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Treatment of severe hospital-acquired and ventilator-associated pneumonia: a systematic review of inclusion and judgment criteria used in randomized controlled trials.

ABSTRACT: BACKGROUND:Hospital-acquired and ventilator-associated pneumonia (HAP/VAP) are often selected for randomized clinical trials (RCTs) aiming at new drug approval. Guidelines for the design of such RCTs have been repeatedly updated by regulatory agencies. We hypothesized that large variability in the enrolled populations, the endpoints assessed and the HAP/VAP definition criteria may impact the results of these studies, and addressed this through a systematic review of HAP/VAP RCTs. METHODS:A search (Pubmed-Embase-ICAAC-ECCMID) of all RCTs published between 1994 and 2016 comparing antimicrobial treatment for HAP/VAP in the intensive care unit was conducted. The populations enrolled, inclusion/exclusion criteria, statistical design and endpoints assessed were recorded. All unpublished RCTs recorded on the ClinicalTrials.gov registry were also screened. RESULTS:From the 93 abstracts reviewed, 39 potentially relevant studies were inspected, leading to 27 studies being included. As expected, illness severity or the proportion with VAP (27-100%) differed greatly among the enrolled populations. The HAP/VAP definition used various clinical and biological criteria, and only 55% of studies required a microbiological sample. The mandatory duration of prior hospital stay was variable; the mechanical ventilation duration was an inclusion criterion in only 41% of VAP studies. Nine studies had non-inferiority design, but nine studies (33%) did not have a pre-specified statistical hypothesis. Clinical cure was the primary endpoint in 24 studies, but was recorded in several populations or as the co-primary endpoint in 13 studies. The definition of clinical cure and the timing of its assessment greatly differed. This variability slightly improved over time but remained significant in the 13 registered but currently unpublished RCTs that we screened. CONCLUSION:Our study provides a description of populations and endpoints of RCTs evaluating antimicrobials for treatment of HAP/VAP in the ICU. There was significant heterogeneity in enrollment criteria, endpoints and statistical design, which may influence the ability of studies to demonstrate differences between studied drugs.

SUBMITTER: Weiss E

PROVIDER: S-EPMC5488424 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

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Treatment of severe hospital-acquired and ventilator-associated pneumonia: a systematic review of inclusion and judgment criteria used in randomized controlled trials.

Weiss Emmanuel E Essaied Wafa W Adrie Christophe C Zahar Jean-Ralph JR Timsit Jean-François JF

Critical care (London, England) 20170627 1

<h4>Background</h4>Hospital-acquired and ventilator-associated pneumonia (HAP/VAP) are often selected for randomized clinical trials (RCTs) aiming at new drug approval. Guidelines for the design of such RCTs have been repeatedly updated by regulatory agencies. We hypothesized that large variability in the enrolled populations, the endpoints assessed and the HAP/VAP definition criteria may impact the results of these studies, and addressed this through a systematic review of HAP/VAP RCTs.<h4>Meth ...[more]

PMID: 28655326

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Project description:ImportanceNon-ventilator-associated hospital-acquired pneumonia (NV-HAP) is a common and deadly hospital-acquired infection. However, inconsistent surveillance methods and unclear estimates of attributable mortality challenge prevention.ObjectiveTo estimate the incidence, variability, outcomes, and population attributable mortality of NV-HAP.Design, setting, and participantsThis cohort study retrospectively applied clinical surveillance criteria for NV-HAP to electronic health record data from 284 US hospitals. Adult patients admitted to the Veterans Health Administration hospital from 2015 to 2020 and HCA Healthcare hospitals from 2018 to 2020 were included. The medical records of 250 patients who met the surveillance criteria were reviewed for accuracy.ExposuresNV-HAP, defined as sustained deterioration in oxygenation for 2 or more days in a patient who was not ventilated concurrent with abnormal temperature or white blood cell count, performance of chest imaging, and 3 or more days of new antibiotics.Main outcomes and measuresNV-HAP incidence, length-of-stay, and crude inpatient mortality. Attributable inpatient mortality by 60 days follow-up was estimated using inverse probability weighting, accounting for both baseline and time-varying confounding.ResultsAmong 6 022 185 hospitalizations (median [IQR] age, 66 [54-75] years; 1 829 475 [26.1%] female), there were 32 797 NV-HAP events (0.55 per 100 admissions [95% CI, 0.54-0.55] per 100 admissions and 0.96 per 1000 patient-days [95% CI, 0.95-0.97] per 1000 patient-days). Patients with NV-HAP had multiple comorbidities (median [IQR], 6 [4-7]), including congestive heart failure (9680 [29.5%]), neurologic conditions (8255 [25.2%]), chronic lung disease (6439 [19.6%]), and cancer (5,467 [16.7%]); 24 568 cases (74.9%) occurred outside intensive care units. Crude inpatient mortality was 22.4% (7361 of 32 797) for NV-HAP vs 1.9% (115 530 of 6 022 185) for all hospitalizations; 12 449 (8.0%) were discharged to hospice. Median [IQR] length-of-stay was 16 (11-26) days vs 4 (3-6) days. On medical record review, pneumonia was confirmed by reviewers or bedside clinicians in 202 of 250 patients (81%). It was estimated that NV-HAP accounted for 7.3% (95% CI, 7.1%-7.5%) of all hospital deaths (total hospital population inpatient death risk of 1.87% with NV-HAP events included vs 1.73% with NV-HAP events excluded; risk ratio, 0.927; 95% CI, 0.925-0.929).Conclusions and relevanceIn this cohort study, NV-HAP, which was defined using electronic surveillance criteria, was present in approximately 1 in 200 hospitalizations, of whom 1 in 5 died in the hospital. NV-HAP may account for up to 7% of all hospital deaths. These findings underscore the need to systematically monitor NV-HAP, define best practices for prevention, and track their impact.

Project description:BackgroundHospital-acquired pneumonia (HAP) is the most common health care-associated infection contributing to death. Studies have indicated that there may be differences in the causative pathogens and outcomes of ventilator-associated pneumonia (VAP) and non-ventilator-associated pneumonia (NV-HAP). However, with limited NV-HAP-specific data available, treatment is generally based on data from studies of VAP. The Phase 3 Assessment of Telavancin for Treatment of Hospital-Acquired Pneumonia (ATTAIN) studies were two double-blind randomized controlled trials that demonstrated the non-inferiority of telavancin to vancomycin for treatment of Gram-positive HAP. We conducted a post hoc subgroup analysis of patients enrolled in the ATTAIN studies who had NV-HAP.MethodsData from the two ATTAIN studies were pooled, and patients with NV-HAP were analyzed. The all-treated (AT) population consisted of all randomized patients who received ≥1 dose of study medication, and the clinically evaluable (CE) population consisted of AT patients who were protocol-adherent or who died on or after study day 3, where death was attributable to the HAP episode under study. The primary endpoint was clinical response (cure, failure, or indeterminate) at the follow-up/test of cure visit, conducted 7-14 days after the end of therapy.ResultsA total of 1,076 patients (71.6% of overall ATTAIN AT population) had NV-HAP (533 and 543 patients in the telavancin and vancomycin treatment groups, respectively). Clinical cure rates in the CE population were similar for patients with NV-HAP treated with telavancin and vancomycin (83.1% [201/242] and 84.1% [233/277], respectively). In patients with methicillin-resistant Staphylococcus aureus isolated at baseline, cure rates in the CE population were 74.8% (77/103) for telavancin and 79.3% (96/121) for vancomycin. The incidence of adverse events, serious adverse events, and deaths in patients with NV-HAP was similar whether patients received telavancin or vancomycin.ConclusionThis post hoc subgroup analysis of the ATTAIN studies demonstrated similar cure rates for telavancin and vancomycin for treatment of NV-HAP.

Project description:IntroductionThe efficacy and safety of telavancin versus vancomycin in microbiologically evaluable patients with hospital-acquired or ventilator-associated pneumonia (HAP/VAP) caused by Staphylococcus aureus with vancomycin minimum inhibitory concentration (MIC) ≥ 1.0 µg/mL was analyzed using data derived from previously reported Assessment of Telavancin for Treatment of Hospital-Acquired Pneumonia (ATTAIN) trials.MethodsThis post hoc subgroup analysis of two randomized, double-blind, comparator-controlled, parallel-group phase 3 trials conducted at 274 sites in 38 countries included 194 microbiologically evaluable patients with HAP/VAP caused by monomicrobial S. aureus with vancomycin MIC ≥ 1.0 µg/mL. Patients received intravenous telavancin (10 mg/kg every 24 h) or intravenous vancomycin (1 g every 12 h with site-specific modifications) for 7-21 days. Efficacy was assessed by clinical cure, defined as improvement or non-progression of radiographic findings at end of treatment and resolution of pneumonia signs and symptoms at follow-up/test-of-cure visits, and survival 28 days post-randomization. Safety was assessed from categorical shifts in creatinine clearance during therapy and adverse events (AEs).ResultsClinical cure rates were numerically greater following telavancin versus vancomycin treatment overall (85.4% vs. 74.3%; treatment difference [95% confidence interval (CI)], 11.1% [- 0.002%, 22.2%]) and in patients aged ≥ 65 years (81.6% vs. 66.2%; treatment difference [95% CI], 15.5% [- 0.9%, 30.2%]) patients with VAP (92.3% vs. 47.6%; treatment difference [95% CI], 44.7% [18.1%, 64.9%]), and patients with baseline Acute Physiology And Chronic Health Evaluation II score ≥ 20 (71.4% vs. 55.6%; treatment difference [95% CI], 15.9% [- 11.7%, 40.5%]). Renal function declined in 7 (7.9%) patients receiving telavancin and 6 (5.7%) patients receiving vancomycin. Survival proportion was numerically higher (85.2% vs. 80.2%; treatment difference [95% CI], 5.0% [- 5.8%, 15.8%]) and AEs were comparable in patients treated with telavancin versus vancomycin.ConclusionTelavancin is an alternative to vancomycin for HAP/VAP caused by S. aureus with vancomycin MIC ≥ 1 µg/mL.FundingTheravance Biopharma R&D, Inc., South San Francisco, CA, USA.

Project description:Ertapenem provides activity against many pathogens commonly associated with hospital-acquired and ventilator-associated bacterial pneumoniae (HABP and VABP, respectively), including methicillin-susceptible Staphylococcus aureus and numerous Gram-negative pathogens with one major gap in coverage, Pseudomonas aeruginosa Pharmacokinetic-pharmacodynamic (PK-PD) target attainment analyses were conducted to evaluate ertapenem against the most prevalent Enterobacteriaceae causing HABP/VABP. The objective of these analyses was to provide dose selection support for and demonstrate the appropriateness of ertapenem to empirically treat patients with HABP/VABP when administered with murepavadin, a novel targeted antimicrobial exhibiting a highly specific spectrum of activity against P. aeruginosa A previously developed population pharmacokinetic model, a total-drug epithelial lining fluid (ELF) to free-drug serum penetration ratio, contemporary in vitro surveillance data for ertapenem against Enterobacteriaceae, and percentage of the dosing interval for which drug concentrations exceed the MIC value (%T>MIC) targets associated with efficacy were used to conduct Monte Carlo simulations for five ertapenem regimens administered over short or prolonged durations of infusion. Overall total-drug ELF percent probabilities of PK-PD target attainment based on a %T>MIC target of 35% among simulated patients with HABP/VABP arising from Enterobacteriaceae based on pathogen prevalence data for nosocomial pneumonia ranged from 89.1 to 92.7% for all five ertapenem regimens evaluated. Total-drug ELF percent probabilities of PK-PD target attainment ranged from 99.8 to 100%, 97.9 to 100%, 10.6 to 74.1%, and 0 to 1.50% at MIC values of 0.06, 0.12, 1, and 4 μg/ml, respectively (MIC90 values for Escherichia coli, Serratia marcescens, Enterobacter species, and Klebsiella pneumoniae, respectively). Results of these analyses provide support for the evaluation of ertapenem in combination with murepavadin for the treatment of patients with HABP/VABP.

Project description:BackgroundEarly appropriate antibiotic therapy reduces morbidity and mortality of severe pneumonia. However, the emergence of bacterial resistance requires the earliest use of antibiotics with the narrowest possible spectrum. The Unyvero Hospitalized Pneumonia (HPN, Curetis) test is a multiplex PCR (M-PCR) system detecting 21 bacteria and 19 resistance genes on respiratory samples within 5 h. We assessed the performance and the potential impact of the M-PCR on the antibiotic therapy of ICU patients.MethodsIn this prospective study, we performed a M-PCR on bronchoalveolar lavage (BAL) or plugged telescoping catheter (PTC) samples of patients with ventilated HAP or VAP with Gram-negative bacilli or clustered Gram-positive cocci. This study was conducted in 3 ICUs in a French academic hospital: the medical and infectious diseases ICU, the surgical ICU, and the cardio-surgical ICU. A multidisciplinary expert panel simulated the antibiotic changes they would have made if the M-PCR results had been available.ResultsWe analyzed 95 clinical samples of ventilated HAP or VAP (72 BAL and 23 PTC) from 85 patients (62 males, median age 64 years). The median turnaround time of the M-PCR was 4.6 h (IQR 4.4-5). A total of 90/112 bacteria were detected by the M-PCR system with a global sensitivity of 80% (95% CI, 73-88%) and specificity of 99% (95% CI 99-100). The sensitivity was better for Gram-negative bacteria (90%) than for Gram-positive cocci (62%) (p = 0.005). Moreover, 5/8 extended-spectrum beta-lactamases (CTX-M gene) and 4/4 carbapenemases genes (3 NDM, one oxa-48) were detected. The M-PCR could have led to the earlier initiation of an effective antibiotic in 20/95 patients (21%) and to early de-escalation in 37 patients (39%) but could also have led to one (1%) inadequate antimicrobial therapy. Among 17 empiric antibiotic treatments with carbapenems, 10 could have been de-escalated in the following hours according to the M-PCR results. The M-PCR also led to 2 unexpected diagnosis of severe legionellosis confirmed by culture methods.ConclusionsOur results suggest that the use of a M-PCR system for respiratory samples of patients with VAP and ventilated HAP could improve empirical antimicrobial therapy and reduce the use of broad-spectrum antibiotics.

Project description:BACKGROUND: Viral pathogens have not generally been regarded as important causes of severe hospital-acquired pneumonia (HAP), except in patients with hematologic malignancy or transplant recipients. We investigated the role and distribution of viruses in adult with severe HAP who required intensive care. METHODS: From March 2010 to February 2012, adult patients with severe HAP required admission to the intensive care unit (ICU), 28-bed medical ICU in a tertiary care hospital, were prospectively enrolled. Respiratory viruses were detected using multiplex reverse-transcription polymerase chain reaction and/or shell vial culture. RESULTS: A total of 262 patients were enrolled and 107 patients (40.8%) underwent bronchoscopic BAL for etiologic diagnosis. One hundred and fifty-six patients (59.5%) had bacterial infections and 59 patients (22.5%) had viral infections. Viruses were detected in BAL fluid specimens of 37 patients (62.7%, 37/59). The most commonly identified viruses were respiratory syncytial virus and parainfluenza virus (both 27.1%, 16/59), followed by rhinovirus (25.4%, 15/59), and influenza virus (16.9%, 10/59). Twenty-one patients (8.0%, 21/262) had bacterial-viral coinfections and Staphylococcus aureus was the most commonly coexisting bacteria (n = 10). Viral infection in non-immunocompromised patients was not uncommon (11.1%, 16/143), although it was not as frequent as that in immunocompromised patients (36.4%, 43/119). Non-immunocompromised patients were significantly older than immunocompromised patients and had significantly higher rates of underlying chronic obstructive pulmonary disease, tuberculous destroyed lung and chronic kidney disease. The 28 day mortalities of patients with bacterial infections, viral infections and bacterial-viral coinfections were not significantly different (29.5%, 35.6% and 19.0%, respectively; p = 0.321). CONCLUSIONS: Viral pathogens are not uncommon in adult patients with severe HAP who required ICU admission. Since viral pathogens may cause severe HAP and could be a potential source of viral transmission, further investigation is required to delineate the role of viral pathogens in severe HAP.

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Treatment of severe hospital-acquired and ventilator-associated pneumonia: a systematic review of inclusion and judgment criteria used in randomized controlled trials.

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Treatment of severe hospital-acquired and ventilator-associated pneumonia: a systematic review of inclusion and judgment criteria used in randomized controlled trials.

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