRE colonization have been noted. [1][2][3][4] Patient colonization with VRE is a major risk factor for developing subsequent infections with these strains. 1,5 The first VRE description dates from 2011 (M. Celeste Melo, personnel data), and VRE infections among hospitalized patients from Natal city (northeastern Brazil) remain low, contrasting with the high rates of VRE infection and colonization of the patients in the southern and southeastern regions, where they have occurred since 1998.…”

“…The methods used to create this database have been described previously. 4 Briefly, this study was a retrospective cohort study of patients with severe sepsis or septic shock conducted at Barnes-Jewish Hospital (BJH), an academic hospital in St Louis, Missouri, between January 1, 2010, and December 31, 2015. Data for this study were obtained from the BJH electronic medical record (EMR) system.…”

“…1,2 Among patients with severe sepsis or septic shock, antipseudomonal β-lactams are valuable first-line treatments and are among the most widely used antibiotics in the critically ill population. 3 Recently, each additional day of cumulative exposure to antipseudomonal β-lactams (specifically cefepime, meropenem, and piperacillin-tazobactam) was associated with increased risk of new resistance emergence in the critically ill. 4 The objective of the current study was to evaluate whether the relationship of that association was linear with each additional day or whether there was a "ceiling effect" in which the associated increase in the risk of new resistance plateaus after a certain duration of exposure.…”

Selection and co-selection of antibiotic resistances amongEscherichia coliby antibiotic use in primary care: an ecological analysis

“…Antibiotics were expressed in DDDs as this at least partly captures the dose and duration of treatment, while this would not be the case when expressing use in terms of items. This is important, because dose and duration has been shown to be an important driver of antibiotic resistance [31-33]. Moreover, using DDDs would facilitate incorporating of hospital prescribing when this data becomes available, as antibiotics used in the hospital are typically expressed in terms of DDDs.…”