LSU Journal Club Effect of Procalcitonin-Based Guidelines vs Standard Guidelines on Antibiotic Use in Lower Respiratory Tract Infections: the ProHOSP Randomized Controlled Trial P. Schuetz, M. Christ- Crain, R. Thomann, C. Falconnier, M. Wolbers, I. Widmer, S. Neidert, T. Fricker, C. Blum, U. Schild, K. Regez, R. Schoenenberger, C. Hensen, T. Bregenzer, C. Hoess, M. Krause, H. Bucher, W. Zimmerli, B. Mueller Allison Leonard, PGY-1 September 18, 2014

Background Why use procalcitonin as a marker? Unreliable “gold standard” for diagnosis and assessment of severity of bacterial infections, distinguishing symptoms of viral from bacterial Other markers include CRP, WBC count, Blood Cx which all have drawbacks Procalcitonin- precursor peptide which increases several thousand fold secondary to microbial infection, inflammation. Level and duration of elevation correlates with severity of condition and mortality Levels increase via transcriptional upregulation of CT- mRNA which in sepsis bypasses normal enzymatic processing Pros of Using PCT as a marker: – Levels unaffected by steroid use, not a product of WBCs, levels increase earlier in infection, can differentiate between bacterial and viral infections [exception malaria] – Shows promise in studies involving PNA, acute endocarditis, UTIs, ?Catheter related infections, febrile neutropenia Cons of using PCT as a marker: – FP reported in trauma, systemic fungal infections, ARDS, patients with cancers [medullary thyroid, small cell in lung, carcinoid, paraneoplastic syndromes] – FN reported in early infections, localized infections, subacute endocarditis – More expensive than CRP, CBC

Research question Is an algorithm using procalcitonin levels to guide antibiotic therapy in LRTI “noninferior” in comparison to standard guidelines for LRTI? Does the procalcitonin algorithm reduce antibiotic use or duration of hospitalization in patients admitted for LRTI? Study panel initially set a number of 7.5% difference in failure rate to be considered “non inferior” Primary outcome measure: “Noninferior” – Adverse outcomes at thirty days following admission: death from any cause, ICU admission for any reason, disease specific complications- lung abscess, empyema, ARDS, reoccurrence of LRTI needing antibiotics Secondary outcome measures: – time of antibiotic treatment, duration of antibiotic therapy, side effects of antibiotics, length of hospitalization

Study Subjects What they were looking for in ER patients to potentially include in the study Primary diagnosis of Lower RTI – presence of one respiratory symptom [cough, sputum, dyspnea, tachypnea, pleuritic pain] + at least 1 finding during auscultation [rales, crepitus] OR 1 sign of infection [Temp over 38 C, shivering, WBC over 10 or under 4] Classification of LRTI: – CAP [new infiltrates on CXR] – acute exacerbation of COPD [Post Bronchodilator spirometry criteria according to GOLD guidelines], – Acute bronchitis [LRTI with absence of underlying lung dx or infiltrates on CXR 18 years or older, symptoms less than 28 days Who they excluded Cannot speak German Cannot give written informed consent Active IV drug users Severe immunosuppression other than steroid use Life threatening comorbidities Immediate need for ICU care Hospital acquired pneumonia patients Patients with chronic infection requiring long term antibiotics

Study Design What type of study is this? Randomized Controlled Trial Interventional type Randomized allocation Endpoint: Safety/efficacy Parallel assignment Single Blinded Assessed for eligibility– then excluded ineligible– then randomized into procalcitonin group or guidelines only group Guidelines only group- followed ATS guidelines for CAP and European guidelines for adult lower RTI Patient safety concerns allowed for preset criteria for physician overruling of PCT algorithm – Severe CAP based on PSI or severe COPD based on GOLD score with Procalcitonin levels indicating no treatment – Immediate need for ICU admission, respiratory/hemodynamic instability, positive urine antigen for Legionella, or after consulting with the study center

Study Protocol for Procalcitonin Group Antibiotic use discouraged in levels ( 0.5 or > 0.25 ug/L) Reevaluation with repeat PCT levels after 6 to 24 hours in those who had antibiotics withheld (with Procalcitonin < 0.1 or < 0.25 ug/L) who have worsening or non-improvement of vital signs Those given antibiotics based on algorithm were reassessed at day 3, 5 and 7 with repeat procalcitonin levels and antibiotics stopped based on the same cutoff values Those who initially had high procalcitonin levels >10 ug/L at admit had antibiotics stopped if levels decreased by 80% In those given antibiotics at discharge the recommended duration of therapy was based on the last procalcitonin level in the hospital : 0.5 ug/L, 5 days > 0.25 ug/L, 3 days < 0.25 ug/L, none Antibiotic choices left up to MD

Adherence In procalcitonin group- algorithm used correctly to initiate or hold antibiotics in 90% of those enrolled in trial Algorithm overruled or stopped based on physician’s judgment in the other 10% I n control group- guidelines were overruled in 20% based on physician judgment

Study Results

Primary End Point [Adverse outcomes] Risk difference in overall outcomes was 3.5% [less than goal of “noninferiority”] with less adverse outcomes in PCT group Overall deaths lower but not significantly different in PCT group

Secondary End Point [Antibiotic exposure] Mean duration of antibiotic exposure was decreased overall as a whole and in all subgroups of procalcitonin patients

Conclusions Procalcitonin algorithm WAS noninferior to algorithm based on guidelines for LRTI and at the same time was effective at reducing antibiotic exposure and associated adverse events Physicians can use procalcitonin values to guide therapy for LRTI without risking more adverse events than if they used standard guidelines PCT values are especially helpful when the etiology and severity of infection are unclear Algorithm has substantial impact on clinical management of patients and also impacts public health by reducing antibiotic exposure/resistance/selection of resistant infections/risks of prolonged antibiotic therapy Other conclusions to note: Patients with proven bacteremia had higher procalcitonin levels and therefore longer duration of treatment Procalcitonin had higher peak levels and took longer to normalize when infection was more severe/systemic No significant differences in hospital stay between PCT and standard guidelines groups

Discussion Strengths Multiple hospital study Large group of patients with ranging comorbidities, infection severity Even distribution of patient characteristics [age, sex, prior AB use, comborbidities, vitals on admit, PSI severity, initial PCT value] Ease of algorithm instructions with computer based guidelines based on lab results Blinded follow up Limitations “Hawthorne effect” “Spillover effect” Large cohort of excluded patients Physician discretion to “pull patients” out of study