PCT-guided Therapy Research Articles

Procalcitonin-guided antibiotic therapy may shorten length of treatment and may improve survival—a systematic review and meta-analysis

BackgroundAppropriate antibiotic (AB) therapy remains a challenge in the intensive care unit (ICU). Procalcitonin (PCT)-guided AB stewardship could help optimize AB treatment and decrease AB-related adverse effects, but firm evidence is still lacking. Our aim was to compare the effects of PCT-guided AB therapy with standard of care (SOC) in critically ill patients.MethodsWe searched databases CENTRAL, Embase and Medline. We included randomized controlled trials (RCTs) comparing PCT-guided AB therapy (PCT group) with SOC reporting on length of AB therapy, mortality, recurrent and secondary infection, ICU length of stay (LOS), hospital LOS or healthcare costs. Due to recent changes in sepsis definitions, subgroup analyses were performed in studies applying the Sepsis-3 definition. In the statistical analysis, a random-effects model was used to pool effect sizes.ResultsWe included 26 RCTs (n = 9048 patients) in the quantitative analysis. In comparison with SOC, length of AB therapy was significantly shorter in the PCT group (MD − 1.79 days, 95% CI: -2.65, − 0.92) and was associated with a significantly lower 28-day mortality (OR 0.84, 95% CI: 0.74, 0.95). In Sepsis-3 patients, mortality benefit was more pronounced (OR 0.46 95% CI: 0.27, 0.79). Odds of recurrent infection were significantly higher in the PCT group (OR 1.36, 95% CI: 1.10, 1.68), but there was no significant difference in the odds of secondary infection (OR 0.81, 95% CI: 0.54, 1.21), ICU and hospital length of stay (MD − 0.67 days 95% CI: − 1.76, 0.41 and MD − 1.23 days, 95% CI: − 3.13, 0.67, respectively).ConclusionsPCT-guided AB therapy may be associated with reduced AB use, lower 28-day mortality but higher infection recurrence, with similar ICU and hospital length of stay. Our results render the need for better designed studies investigating the role of PCT-guided AB stewardship in critically ill patients.Graphical abstract

An algorithm for PCT-guided antimicrobial therapy: a consensus statement by Japanese experts.

In Japan, a national antimicrobial resistance (AMR) action plan was adopted in 2016, advocating a 20% reduction in antibiotic consumption by 2020. However, there is still room for improvement to accomplish this goal. Many randomized controlled trials have reported that procalcitonin (PCT)-guided antimicrobial therapy could help to reduce antibiotic consumption without negative health effects, specifically in acute respiratory infections. In September 2018, some experts in Europe and the USA proposed algorithms for PCT-guided antimicrobial therapy in mild to moderate infection cases outside the ICU and severe cases in the ICU (the international experts consensus). Thereafter, a group of Japanese experts, including specialists in intensive care medicine, emergency medicine, respiratory medicine and infectious diseases, created a modified version of a PCT-guided algorithm (Japanese experts consensus). This modified algorithm was adapted to better fit Japanese medical circumstances, since PCT-guided therapy is not widely used in daily clinical practice in Japan. The Japanese algorithm has three specific characteristics. First, the target patients are limited to only hospitalized ICU or non-ICU patients. Second, pneumonia due to Pseudomonas aeruginosa, Staphylococcus aureus and Legionella species are excluded. Finally, a different timing of PCT follow-up measurement was proposed to meet restrictions of the Japanese medical insurance system. The adapted algorithms has high potential to further improve the safe reduction in antibiotic consumption in Japan, while reducing the spread of AMR pathogens.

Reduction of Duration of Antibiotic Therapy for Suspected Early-Onset Sepsis in Late-Preterm and Term Newborns After Implementation of a Procalcitonin-Guided Algorithm: A Population-Based Study in Central Switzerland

Background: Suspected early-onset sepsis (EOS) is the main reason for antibiotic therapy at the start of life. Prolonged antibiotic therapy for culture-negative sepsis is often reported. Antibiotic stewardship is mandatory due to the potential negative effects of unnecessary antibiotics. Procalcitonin (PCT)-guided therapy is one possible strategy with published evidence to shorten antibiotic therapy. The aim of this study is to analyze the feasibility and the performance of the published PCT-algorithm in the clinical setting without study support.Methods: This is a retrospective, population-based study regarding duration of antibiotic therapy for suspected EOS in Central Switzerland between 2014 and 2018. All neonates >34 0/7 weeks of gestational age started on antibiotic therapy for suspected EOS within the first 3 calendar days of life were included. The Procalcitonin-guided algorithm according to the NeoPInS study was used as strategy to determine duration of antibiotic therapy.Results: In a population-based cohort of 35,642 life born neonates, the duration of antibiotic therapy of 879 neonates (2.5% of the cohort) treated for suspected EOS was 4 calendar days (median, IQR 2–5). We observed a statistically significant reduction from 4 (median, IQR 3–6) to 3 calendar days (median, IQR 2–4) from 2014 to 2018. Duration of antibiotic therapy was independent of gestational age (late-preterm vs. term neonates), of the presence of risk factors or clinical signs, but dependent on the presence of abnormal laboratory measurements (C-reactive protein > 10 mg/l or leukocytopenia <5 Giga/l) before start of antibiotic therapy (p < 0.01).Conclusions: PCT-guided therapy using the NeoPInS algorithm is feasible and may lead to reduced duration of antibiotic therapy for suspected EOS as reported in the original study. We observed a learning curve to the new algorithm which may be explained as change process. The use of biomarker to guide duration of antibiotic therapy for suspected EOS may have unintended consequences with prolongation of antibiotic therapy in some cases.

Diagnostic Stewardship in Lower Respiratory Tract Infections Using Procalcitonin

Background: A team of infectious diseases physicians, infectious diseases pharmacists, clinical laboratorians, and researchers collaborated to assess the management of lower respiratory tract infections (LRTIs). In 1 sample from our institution, 96.1% of pneumonia cases were prescribed antibiotics, compared to 85.0% in a comparison group. A collaborative effort led to the development of a protocol for procalcitonin (PCT)-guided antibiotic prescribing that was approved by several hospital committees, including the Antimicrobial Stewardship Committee and the Healthcare Pharmacy &amp; Therapeutics Committee in December 2020. The aim of this analysis was to develop baseline information on PCT ordering and antibiotic prescribing patterns in LRTIs. Methods: We evaluated all adult inpatients (March–September 2019 and 2020) with a primary diagnosis of LRTI who received at least 1 antibiotic. Two cohorts were established to observe any potential differences in the 2 most recent years prior to adoption of the PCT protocol. Data (eg, demographics, specific diagnosis, length of stay, antimicrobial therapy and duration, PCT labs, etc) were obtained from the UK Center for Clinical and Translational Science, and the study was approved by the local IRB. The primary outcome of interest was antibiotic duration; secondary outcomes of interest were PCT orders, discharge antibiotic prescription, and inpatient length of stay. Results: In total, 432 patients (277 in 2019 and 155 in 2020) were included in this analysis. The average patient age was 61.2 years (SD, ±13.7); 47.7% were female; and 86.1% were white. Most patients were primarily diagnosed with pneumonia (58.8%), followed by COPD with complication (40.5%). In-hospital mortality was 3.5%. The minority of patients had any orders for PCT (29.2%); among them, most had only 1 PCT level measured (84.1%). The median length of hospital stay was 4 days (IQR, 2–6), and the median duration of antibiotic therapy was 4 days (IQR, 3–6). Conclusions: The utilization of PCT in LRTIs occurs in the minority of patient cases at our institution and mostly as a single measurement. The development and implementation of a PCT-guided therapy could help optimize antibiotic usage in patients with LRTIs.Funding: NoDisclosures: None

Procalcitonin in special patient populations: Guidance for antimicrobial therapy.

Procalcitonin (PCT) is an endogenous hormone that increases reliably in response to bacterial infection, and measurement of serum PCT levels is recommended to help guide antimicrobial therapy. The utility of PCT assessment in special patient populations (eg, patients with renal dysfunction, cardiac compromise, or immunocompromised states and those undergoing acute care surgery) is less clear. The evidence for PCT-guided antimicrobial therapy in special populations is reviewed. In the presence of bacterial infection, nonneuroendocrine PCT is produced in response to bacterial toxins and inflammatory cytokines, resulting in markedly elevated levels of serum PCT. Cytokine induction in nonbacterial inflammatory processes activated by acute care surgery may alter the interpretation of PCT levels. The reliability of PCT assessment has also been questioned in patients with renal dysfunction, cardiac compromise, or immunosuppression. In many special populations, serum PCT may be elevated at baseline and increase further in the presence of infection; thus, higher thresholds for diagnosing infection or de-escalating therapy should be considered, although the optimal threshold to use in a specific population is unclear. Procalcitonin-guided antimicrobial therapy may be recommended in certain clinical situations. Procalcitonin may be a reliable marker of infection even in special populations with baseline elevations in serum PCT. However, due to unclear threshold values and the limited inclusion of special populations in relevant clinical trials, PCT levels should be considered along with clinical criteria, and antibiotics should never be initiated or withheld based on PCT values alone. Procalcitonin measurement may have a role in guiding de-escalation of antibiotic therapy in special populations; however, the clinician should be aware of disease states and concomitant therapies that may affect interpretation of results.

Procalcitonin as a Guide of Antibiotics Administration in Lower Respiratory Tract Infection

Background: Pneumonia is one of the common infection-related death. Recently use of biomarkers in diagnostic and therapeutic approach to pneumonia has been considered. The aim of our study is to evaluate the length of antibiotic treatment, length of hospitalization and medical outcomes in procalcitonin-guided antibiotic therapy in patients with pneumonia. Methods: In a randomized controlled trial study with 134 hospitalized patients with the diagnosis of pneumonia were enrolled to the study and randomly divided into two groups, procalcitonin group (PCT-guided therapy) and control group (customary clinical guidelines). All patients had 14 days follow up. Data were analyzed with appropriate statistical analysis and using version 16 of SPSS statistical software. Results: Totally, the assessed patients were in the range of 18-94 years old and the mean of age in control group was 62.87 ± 19.20 years and mean age of PCT group was 58.34 ± 19.32 years. Length of antibiotic treatment in the PCT group was 3.17 days’ vs 11.38 days in the control group (P &lt; 0.0001). Length of hospitalization in the PCT group was 4.53 days’ vs 6.75 days in the control group that was significantly reduced (P &lt; 0.0001). In 14 days follow up all patients had not any complication and clinically improved. Conclusions: In conclusion, procalcitonin-guided antibiotic treatment in patients with acute respiratory infections effectively reduced antibiotic exposure and antibiotic side-effects while reducing the length of hospitalization and treatment duration and accordingly, decrease the expenditure of patients’ treatment and avoid antibiotic resistance.

Introduction of Procalcitonin Testing and Antibiotic Utilization for Acute Exacerbations of Chronic Obstructive Pulmonary Disease.

Background:The majority of acute exacerbations of chronic obstructive pulmonary disease (AECOPD) are triggered by nonbacterial causes, yet most patients receive antibiotics. Treatment guided by procalcitonin (PCT), a sensitive biomarker of bacterial infection, safely decreases antibiotic use in many controlled trials. We evaluated PCT implementation for inpatients with AECOPD at a large academic hospital.Methods:All patients admitted for AECOPD during the first 6 months of PCT-guided therapy were eligible for inclusion in this retrospective cohort study. Patients with PCT performed were compared with those without PCT. The primary outcome was antibiotic days of therapy (DOT). Secondary outcomes included 30-day readmission and mortality.Results:Of the 238 AECOPD admissions, 73 (31%) had PCT performed. Procalcitonin-tested patients were more likely to meet systemic inflammatory response syndrome (SIRS) criteria, require intensive care unit (ICU)-level care, and have a longer length of stay (LOS) compared with those without PCT. Even after adjustment for these factors, PCT-tested patients received more inpatient DOT and there was no difference in total DOT. However, a low PCT value (<0.25 ng/mL) was associated with a 25.5% (P ⩽ .001) decrease in intravenous (IV) antibiotic DOT. Guideline-recommended follow-up testing was rare (12%). Procalcitonin measurement had no effect on 30-day readmission or mortality.Conclusions:In this real-world analysis of inpatients with AECOPD, PCT-guided therapy was poorly adopted by providers and was not associated with a decrease in total antibiotic DOT. However, a low PCT level was associated with a 25.5% decrease in IV antibiotic DOT, suggesting increased comfort stepping down from IV to PO therapy.

Procalcitonin-Guided Treatment on Duration of Antibiotic Therapy and Cost in Septic Patients (PRODA): a Multi-Center Randomized Controlled Trial.

BackgroundThe objective of this study was to establish the efficacy and safety of procalcitonin (PCT)-guided antibiotic discontinuation in critically ill patients with sepsis in a country with a high prevalence of antimicrobial resistance and a national health insurance system.MethodsIn a multi-center randomized controlled trial, patients were randomly assigned to a PCT group (stopping antibiotics based on a predefined cut-off range of PCT) or a control group. The primary end-point was antibiotic duration. We also performed a cost-minimization analysis of PCT-guided antibiotic discontinuation.ResultsThe two groups (23 in the PCT group and 29 in the control group) had similar demographic and clinical characteristics except for need for renal replacement therapy on ICU admission (46% vs. 14%; P = 0.010). In the per-protocol analysis, the median duration of antibiotic treatment for sepsis was 4 days shorter in the PCT group than the control group (8 days; interquartile range [IQR], 6–10 days vs. 14 days; IQR, 12–21 days; P = 0.001). However, main secondary outcomes, such as clinical cure, 28-day mortality, hospital mortality, and ICU and hospital stays were not different between the two groups. In cost evaluation, PCT-guided therapy decreased antibiotic costs by USD 30 (USD 241 in the PCT group vs. USD 270 in the control group). The results of the intention-to-treat analysis were similar to those obtained for the per-protocol analysis.ConclusionPCT-guided antibiotic discontinuation in critically ill patients with sepsis could reduce the duration of antibiotic use and its costs with no apparent adverse outcomes.Trial RegistrationClinicalTrials.gov Identifier: NCT02202941

Procalcitonin as a Biomarker in Rhinosinusitis: A Systematic Review.

(1) To describe the existing literature on procalcitonin (PCT) as a biomarker in patients with acute rhinosinusitis (ARS), (2) to analyze outcomes in ARS patients who were treated with PCT-guided therapy versus traditional management, and (3) to compare PCT to other biomarkers used in diagnosis of bacterial ARS. Data Sources: PubMed and Embase. Review Methods: A systematic search in the PubMed and Embase databases was performed to identify studies related to PCT as a biomarker in ARS. After critical appraisal of validity by 2 authors, 6 studies with a total of 313 patients were selected for data extraction and analysis. We identified 2 randomized control trials (RCTs) of PCT-based guidelines for antibiotic management of ARS in outpatient settings and 4 observational studies that compared PCT to other biomarkers in patients with ARS. The 2 RCTs demonstrated a reduction (41.6% in 1 study and 71% in the other) in antibiotic prescription rate in the PCT-guided group versus the control group with no change in the number of days with impaired activity due to illness (9.0 vs 9.0 days [ P = .96]; 8.1 vs 8.2 days [95% confidence interval -0.7 to 0.7]), number of days of work missed, and percentage of patients with persistent symptoms at 28 days. In the observational cohort studies, PCT did not consistently correlate with C-reactive protein, body temperature, and/or white blood cell counts. The limited existing literature on the role of PCT in diagnosis, management, and prediction of clinical outcomes in ARS suggests that PCT-based guidelines for antibiotic prescription are a safe and effective method of minimizing unnecessary antibiotic use.

1968. Procalcitonin-Guided Antibiotic Therapy for Lower Respiratory Tract Infections in a US Academic Medical Center

BackgroundEuropean trials using procalcitonin (PCT)-guided antibiotic therapy for patients with lower respiratory tract infections (LRTI) have resulted in significant reductions in antibiotic use without increasing adverse outcomes. Few prospective studies have examined PCT-guided antibiotic therapy for LRTI in the United States. Our objective was to examine whether an PCT algorithm compared with standard practice would reduce antibiotic exposure in patients with LRTI [pneumonia and acute exacerbations of chronic obstructive pulmonary disease (AECOPD)] in an American urban academic hospital.MethodsFrom April 17, 2017 until November 1, 2017, consecutive patients admitted to a medicine service were enrolled in the PCT intervention if they were receiving antibiotics for LRTI and gave consent. Providers were encouraged to discontinue antibiotics using a PCT algorithm with predefined cutoffs. Serum PCT was measured in the hospital laboratory once daily. Results and recommendations were communicated to providers by study team and in the medical record. Control patients were selected by reviewing charts for patients admitted to a medicine service for LRTI from December 1, 2016 to April 16, 2017. The primary endpoint was median antibiotic duration. Overall adverse outcomes at 30 days comprised death, transfer to an intensive care unit, antibiotic side effects, Clostridium difficile infection, disease- specific complications, and new antibiotic prescription for LRTI after discharge.Results174 patients were enrolled in the intervention group and 200 patients in the control group. Intervention group providers complied with the PCT algorithm in 75% of encounters. The rate of overall adverse outcomes was similar in PCT and control groups (21.8% vs. 23.5%; difference, –0.02; 95% CI, –0.10 to 0.07). PCT-guided therapy reduced the median antibiotic duration for pneumonia from 7 days to 6 (P = 0.05), and AECOPD from 4 days to 3 (P = 0.01). Noncompliance with the PCT algorithm resulted in 260 excess antibiotic days in 44 patients.ConclusionIn our center, 75% adherence to a PCT-guided algorithm safely reduced the duration of antibiotics for treating LRTI. Incentivizing providers to comply with PCT-guided algorithms could lead to further reductions in antibiotic use.Disclosures J. Townsend, BRAHMS: Grant Investigator, Research grant.

Procalcitonin-guided antibiotic therapy in patients with fever in a general emergency department population: a multicentre non-inferiority randomized clinical trial (HiTEMP study)

ObjectivesOveruse of broad-spectrum antibiotics in emergency departments (EDs) results in antibiotic resistance. We determined whether procalcitonin (PCT) -guided therapy can be used to reduce antibiotic regimens in EDs by investigating efficacy, safety and accuracy. MethodsThis was a non-inferiority multicentre randomized clinical trial, performed in two Dutch hospitals. Adult patients with fever ≥38.2°C (100.8°F) in triage were randomized between standard diagnostic workup (control group) and PCT-guided therapy, defined as standard workup with the addition of one single PCT measurement. The treatment algorithm encouraged withholding antibiotic regimens with PCT <0.5 μg/L, and starting antibiotic regimens at PCT ≥0.5 μg/L. Exclusion criteria were immunocompromised conditions, pregnancy, moribund patients, patients <72 h after surgery or requiring primary surgical intervention. Primary outcomes were efficacy, defined as number of prescribed antibiotic regimens; safety, defined as combined safety end point consisting of 30 days mortality, intensive-care unit admission, ED return visit within 2 weeks; accuracy, defined as sensitivity, specificity and area-under-the-curve (AUC) of PCT for bacterial infections. Non-inferiority margin for safety outcome was 7.5%. ResultsBetween August 2014 and January 2017, 551 individuals were included. In the PCT-guided group (n = 275) 200 (73%) patients were prescribed antibiotic regimens, in the control group (n = 276) 212 (77%) patients were prescribed antibiotics (p 0.28). There was no significant difference in combined safety end point between the PCT-guided group, 29 (11%), and control group, 46 (16%) (p 0.16), with a non-inferiority margin of 0.46% (n = 526). AUC for confirmed bacterial infections for PCT was 0.681 (95% CI 0.633–0.730), and for CRP was 0.619 (95% CI 0.569–0.669). ConclusionsPCT-guided therapy was non-inferior in terms of safety, but did not reduce prescription of antibiotic regimens in an ED population with fever. In this heterogeneous population, the accuracy of PCT in diagnosing bacterial infections was poor. Trial Registration in Netherlands trial registerhttp://www.trialregister.nl/trialreg/admin/rctview.asp?TC=4949.

A meta-analysis to assess usefulness of procalcitonin-guided antibiotic usage for decision making.

Background & objectives:Development of antibacterial resistance and its association with antibiotic overuse makes it necessary to identify a specific and sensitive biomarker for the diagnosis of bacterial infection and guiding antibiotic therapy. Procalcitonin (PCT), as a sepsis biomarker, may play a role in guiding antibiotics treatment in hospital settings. The aim of the current meta-analysis was to analyze the utility of PCT on various outcomes of interest in inpatients.Methods:Different databases were searched for randomized controlled trials comparing PCT-guided therapy with standard therapy in admitted patients with bacterial infections. Twenty six articles were found suitable for full text search and of these, 16 studies were considered finally for data extraction.Results:There were no significant differences found in total mortality [pooled odds ratio (OR) 1.04, 95% confidence interval (CI) 0.89-1.22, P=0.63], 28-day mortality (pooled OR 0.97, 95% CI 0.80-1.19, P=0.79), need of Intensive Care Unit admission (OR=0.80, 95% CI 0.59-1.09, P=0.16) and duration of stay in hospital (pooled mean difference −0.01, 95% CI −0.50-0.49, P=0.98) between treatment and control groups. PCT-guided treatment significantly decreased the duration of antibiotic treatment (pooled mean difference −2.79, 95% CI −3.52-−2.06, P<0.00001).Interpretation & conclusions:PCT-guided therapy significantly decreased antibiotics exposure and thus treatment cost. However, the hard endpoints did not demonstrate any significant benefits, possibly due to low power to detect differences and/or the presence of comorbidities.

The Randomized Controlled STRAWINSKI Trial: Procalcitonin-Guided Antibiotic Therapy after Stroke.

Pneumonia is among the most common acute complications after stroke and is associated with poor long-term outcome. Biomarkers may help identifying stroke patients at high risk for developing stroke-associated pneumonia (SAP) and to guide early treatment. This trial investigated whether procalcitonin (PCT) ultrasensitive (PCTus)-guided antibiotic treatment of SAP can improve functional outcome after stroke. In this international, multicenter, randomized, controlled clinical trial with blinded assessment of outcomes, patients with severe ischemic stroke in the middle cerebral artery territory were randomly assigned within 40 h after symptom onset to PCTus-based antibiotic therapy guidance in addition to stroke unit care or standard stroke unit care alone. The primary endpoint was functional outcome at 3 months, defined according to the modified Rankin Scale (mRS) and dichotomized as acceptable (≤4) or unacceptable (≥5). Secondary endpoints included usage of antibiotics, infection rates, days of fever, and mortality. The trial was registered with http://ClinicalTrials.gov (Identifier NCT01264549). In the intention-to-treat-analysis based on 227 patients (112 in PCT and 115 in control group), 197 patients completed the 3-month follow-up. Adherence to PCT guidance was 65%. PCT-guided therapy did not improve functional outcome as measured by mRS (odds ratio 0.79; 95% confidence interval 0.45-1.35, p = 0.47). Pneumonia rate and mortality were similar in both groups. Days with fever tended to be lower (p = 0.055), whereas total number of days treated with antibiotics were higher (p = 0.004) in PCT compared to control group. A post hoc analysis including all PCT values in the intention-to-treat population demonstrated a significant increase on the first day of infection in patients with pneumonia and sepsis compared to patients with urinary tract infections or without infections (p < 0.0001). PCTus-guided antibiotic therapy did not improve functional outcome at 3 months after severe ischemic stroke. PCT is a promising biomarker for early detection of pneumonia and sepsis in acute stroke patients.

Higher diagnostic accuracy and cost-effectiveness using procalcitonin in the treatment of emergency medicine patients with fever (The HiTEMP study): a multicenter randomized study.

BackgroundFever is a common symptom in the emergency department(ED). Fever can be caused by bacterial infections, which are treated with antibiotics. Often, bacterial infections cannot be ruled out in the ED using standard diagnostics, and empiric antibiotic treatment is started. Procalcitonin(PCT) is a biomarker for bacterial infections, but its role in an undifferentiated ED population remains unclear. We hypothesize that PCT-guided therapy may reduce antibiotics prescription in undifferentiated febrile ED patients. The primary objectives of this study are to determine a) the efficacy, b) the safety of PCT-guided therapy, and c) the accuracy of the biomarker PCT for bacterial infections. The secondary objective is to study the cost-effectiveness of PCT-guided therapy.Methods/designThis is a multicenter noninferiority randomized controlled trial. All adult ED patients with fever(≥38.2 °C) are randomized between standard care with and without the addition of a PCT level, after written informed consent.For efficacy, the reduction of patients receiving antibiotics is calculated, using a superiority analysis: differences between the PCT-guided group and control group are assessed using a Fisher’s exact test, and a multivariable logistic regression analysis to account for the effects of demographic and medical variables on the percentage of febrile patients receiving antibiotics.Safety consists of a composite endpoint, defined as mortality, intensive care admission and ED return visit within 14 days. Noninferiority of PCT will be tested using a one-sided 95 % confidence interval for the difference in the composite safety endpoint between the PCT-guided and control groups using a noninferiority margin of 7.5 %.Accuracy of PCT and CRP for the diagnosis of bacterial infections will be reported, using the sensitivity, specificity, and the area under the receiver-operating-characteristic curve in the definitive diagnosis of bacterial infections.The sample size is 550 patients, which was calculated using a power analysis for all primary objectives. Enrollment of patients started in August 2014 and will last 2 years.DiscussionPCT may offer a more tailor-made treatment to the individual ED patient with fever. Prospective costs analyses will reveal the economic consequences of implementing PCT-guided therapy in the ED.This trial is registered in the Dutch trial registerNTR4949

Procalcitonin guidance for reduction of antibiotic use in patients hospitalized with severe acute exacerbations of asthma: a randomized controlled study with 12-month follow-up.

IntroductionPatients with severe acute exacerbations of asthma often receive inappropriate antibiotic treatment. We aimed to determine whether serum procalcitonin (PCT) levels can effectively and safely reduce antibiotic exposure in patients experiencing exacerbations of asthma.MethodsIn this randomized controlled trial, a total of 216 patients requiring hospitalization for severe acute exacerbations of asthma were screened for eligibility to participate and 169 completed the 12-month follow-up visit. Patients were randomized to either PCT-guided (PCT group) or standard (control group) antimicrobial therapy. In the control group, patients received antibiotics according to the attending physician’s discretion; in the PCT group, patients received antibiotics according to an algorithm based on serum PCT levels. The primary end point was antibiotic exposure; secondary end points were clinical recovery, length of hospital stay, clinical and laboratory parameters, spirometry, number of asthma exacerbations, emergency room visits, hospitalizations and need for corticosteroid use due to asthma.ResultsPCT guidance reduced antibiotic prescription (48.9% versus 87.8%, respectively; P < 0.001) and antibiotic exposure (relative risk, 0.56; 95% confidence interval, 0.44 to 0.70; P < 0.001) compared to standard therapy. There were no significant differences in clinical recovery, length of hospital stay or clinical, laboratory and spirometry outcomes in both groups. Number of asthma exacerbations, emergency room visits, hospitalizations and need for corticosteroid use due to asthma were similar during the 12-month follow-up period.ConclusionA PCT-guided strategy allows antibiotic exposure to be reduced in patients with severe acute exacerbation of asthma without apparent harm.Trial registrationChinese Clinical Trial Register ChiCTR-TRC-12002534 (registered 26 September 2012)

Stop Antibiotics on guidance of Procalcitonin Study (SAPS): a randomised prospective multicenter investigator-initiated trial to analyse whether daily measurements of procalcitonin versus a standard-of-care approach can safely shorten antibiotic duration in intensive care unit patients - calculated sample size: 1816 patients

BackgroundUnnecessary long-term use of broad-spectrum antibiotics is linked to the emergence and selection of resistant bacteria, prolonged hospitalisation and increased costs. Several clinical trials indicate that the biomarker procalcitonin (PCT) can guide antibiotic therapy. Some of these trials have shown a promising reduction in the number of antibiotic prescriptions, duration of antibiotic therapy and even length of stay in the ICU, although their size and selection criteria limit their external validity. The objectives of the Stop Antibiotics on guidance of Procalcitonin Study (SAPS) are to evaluate whether daily PCT can improve “real-life” antibiotic use in Dutch ICU’s by reduction of the duration of antibiotic treatment without an increase of recurrent infections and mortality.Methods/DesignMulticenter randomised controlled intervention trial. Powered for superiority of the primary efficacy endpoint and non-inferiority on the primary safety endpoints (non-inferiority margin is set on 8%).Inclusion criteria: (1) ICU-patients aged ≥18 years and (2) receiving antibiotics for a presumed or proven infection and (3) signed informed consent. Exclusion criteria: (1) patients who require prolonged antibiotic therapy, (2) suffer from Mycobacterium tuberculosis, (3) cystic fibrosis, (4) viral or parasitic infections and (5) those that are severely immunocompromised or (6) moribund.The intervention consists solely of an advice to discontinue antibiotic treatment in case PCT has decreased by more than 80% of its peak level (relative stopping threshold) or decrease below a value of 0.5 ng/ml (absolute stopping threshold).The study hypothesis is that PCT-guided therapy is non-inferior to standard care based on implemented guidelines and local expertise, whilst reducing antibiotic usage. Computerised 1:1 randomisation will allocate 908 patients per arm. Arm 1: standard of care. Arm 2: procalcitonin-guided therapy. The primary efficacy endpoint is consumption of antibiotics expressed as the defined daily dosage and duration of antibiotic therapy expressed in days of therapy. This trial is designed to shorten antibiotics safely, therefore the primary safety endpoint is mortality measured at 28 day and 1 year.DiscussionThis will be the largest procalcitonin-guided antibiotic intervention trial in ICU setting thus far. Currently 1600 of the planned 1816 patients are randomised (November 2012). The first interim analysis has passed without any safety or futility issues.Trial registrationTrial registration number at http://www.clinicaltrials.gov: Id. Nr. NCT01139489 , at http://www.trialregister.nl: Id.nr. NTR1861.

Efficacy and Safety of Procalcitonin-Guided Antibiotic Therapy in Lower Respiratory Tract Infections.

Background: In 14 randomized controlled studies to date, a procalcitonin (PCT)-based algorithm has been proven to markedly reduce the use of antibiotics along with an unimpaired high safety and low complication rates in patients with lower respiratory tract infections (LRTIs). However, compliance with the algorithm and safety out of controlled study conditions has not yet been sufficiently investigated. Methods: We performed a prospective international multicenter observational post-study surveillance of consecutive adults with community-acquired LRTI in 14 centers (Switzerland (n = 10), France (n = 3) and the United States (n = 1)). Results: Between September 2009 and November 2010, 1,759 patients were enrolled (median age 71; female sex 44.4%). 1,520 (86.4%) patients had a final diagnosis of LRTI (community-acquired pneumonia (CAP), 53.7%; acute exacerbation of chronic obstructive pulmonary disease (AECOPD), 17.1%; and acute bronchitis, 14.4%). Compliance with the PCT-guided therapy (overall 68.2%) was highest in patients with bronchitis (81.0% vs. AECOPD, 70.1%; CAP, 63.7%; p < 0.001), outpatients (86.1% vs. inpatients, 65.9%; p < 0.001) and algorithm-experienced centers (82.5% vs. algorithm-naive, 60.1%; p < 0.001) and showed significant geographical differences. The initial decision about the antibiotic therapy was based on PCT value in 72.4%. In another 8.6% of patients, antibiotics were administered despite low PCT values but according to predefined criteria. Thus, the algorithm was followed in 81.0% of patients. In a multivariable Cox hazard ratio model, longer antibiotic therapy duration was associated with algorithm-non-compliance, country, hospitalization, CAP vs. bronchitis, renal failure and algorithm-naïvety of the study center. In a multivariable logistic regression complications (death, empyema, ICU treatment, mechanical ventilation, relapse, and antibiotic-associated side effects) were significantly associated with increasing CURB65-Score, CAP vs. bronchitis, multilobar pneumonia, but not with algorithm-compliance. Discussion: Cultural and geographic differences in antibiotic prescribing affected the compliance with our PCT-guided algorithm. Efforts to reinforce compliance are needed. Antibiotic stewardship with PCT is possible, effective and safe without increasing the risk of complications in real-life conditions.

Procalcitonin-guided therapy in intensive care unit patients with severe sepsis and septic shock – a systematic review and meta-analysis

IntroductionProcalcitonin (PCT) algorithms for antibiotic treatment decisions have been studied in adult patients from primary care, emergency department, and intensive care unit (ICU) settings, suggesting that procalcitonin-guided therapy may reduce antibiotic exposure without increasing the mortality rate. However, information on the efficacy and safety of this approach in the most vulnerable population of critically ill patients with severe sepsis and septic shock is missing.MethodTwo reviewers independently performed a systematic search in PubMed, Embase, ISI Web of Knowledge, BioMed Central, ScienceDirect, Cochrane Central Register of Controlled Trials, http://www.ClinicalTrials.gov and http://www.ISRCTN.org.Eligible studies had to be randomized controlled clinical trials or cohort studies which compare procalcitonin-guided therapy with standard care in severe sepsis patients and report at least one of the following outcomes: hospital mortality, 28-day mortality, duration of antimicrobial therapy, length of stay in the intensive care unit or length of hospital stay. Disagreements about inclusion of studies and judgment of bias were solved by consensus.ResultsFinally seven studies comprising a total of 1,075 patients with severe sepsis or septic shock were included in the meta-analysis.Both hospital mortality (RR [relative risk]: 0.91, 95%CI [confidence interval]: 0.61; 1.36) and 28-day mortality (RR: 1.02, 95%CI: 0.85; 1.23) were not different between procalcitonin-guided therapy and standard treatment groups.Duration of antimicrobial therapy was significantly reduced in favor of procalcitonin-guided therapy (HR [hazard ratio]: 1.27, 95%CI: 1.01; 1.53). Combined estimates of the length of stay in the ICU and in hospital did not differ between groups.ConclusionProcalcitonin-guided therapy is a helpful approach to guide antibiotic therapy and surgical interventions without a beneficial effect on mortality. The major benefit of PCT-guided therapy consists of a shorter duration of antibiotic treatment compared to standard care.Trials are needed to investigate the effect of PCT-guided therapy on mortality, length of ICU and in-hospital stay in severe sepsis patients.

Procalcitonin to Guide Duration of Antimicrobial Therapy in Intensive Care Units: A Systematic Review

Can the use of serum procalcitonin levels safely reduce antimicrobial use in intensive care unit (ICU) patients? We performed a systematic literature review that identified 6 published randomized controlled trials comparing PCT-guided antimicrobial therapy to usual care in ICU patients, extracting data on ICU and patient characteristics, PCT guideline content, intensity of antimicrobial exposure, ICU length of stay, infection relapse, and mortality. Procalcitonin guidance was associated with significantly reduced antimicrobial exposure (effect sizes, 19.5%-38%) in all 5 studies assessing its impact on treatment duration but did not significantly impact antimicrobial exposure in the study assessing treatment initiation only. Length of ICU stay was significantly decreased in 2 studies but was unchanged in the others. Neither infection relapse nor mortality varied significantly in any of the studies. Procalcitonin guidance of antimicrobial duration appears to decrease antimicrobial use in the ICU safely and significantly and may also decrease the length of stay in the ICU.

Effect of Procalcitonin-Guided Treatment in Patients with Infections: a Systematic Review and Meta-Analysis

The aim of this study was to review the effectiveness of procalcitonin (PCT)-guided therapy in comparison to standard therapy in patients with suspected or confirmed bacterial infections in terms of antibiotic prescription at inclusion, duration of antibiotic therapy, total antibiotic exposure days/1,000 days, length of stay in the intensive care unit (ICU), length of stay in the hospital, and mortality. MEDLINE, EMBASE, Web of Science, and the Cochrane central register of controlled trials were searched up to November 2008. Studies considered to be eligible were randomized controlled trials comparing PCT-guided therapy with standard therapy in adult patients with bacterial infections. No language restriction was applied. Data were combined in a meta-analysis using random-effect models. Seven studies with 1,458 patients were included. PCT-guided therapy was associated with a significant reduction in antibiotic prescription at inclusion (four studies; pooled odds ratio [OR] 0.506, 95% confidence interval [CI] 0.290-0.882, p = 0.016), duration of antibiotic therapy (six studies; weighted mean difference [WMD] 2.785, 95% CI 1.225-4.345, p = 0.000), total antibiotic exposure days/1,000 days (four studies; pooled relative risk [RR] 1.664, 95% CI 1.155-2.172, p = 0.000), and length of stay in the ICU (three studies; 292 patients; pooled WMD 3.49 days, 95% CI 1.28-5.70, p = 0.002). There were no significant differences in length of stay in the hospital (three studies; pooled WMD 1.003, 95% CI -0.430 to 2.437, p = 0.17) and mortality (seven studies; pooled OR 0.838, 95% CI 0.571-1.229, p = 0.365). Based on the results of this meta-analysis, it would appear that an algorithm based on serial PCT measurements would allow a more judicious use of antibiotics than currently occurs during the traditional treatment of patients with infections. PCT-guided antibiotic treatment appears to be safe and may also improve clinical outcome.