September 16, 2009 — Procalcitonin (PCT) measurements may reduce rates of antibiotic use for lower respiratory tract infections (LRTIs), according to the results of a multicenter, noninferiority, randomized controlled trial reported in the September 9 issue of the Journal of the American Medical Association.
"Unnecessary antibiotic use importantly contributes to increasing bacterial resistance and increases medical costs and the risks of drug-related adverse events," write Philipp Schuetz, MD, from University Hospital Basel in Basel, Switzerland, and colleagues from the ProHOSP Study Group. "The most frequent indication for antibiotic prescriptions in the northwestern hemisphere is...LRTIs, which range in severity from self-limited acute bronchitis to severe acute exacerbation of chronic obstructive pulmonary disease (COPD), and to life-threatening bacterial community-acquired pneumonia (CAP)....In previous smaller trials, a...PCT algorithm reduced antibiotic use in patients with...LRTIs."
The goal of this study was to determine whether a PCT algorithm would reduce antibiotic use without increasing the risk for serious adverse outcomes in patients with LRTIs. Between October 2006 and March 2008, a total of 1359 patients with mostly severe LRTIs seen in emergency departments of 6 tertiary care hospitals in Switzerland were randomly assigned to a PCT group or to a control group. In the PCT group, antibiotic administration was based on a PCT algorithm with predefined cutoff ranges for starting or stopping antibiotics, whereas in the control group, antibiotics were prescribed according to standard guidelines.
Serum PCT level was measured locally in each hospital, and instructions were Web-based. The primary endpoint of the study was noninferiority of the composite adverse outcomes of death, intensive care unit admission, disease-specific complications, or recurrent infection requiring antibiotic treatment within 30 days. The predefined noninferiority boundary was 7.5%. Other study endpoints were antibiotic exposure and adverse effects from antibiotics.
The PCT and control groups had similar rates of overall adverse outcomes (15.4% [n = 103] vs 18.9% [n = 130]; difference, −3.5%; 95% confidence interval [CI], −7.6% to 0.4%). The mean duration of antibiotic exposure was lower in all patients:
PCT vs control groups: 5.7 vs 8.7 days; relative change, −34.8%; 95% CI, −40.3% to −28.7%;
Patients with CAP (n = 925): 7.2 vs 10.7 days; −32.4%; 95% CI, −37.6% to −26.9%;
Patients with exacerbation of COPD (n = 228): 2.5 vs 5.1 days; −50.4%; 95% CI, −64.0% to −34.0%; and
Patients with acute bronchitis (n = 151): 1.0 vs 2.8 days; −65.0%; 95% CI, −84.7% to −37.5%.
Compared with the control group, the PCT group had less frequent antibiotic-associated adverse effects (19.8% [n = 133] vs 28.1% [n = 193]; difference, −8.2%; 95% CI, −12.7% to −3.7%).
"In patients with LRTIs, a strategy of PCT guidance compared with standard guidelines resulted in similar rates of adverse outcomes, as well as lower rates of antibiotic exposure and antibiotic-associated adverse effects," the study authors write. "Particularly in countries with higher antibiotic prescription rates than Switzerland, PCT guidance will have substantial clinical and public health implications to reduce antibiotic exposure and associated risks of adverse effects and antibiotic resistance."
Limitations of this study include use of composite endpoints, the Hawthorne effect (physicians knowing they will be monitored may better adhere to guidelines), and spillover effect (the intervention with PCT testing may have affected antibiotic prescription patterns in the control group). In addition, the final decision to withhold or decrease antibiotic treatment was left to the discretion of the attending physician in both groups.
In an accompanying editorial, Donald M. Yealy, MD, from the University of Pittsburgh School of Medicine, and Michael J. Fine, MD, MSc, from the University of Pittsburgh Medical Center, both in Pennsylvania, discuss additional study limitations but suggest that the investigators "have charted the waters for more tailored management of LRTIs."
"In the future, an increasing number of such 'theragnostic' approaches are likely to be possible in which blood samples or tissue specimens can be used to quickly measure microbial fragments, circulating markers of organ stress and system responses, and genetic patterns that predict clinical outcomes, drug effectiveness, or both," Drs. Yealy and Fine write. "PCT-guided care is an initial step toward such a tailored approach that could lead to more appropriate antibiotic therapy for patients with LRTI, while promoting antibiotic stewardship for the entire population."
This study was supported in part by the Swiss National Science Foundation; Santé Suisse; the Gottfried and Julia Bangerter-Rhyner-Foundation; the University Hospital Basel; the Medical University Clinic Liestal; the Medical Clinic Buergerspital Solothurn; the Cantonal Hospitals Muensterlingen, Aarau, and Lucerne; the Swiss Society for Internal Medicine; and University Hospital Basel.
BRAHMS Inc, the major maker of the PCT assay, provided all assay-related material, Kryptor machines if not already available onsite, and kits and maintenance required for 10,000 measurements related to the study.
Three of the study authors have received support from BRAHMS Inc. Dr. Yealy has conducted National Institutes of Health–funded research in which Brahms AG provided biomarker assays. The other study authors and Dr. Fine have disclosed no relevant financial relationships.
JAMA. 2009;302:1059-1066, 1115-1116. Abstract
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