The US Food and Drug Administration approved the blood infection biomarker procalcitonin for the purpose of guiding antibiotic therapy in the context of acute respiratory infections and sepsis in February, 2017.1 Procalcitonin is a calcitonin-related gene product expressed by human epithelial cells in response to bacterial infections and is conversely downregulated during viral infections.2, 3 Study findings have shown that procalcitonin concentrations fall rapidly during recovery from acute bacterial infections.4 As a surrogate marker of host response to bacterial infections, procalcitonin has therefore been proposed as an adjunct to traditional clinical and diagnostic parameters in helping to manage patients presenting with clinical symptoms suggestive of systemic infections and to guide antibiotic prescribing practices.5
Acute respiratory tract illnesses are one of the leading causes of adult hospital admissions and death worldwide, and are associated with antibiotic overuse.6 Although more than 40% of respiratory infections have a viral cause, imprecise bacterial diagnostics and provider concerns about co-infection prompt antibiotic prescription in most cases.7 Several trials have reported significant reductions in antibiotic exposure, when procalcitonin was used to guide decisions about initiation of antibiotics in low-risk patients (eg, patients with a clinical syndrome of bronchitis in the emergency department) and duration of treatment in high-risk patients (eg, in patients with pneumonia).8 However, although one trial9 found a reduction in mortality associated with procalcitonin-guided antibiotic stewardship in the intensive care unit (ICU), conclusive evidence on the safety of this approach across clinical settings and different types of respiratory infections has been impeded by insufficient statistical power in most individual trials.9 Moreover, previous meta-analyses10, 11, 12 concluded that although procalcitonin use was effective at reducing antibiotic exposure, results about the effect of procalcitonin-guided antibiotic stewardship on clinical outcomes were inconclusive. These meta-analyses, however, were based on aggregate data rather than individual patient-level data, restricting the ability to harmonise outcome definitions and to assess differences between subgroups, and also had a more narrow focus and thus only included a limited number of trials.
Research in context
Evidence before this study
Use of the blood infection marker procalcitonin has gained much attention in the past 10 years as adjunct to clinical judgment in discriminating viral and bacterial infections and guiding both prescription and duration of antibiotic therapy. Several individual trials showed positive effects with a reduction of antibiotic exposure in patients with respiratory infections. Yet, there is ongoing concern about safety of this approach regarding mortality. Previous meta-analyses reported no significant effect on mortality, but confidence intervals were large and harm could thus not be excluded. Based on a protocol previously published in the published in the Cochrane Library, we did a systematic literature search on the Cochrane Central Register of Controlled Trials (CENTRAL; January, 2017, issue 1), MEDLINE (1966 to February, 2017), and Embase (1980 to February, 2017). We searched PubMed using the search terms “Calcitonin”, “Procalcitonin”, “ProCT” and “Anti-Bacterial Agents”, “antibiotic”, “Antibiotics”, “antibacterial, “anti-bacterial”, “amoxicillin, “penicillin”, “ampicillin”, “cotrimoxazole”, “chloramphenicol”, “trimethoprim”, “sulphamethoxazole”, “tmp smx” and “Biomarkers”, “Marker”, “Level”, “levels”, Guide”, “Guidance” and “randomised controlled trial”, “controlled clinical trial”, “randomized”, “randomised”, “placebo”, “drug therapy”, “randomly”, “trial”, “groups”, but not “animals”, “not humans”. For other data sources, we used similar key search terms as above. Individual patient data were collected from eligible randomised controlled trials that assessed adults with a clinical diagnosis of upper or lower acute respiratory tract infection.
Added value of this study
This study showed substantial relative and absolute reductions in antibiotic use in patients with respiratory infections managed by procalcitonin protocols compared with patients in the control group. Although such reductions were found in previous research, importantly in this large cohort of patients, we also found an improvement in clinical outcomes, namely a reduction in 30-day mortality and antibiotic side-effects. This analysis is the first report, to our knowledge, that shows clinical benefits beyond antibiotic reductions with the use of procalcitonin protocols.
Implications of all the available evidence
This report integrates most of the available evidence on procalcitonin in patients with acute respiratory infection from randomised trials. Given the positive results regarding antibiotic reduction and improvements in clinical outcomes, this report strengthens the rationale to use procalcitonin to support antibiotic stewardship decisions in patients with acute respiratory infections.
We therefore did a search and meta-analysis of individual patient data from 26 randomised-controlled trials,9, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37 based on a prespecified Cochrane protocol,38, 39 to comprehensively and definitively assess the safety of using procalcitonin to guide antibiotic decisions in patients with respiratory illnesses from different clinical settings and with different types of respiratory infections. This analysis is an update of a previous meta-analysis published in 2012,39 and an extended version of this review will be published in the Cochrane Library.