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.

IMPORTANCE Calcium channel blockers, specifically dihydropyridine calcium channel blockers (DH CCBs, eg, amlodipine), may cause lower-extremity edema. Anecdotal reports suggest this may result in a prescribing cascade, where DH CCB-induced edema is treated with loop diuretics. OBJECTIVE To assess the magnitude and characteristics of the DH CCB prescribing cascade. DESIGN, SETTING, AND PARTICIPANTS This cohort study used a prescription sequence symmetry analysis to assess loop diuretic initiation before and after the initiation of DH CCBs among patients aged 20 years or older without heart failure. Data from a private insurance claims database from 2005 to 2017 was analyzed. Use of loop diuretics associated with initiation of angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and other commonly used medications was used as negative controls. Data were analyzed from March 2019 through October 2019. EXPOSURES Initiation of DH CCB or negative control medications. MAIN OUTCOMES AND MEASURES The temporality of loop diuretic initiation relative to DH CCB or negative control initiation. Secular trend-adjusted sequence ratios (aSRs) with 95% CIs were calculated using data from 360 days before and after initiation of DH CCBs. RESULTS Among 1 206 093 DH CCB initiators, 55 818 patients (4.6%) (33 100 [59.3%] aged <65 years; 32 916 [59.0%] women) had a new loop diuretic prescription 360 days before or after DH CCB initiation, resulting in an aSR of 1.87 (95% CI, 1.84-1.90). An estimated 1.44% of DH CCB initiators experienced the prescribing cascade. The aSR was disproportionately higher among DH CCB initiators who were prescribed high doses (aSR, 2.20; 95% CI, 2.13-2.27), initiated amlodipine (aSR, 1.89; 95% CI, 1.86-1.93), were men (aSR, 1.96; 95% CI, 1.91-2.01), and used fewer antihypertensive classes (aSR, 2.55; 95% CI, 2.47-2.64). The evaluation of ACE inhibitors or ARBs as negative controls suggested hypertension progression may have tempered the incidence of the prescribing cascade (aSR for ACE inhibitors and ARBs, 1.27; 95% CI, 1.24-1.29). CONCLUSIONS AND RELEVANCE This study found an excessive use of loop diuretics following initiation of DH CCBs that cannot be completely explained by secular trends or hypertension progression. The prescribing cascade was more pronounced among those initially prescribed a high dose of DH CCBs.