Confounding by indication of the safety of de-escalation in community-acquired pneumonia: A simulation study embedded in a prospective cohort

Autoři: Inger van Heijl aff001;  Valentijn A. Schweitzer aff002;  C. H. Edwin Boel aff003;  Jan Jelrik Oosterheert aff004;  Susanne M. Huijts aff005;  Wendelien Dorigo-Zetsma aff006;  Paul D. van der Linden aff001;  Marc J. M. Bonten aff002;  Cornelis H. van Werkhoven aff002
Působiště autorů: Department of Clinical Pharmacy, Tergooi hospital, Hilversum, The Netherlands aff001;  Julius Center for Health Sciences and Primary care, University Medical Centre Utrecht, Utrecht, The Netherlands aff002;  Department of Medical Microbiology, University Medical Centre Utrecht, Utrecht, The Netherlands aff003;  Department of Internal Medicine & Infectious Diseases, University Medical Centre Utrecht, Utrecht, The Netherlands aff004;  Department of Pulmonary Medicine, University Medical Centre Utrecht, Utrecht, The Netherlands aff005;  Department of Medical Microbiology, Tergooi hospital, Hilversum, The Netherlands aff006
Vyšlo v časopise: PLoS ONE 14(9)
Kategorie: Research Article
prolekare.web.journal.doi_sk: 10.1371/journal.pone.0218062


Observational studies have demonstrated that de-escalation of antimicrobial therapy is independently associated with lower mortality. This most probably results from confounding by indication. Reaching clinical stability is associated with the decision to de-escalate and with survival. However, studies rarely adjust for this confounder. We quantified the potential confounding effect of clinical stability on the estimated impact of de-escalation on mortality in patients with community-acquired pneumonia. Data were used from the Community-Acquired Pneumonia immunization Trial in Adults (CAPiTA). The primary outcome was 30-day mortality. We performed Cox proportional-hazards regression with de-escalation as time-dependent variable and adjusted for baseline characteristics using propensity scores. The potential impact of unmeasured confounding was quantified through simulating a variable representing clinical stability on day three, using data on prevalence and associations with mortality from the literature. Of 1,536 included patients, 257 (16.7%) were de-escalated, 123 (8.0%) were escalated and in 1156 (75.3%) the antibiotic spectrum remained unchanged. Crude 30-day mortality was 3.5% (9/257) and 10.9% (107/986) in the de-escalation and continuation groups, respectively. The adjusted hazard ratio of de-escalation for 30-day mortality (compared to patients with unchanged coverage), without adjustment for clinical stability, was 0.39 (95%CI: 0.19–0.79). If 90% to 100% of de-escalated patients were clinically stable on day three, the fully adjusted hazard ratio would be 0.56 (95%CI: 0.27–1.12) to 1.04 (95%CI: 0.49–2.23), respectively. The simulated confounder was substantially stronger than any of the baseline confounders in our dataset. Quantification of effects of de-escalation on patient outcomes without proper adjustment for clinical stability results in strong negative bias. This study suggests the effect of de-escalation on mortality needs further well-designed prospective research to determine effect size more accurately.

Klíčová slova:

Antibiotics – Antimicrobials – Death rates – Heart rate – Oxygen – Pneumonia – Randomized controlled trials – Observational studies


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