Excess Antibiotic Treatment Duration and Adverse Events in Patients Hospitalized With Pneumonia

Pneumonia is the most common reason for inpatient antibiotic use and overuse (1). Historically, providers prescribed long durations of antibiotic therapy for pneumonia because of concerns that short courses could lead to disease relapse or progression (2, 3). However, recent studies, including multiple randomized controlled trials and systematic reviews, have demonstrated that shorter antibiotic therapy is safe and equally effective for most patients with pneumonia (49). Conversely, longer treatment places patients at risk for antibiotic-associated adverse events, Clostridioides difficile infection, and multidrug-resistant organisms (1012). To minimize harm, antibiotic stewardship guidelines recommend that hospitals implement interventions to reduce antibiotic therapy to the shortest effective duration (1315). However, patients often receive excess antibiotic therapy. We used data from an ongoing cohort study of medical patients hospitalized with community-acquired pneumonia (CAP) or health careassociated pneumonia (HCAP) in 43 hospitals across Michigan to quantify excess antibiotic treatment duration, determine factors associated with it, and evaluate its relationship with outcomes. Methods The Michigan Hospital Medicine Safety Consortium The Michigan Hospital Medicine Safety Consortium (HMS) is a statewide multi-institutional collaborative quality initiative sponsored by Blue Cross Blue Shield of Michigan and Blue Care Network. Its goal is to improve the quality of care for hospitalized medical patients who are at risk for adverse events. Participation in HMS is voluntary, and hospitals that join collect and share data to improve patient care and outcomes (16, 17). Of the 92 noncritical access, nonfederal hospitals in Michigan, 43 (47%) participate in HMS and share data on antibiotic use. In 2017, HMS began an initiative to improve antibiotic use in patients hospitalized with pneumonia. Since inception, HMS has provided hospitals with education on best practices for antibiotic prescribing and hospital-specific feedback on antibiotic use. The consortium's data collection and quality assurance procedures have been previously described (18). Briefly, trained abstractors consecutively screen patients 30 days after discharge and include the first patient who meets inclusion criteria on each day. Data are collected retrospectively from 90 days before admission until 30 days after discharge or until follow-up is terminated by a major complication (such as death). Data are collected from medical records by using a standardized data dictionary and operations manual. Patients are contacted for additional outcome data by telephone follow-up with a standardized script. Inclusion and Exclusion Criteria Patients were eligible for inclusion if they were adult medical patients receiving general care who were discharged between January 2017 and April 2018 with community-onset pneumonia, including CAP or HCAP (the latter involving nursing home residence, hospitalization within 90 days, intravenous chemotherapy, home wound care or infusion therapy, or long-term hemodialysis) (19). To improve specificity of pneumonia diagnostic criteria (20), patients were included only if they had all of the following: a discharge diagnostic code for pneumonia (20), symptoms and radiographs consistent with pneumonia (21), receipt of at least 4 days of antibiotic treatment (to exclude brief empirical treatment) (22), and receipt of antibiotics on day 1 or 2 of hospitalization (to exclude hospital-acquired pneumonia [pneumonia developing 48 hours after hospitalization]) (20). As in prior studies (23), patients who received insufficient antibiotic therapy (duration 2 days shorter than the shortest effective duration recommended by guidelines) were excluded because their treatment was probably stopped due to an alternative diagnosis. Patients were not eligible for inclusion if they received care in an intensive care unit or were on a ventilator at any point during hospitalization, were being treated for an additional infection unrelated to pneumonia (such as cellulitis), were pregnant, were severely immunocompromised (Appendix), had Legionella or a fungal pathogen, had a condition requiring longer antibiotic treatment (for example, bacteremia or empyema), were admitted under comfort care, or left against medical advice. For patients with multiple hospitalizations, only the first was included. Patients were included in the main analyses but were ineligible for a follow-up call if they were confirmed to have died; to be hospitalized; or to be in inpatient hospice, an extended care facility, or prison 30 days after hospital discharge. Primary Outcome The primary outcome was the rate of excess antibiotic treatment duration (excess days per 30-day period). Excess days were calculated by subtracting each patient's shortest effective (expected) treatment duration from the actual duration. Consistent with national guidelines, expected antibiotic treatment duration was determined on the basis of classification of pneumonia (CAP vs. HCAP), organism, and time to clinical stability (defined as being afebrile for 48 hours and having 1 vital sign abnormality) (15, 19, 21). Patients with CAP were expected to have a treatment duration of at least 5 days, with longer courses expected only if time to clinical stability was longer (4, 21, 24). Patients with HCAP, Staphylococcus aureus, or a nonfermenting Gram-negative bacillus (for example, Pseudomonas aeruginosa) were expected to have a treatment duration of at least 7 days (details are provided in the Appendix) (15). Treatment duration was defined as the sum of the number of days with inpatient antibiotics administered plus the number of days of antibiotic treatment prescribed at discharge. If patients had a positive culture result, only antibiotics that were effective against the isolated pathogen counted toward the duration. To allow for variation in the timing of antibiotic administration and to be conservative in our estimates, treatment duration was considered to be appropriate if the actual duration was within 1 day of the expected duration. Predictor Variables We used the following predictor variables: demographic characteristics; pneumonia severity index; receipt in prior 90 days of any intravenous antibiotic, fluoroquinolone, or linezolid (given their association with development of multidrug-resistant organisms and/or activity against methicillin-resistant S aureus or Pseudomonas species) (19, 25, 26); signs or symptoms of pneumonia on day 1 or 2 of hospitalization; days to clinical stability; length of stay; CAP versus HCAP; diagnostic testing (for example, culture, procalcitonin, or antigen testing); concurrent exacerbation of chronic obstructive pulmonary disease (COPD) or congestive heart failure (CHF); specialty of the attending physician at admission; misdiagnosis of CAP versus HCAP (for example, documentation of CAP despite identifiable risk factor for HCAP); documentation of total antibiotic treatment duration in discharge summary; number of hospital beds; hospital profit type (for example, nonprofit); and self-reported hospital academic status. Patient Outcomes Outcomes were collected 30 days after discharge and included death; hospital readmission; emergency department visit; and antibiotic-associated adverse events, which included C difficile infection, provider-documented adverse events (for example, QT prolongation), and patient-reported adverse events obtained via a scripted question during the telephone call (Have you had any side effects from your prescribed antibiotic? ). Patients who answered yes were asked about symptoms, additional care, and discontinuation of antibiotic therapy. Statistical Analysis To evaluate individual predictors associated with rates of excess antibiotic treatment duration (excess days per 30-day period), we first performed bivariable analyses using negative binomial generalized estimating equation (GEE) models with an exchangeable correlation structure to account for hospital clustering. Coefficients were exponentiated to yield incidence rate ratios comparing rates of excess duration in different patient groups (for example, patients with HCAP vs. CAP). We next performed multivariable analysis to determine predictors associated with rates of excess treatment duration, using a negative binomial GEE model with stepwise selection based on covariate contributions to model fit (using the Schwarz criterion) (27). Missing data for individual variables (such as race) were imputed through a 10-fold multiple imputation procedure (Markov-chain Monte Carlo) and combined using standard rules (28). Coefficients were exponentiated to yield incidence rate ratios. Finally, we report odds ratios (ORs) to evaluate whether days of excess treatment were associated with outcomes. Odds ratios were derived from logit GEE models with inverse probability of treatment weighting (29) by baseline covariates that were known to be associated with outcomes (Appendix) or were significant in the multivariable analysis model (23, 3033). All tests were 2-sided, and a P value less than 0.050 was considered statistically significant. SAS, version 9.4 (SAS Institute), was used for analyses (Appendix Table 1) Appendix Table 1. Statistical Appendix Data are limited on whether the shortest effective treatment duration for patients with complicated CAP (moderate immunocompromise [Appendix], structural lung disease, and moderate to severe COPD) is 5 days or 7 days (6). Thus, we conducted a sensitivity analysis in which patients with complicated CAP had a shortest expected duration of 7 days. Furthermore, because clinical stability may also be defined as being afebrile for 48 hours and having no vital sign abnormalities (vs. 1) (34), we conducted a sensitivity analysis based on this definition. Finally, given the large number of patients who received 0 days of excess treatment, we performed sensitivity ana