Potential Impact of Rapid Multiplex PCR on Antimicrobial Therapy Guidance for Ventilated Hospital-Acquired Pneumonia in Critically Ill Patients, A Prospective Observational Clinical and Economic Study.

Objectives: To investigate the potential impact of the syndromic multiplex FilmArray® Pneumonia plus Panel (FAPP) on the antimicrobial treatment guidance of patients with ventilated hospital-acquired pneumonia (VHAP). Methods: Respiratory fluids from 100 adult patients with VHAP, receiving invasive mechanical ventilation in three intensive care units from one French university hospital, were tested prospectively using FAPP. Conventional cultures were performed in parallel as routine practice. Clinicians were left blinded to the FAPP results. Antimicrobial therapies based on FAPP results were simulated by independent blinded experts according to a predefined algorithm and compared to 1) those prescribed in practice according to local guidelines (real-life), and 2) those that complied with the international ERS/ESICM/ESCMID/ALAT recommendations. The primary endpoint was the number of days of broad-spectrum antimicrobial therapy. Secondary endpoints were the rates of microbiological treatment failure and cost-effectiveness ratio. Results: The predicted median duration of broad-spectrum antibiotics was 0 [0-1.25] day in the FAPP-based simulation, versus 2 [0-6] days in real-life (p<0.0001) and 2 [2-3.25] days in the recommendations-based simulation (p<0.0001). Treatment failure was predicted in 3% of cases with FAPP results versus observed in 11% in real-life (p=0.08) and 6% with recommendations-based simulation (p=0.37). The incremental cost-effectiveness ratio was 1 121 € [-7021; 6794] to avoid one day of non-optimized antimicrobial therapy. Conclusions: Our results suggest that using FAPP in patients with VHAP has the potential to reduce the use of broad-spectrum antimicrobial therapy without increasing the risk of microbial treatment failure.

Eficacia y seguridad de ceftazidima-avibactam para el tratamiento de pacientes adultos con neumonía intrahospitalaria asociada a ventilación mecánica causada por bacterias gram negativas productoras de carbapenemasas y resistentes a colistina / Efficacy and safety of ceftazidime-avibactam for the treatment of adult patients with hospital-acquired pneumonia associated with mechanical ventilation caused by colistin-resistant gram-negative carbapenemase-producing bacteria

INTRODUCCIÓN: El presente dictamen expone la evaluación de la eficacia y seguridad de ceftazidima-avibactam (C-A) para el tratamiento de pacientes adultos con neumonía intrahospitalaria asociada a ventilación mecánica (NAVM) causada por bacterias gram negativas productoras de carbapenemasas y resistentes a colistina. La neumonía intrahospitalaria es la principal causa de muerte por infecciones adquiridas en el hospital. Aproximadamente, el 80 % de las neumonías intrahospitalarias corresponden a neumonías intrahospitalarias asociadas a ventilador mecánico (NAVM) con una mortalidad que puede llegar al 76 %, cuando la infección es causada por patógenos de alto riesgo. Actualmente, existen patógenos gram negativos extremadamente resistentes que producen betalactamasas capaces de hidrolizar antibióticos carbapenémicos llamados bacterias gram negativas productoras de carbapenemasas. Hasta la fecha, existen pocas alternativas para el tratamiento de NAVM causada por bacterias productoras de carbapenemasas. Como opciones de última línea, se tienen esquemas basados en colistina más carbapenémicos. En EsSalud, estos pacientes tienen a su disposición esta combinación como última línea de tratamiento; sin embargo, algunos pacientes presentan infecciones resistentes a estos antibióticos, por lo cual no disponen de una alternativa terapéutica para controlar la infección. Así, los especialistas de EsSalud sugieren el uso de ceftazidima-avibactam (C-A) para el tratamiento de la NAVM por bacterias gram negativas productoras de carbapenemasas y resistentes a colistina. La ceftazidima es una cefalosporina que inhibe la síntesis de la pared celular bacteriana, y el avibactam es un inhibidor de beta-lactamasa. Ambos son antibióticos cuya presentación en forma combinada ha sido aprobada por la Food and Drug Administration (FDA) y la European Medicines Agency (EMA) para el tratamiento de pacientes NAVM ocasionado por bacterias gram negativas. METODOLOGÍA: Se llevó a cabo una búsqueda bibliográfica exhaustiva con el objetivo de identificar la mejor evidencia sobre la eficacia y seguridad de C-A para el tratamiento de pacientes adultos con NAVM causada por bacterias gram negativas productoras de carbapenemasas y resistentes a colistina. La búsqueda se inició con la revisión de la información sobre el uso del medicamento de acuerdo con entidades reguladoras como FDA, EMA, DIGEMID y la Organización Mundial de la Salud (OMS). La búsqueda bibliográfica se realizó en las bases de datos PubMed, The Cochrane Library y LILACS. Asimismo, se realizó una búsqueda manual dentro de las páginas web pertenecientes a grupos que realizan evaluación de tecnologías sanitarias y guías de práctica clínica (GPC) incluyendo la National Institute for Health and Care Excellence (NICE), Canadian Agency for Drugs and Technologies in Health (CADTH), Scottish Medicines Consortium (SMC), Scottish Intercollegiate Guidelines Network (SIGN), Institute for Clinical and Economic Review (ICER), El Instituto de Calidad y Eficiencia en la Atención de la Salud (IQWiG, por sus siglas en alemán), la Base Regional de Informes de Evaluación de Tecnologías en Salud de las Américas (BRISA), la OMS, el Ministerio de Salud del Perú (MINSA) y el Instituto de Evaluación de Tecnologías en Salud e Investigación (IETSI). Además, se realizó una búsqueda de GPC de las principales sociedades o instituciones especializadas en infectología, tales como: Infectious Diseases Society of America (IDSA), European Respiratory Society (ERS), European Society of Intensive Care Medicine (ESICM), European Society of Clinical Microbiology and Infectious Diseases (ESCMID) y la Asociación Latinoamericana del Tórax (ALAT). Finalmente, se realizó una búsqueda en la página web de registro de ensayos clínicos (EC) www.clinicaltrials.gov, para identificar EC en curso o que no hayan sido publicados aún. RESULTADOS: Se llevó a cabo una búsqueda de evidencia científica relacionada al uso de C-A como tratamiento de pacientes adultos con NAVM causada por bacterias gram negativas productoras de carbapenemasas y resistentes a colistina. La presente sinopsis describe la evidencia disponible según el tipo de publicación, siguiendo lo indicado en los criterios de elegibilidad (GPC, ETS, RS con o sin meta análisis o metaanálisis en red y estudios primarios) que se obtuvieron de la búsqueda sistemática y la búsqueda adicional realizada en PubMed. CONCLUSIONES:  El presente dictamen preliminar tuvo por objetivo evaluar la mejor evidencia disponible en torno a la eficacia y seguridad de C-A en comparación la mejor terapia de soporte (continuar con carbapenémicos, colistina u otros), como tratamiento de pacientes adultos con NAVM causada por bacterias gram negativas productoras de carbapenemasas y resistentes a colistina. No se identificaron GPC, ETS, RS o ECA que respondan a la pregunta PICO del presente dictamen. Tras ampliar los criterios de búsqueda y selección considerando los términos relacionados a la intervención y agentes gram negativos resistentes a carbapenémicos, se identificaron 4 estudios observacionales comparativos que incluían a la población de la pregunta PICO del presente dictamen. De los cuatro estudios incluidos, dos mostraron diferencia a favor de C-A en términos de mortalidad, tres reportaron respuesta clínica a favor de C-A y uno mostró mayor erradicación microbiológica a favor de C-A. Además, dos estudios que evaluaron seguridad estimaron que C-A tendría un mejor perfil de seguridad (menor daño renal) que otros antibióticos (entre ellos carbapenémicos y colistina). Debido al diseño y las limitaciones de estos estudios observacionales, no es posible establecer una relación causa-efecto entre el uso de C-A y los desenlaces evaluados. Sin embargo, sí nos ofrecen una descripción de la actividad antibacteriana y el perfil de seguridad de C-A. La NAVM es una enfermedad con alta mortalidad y los pacientes con NAVM por bacterias gram negativas productoras de carbapenemasas y resistentes a colistina, no cuentan con una alternativa de tratamiento (vacío terapéutico) en EsSalud. La mejor terapia de soporte (continuar con carbapenémicos, colistina u otros disponibles en EsSalud), aumentaría el riesgo de desarrollar eventos adversos y resistencia bacteriana. Dicha resistencia bacteriana pone en riesgo a otros pacientes hospitalizados de adquirir infecciones resistentes, además incrementaría la estancia hospitalaria, los costos de atención y la mortalidad. Por lo expuesto, el IETSI aprueba el uso de C-A en pacientes pacientes adultos con NAVM causada por bacterias gram negativas productoras de carbapenemasas y resistentes a colistina, como producto farmacéutico no incluido en el Petitorio Farmacológico de EsSalud. La vigencia del presente dictamen es de un año, según lo establecido en el Anexo N° 1 y la continuación de dicha aprobación estará sujeta a la evaluación de los resultados obtenidos y de mayor evidencia que pueda surgir en el tiempo.

Application of physiologically based pharmacokinetic modeling to predict the pharmacokinetics of telavancin in obesity with renal impairment.

PURPOSE: U.S. Food and Drug Administration (FDA) recommended telavancin dosing is based on total body weight (TBW) but lacks adjusted regimens for obese subjects with varying renal function. Our aim was to develop a physiologically based pharmacokinetic (PBPK) model of telavancin to design optimized dosing regimens for obese patients with hospital-acquired pneumonia (HAP) and varying renal function. METHODS: The PBPK model was verified using clinical pharmacokinetic (PK) data of telavancin in healthy populations with varying renal function and obese populations with normal renal function. Then, the PBPK model was applied to predict the PK in obese HAP patients with renal impairment (RI). RESULTS: The fold error values of PK parameters (AUC, Cmax, Tmax) were all within 1.5. The telavancin AUC0-inf was predicted to increase 1.07-fold in mild RI, 1.23-fold in moderate RI, 1.41-fold in severe RI, and 1.57-fold in end-stage renal disease (ESRD), compared with that in obese HAP with normal renal function. The PBPK model combined with Monte Carlo simulations (MCS) suggested that dose adjustment based on a 750-mg-fixed dose could achieve effectiveness with reduced risk of toxicity, compared with current TBW-based dosing recommendations. CONCLUSION: The PBPK simulation proposed that using TBW-based regimen in obesity with RI should be avoided. Dose recommendations in obesity from the PBPK model are 750 mg daily for normal renal function and mild RI, 610 mg daily for moderate RI, 530 mg daily for severe RI, and 480 mg daily for ESRD.

Intrapulmonary Pharmacokinetics of Cefepime and Enmetazobactam in Healthy Volunteers: Towards New Treatments for Nosocomial Pneumonia.

Cefepime-enmetazobactam is a novel ß-lactam-ß-lactamase inhibitor combination with broad-spectrum antimicrobial activity against a range of multidrug-resistant Enterobacteriaceae This agent is being developed for a range of serious hospital infections. An understanding of the extent of partitioning of ß-lactam-ß-lactamase inhibitor combinations into the human lung is required to better understand the potential role of cefepime-enmetazobactam for the treatment of nosocomial pneumonia. A total of 20 healthy volunteers were used to study the intrapulmonary pharmacokinetics of a regimen of 2 g cefepime-1 g enmetazobactam every 8 h intravenously (2 g/1 g q8h i.v.). Each volunteer contributed multiple plasma samples and a single epithelial lining fluid (ELF) sample, obtained by bronchoalveolar lavage. Concentrations of cefepime and enmetazobactam were quantified using liquid chromatography-tandem mass spectrometry. The pharmacokinetic data were modeled using a population methodology, and Monte Carlo simulations were performed to assess the attainment of pharmacodynamic targets defined in preclinical models. The concentration-time profiles of both agents in plasma and ELF were similar. The mean ± standard deviation percentage of partitioning of total drug concentrations of cefepime and enmetazobactam between plasma and ELF was 60.59% ± 28.62% and 53.03% ± 21.05%, respectively. Using pharmacodynamic targets for cefepime of greater than the MIC and free enmetazobactam concentrations of >2 mg/liter in ELF of 20% of the dosing interval, a regimen of cefepime-enmetazobactam of 2 g/0.5 g q8h i.v. infused over 2 h resulted in a probability of target attainment of ≥90% for Enterobacteriaceae with cefepime-enmetazobactam MICs of ≤8 mg/liter. This result provides a rationale to further consider cefepime-enmetazobactam for the treatment of nosocomial pneumonia caused by multidrug-resistant Enterobacteriaceae.

Assessment of the impact of clinical recommendations on antibiotic use for CAP and HCAP: results from an implementation program in an Academic Hospital.

BACKGROUND: Local guidelines and recommendations to treat common infectious diseases are a cornerstone of most Antimicrobial Stewardship programs. The evaluation of the adherence to guidelines is an effective quality measure of the programs themselves; the proposed evaluation model aimed at examining antibiotic treatment for pneumonia. STUDY DESIGN: A retrospective pre-post intervention study was conducted in a North-Eastern Italian Academic Hospital. METHODS: 231 patients with Community-Acquired Pneumonia and 95 with Healthcare-Associated Pneumonia were divided into pre- and post-intervention groups (188 and 138, respectively). A course and a pocket summary of Pneumonia Regional Recommendations were the stewardship activities adopted. The compliance degree of prescriptions with Regional Recommendations was tested for drug(s), dosage and duration of treatment in both groups for Community-Acquired and Healthcare-Associated Pneumonia and a comparison with International guidelines was performed. RESULTS: A significant improvement in the compliance with Regional Recommendations for the variable drug emerged for Community-Acquired (38.8% vs 52.2%), but not for Healthcare-Associated Pneumonia; no significant variation in compliance was registered for dosage and duration of treatment. The significant decrease in consumption of levofloxacin showed the positive impact of the Regional Antimicrobial Stewardship programs. A high level of adherence to International Guidelines for the variable drug for Community-Acquired Pneumonia was found in both groups (75.5% and 77.2%, respectively). CONCLUSIONS: Our study highlighted that room for improvement in antibiotic prescription in Community-Acquired and Healthcare-Associated Pneumonia currently remains. New strategies for a better use of the adopted tools and definition of new antimicrobial stewardship initiatives are needed to improve compliance to Regional Recommendations.

Cost-effectiveness Comparison of Ceftazidime/Avibactam Versus Meropenem in the Empirical Treatment of Hospital-acquired Pneumonia, Including Ventilator-associated Pneumonia, in Italy.

PURPOSE: Ceftazidime/avibactam (CAZ-AVI) is a fixed-dose combination antibiotic approved in Europe and the United States for patients with hospital-acquired pneumonia, including ventilator-associated pneumonia (HAP/VAP). The economic benefits of a new drug such as CAZ-AVI are required to be assessed against those of available comparators, from the perspective of health care providers and payers, through cost-effectiveness and cost-utility analyses. The objective of this analysis was to compare the cost-effectiveness of CAZ-AVI versus meropenem in the empirical treatment of appropriate hospitalized patients with HAP/VAP caused by gram-negative pathogens, from the perspective of publicly funded health care in Italy (third-party perspective, based on the data from the REPROVE (Ceftazidime-Avibactam Versus Meropenem In Nosocomial Pneumonia, Including Ventilator-Associated Pneumonia) clinical study; ClinicalTrials.gov NCT01808092). METHODS: A patient-level, sequential simulation model of the HAP/VAP clinical course was developed using spreadsheet software. The analysis focused on direct medical costs. The time horizon of the model selected was 5 years, with an annual discount rate of 3% on costs and quality-adjusted life-years (QALYs). Clinical inputs for treatment comparisons were mainly obtained from the REPROVE clinical study data. In addition to clinical outcomes observed in the trial, the model incorporated impact of resistance pathogens, based on data from published studies and expert opinion. Certain assumptions were made for some model parameters due to a lack of data. FINDINGS: The analysis demonstrated that the intervention sequence (CAZ-AVI followed by colistin + high-dose meropenem) versus the comparator sequence (meropenem followed by colistin + high-dose meropenem) provided a better clinical cure rate (+13.52%), which led to a shorter hospital stay (-0.40 days per patient), and gains in the number of life-years (+0.195) and QALYs (+0.350) per patient. The intervention sequence had an estimated net incremental total cost of €1254 ($1401) per patient, and the estimated incremental cost-effectiveness ratio was €3581 ($4000) per QALY gained, well below the willingness-to-pay threshold of €30,000 ($33,507) per QALY in Italy. IMPLICATIONS: The model results showed that CAZ-AVI is expected to provide clinical benefits in hospitalized patients with HAP/VAP in Italy at an acceptable cost compared to meropenem.

A successful program preventing nonventilator hospital-acquired pneumonia in a large hospital system.

OBJECTIVE: To develop and evaluate a program to presvent hospital-acquired pneumonia (HAP). DESIGN: Prospective, observational, surveillance program to identify HAP before and after 7 interventions. An order set automatically triggered in programmatically identified high-risk patients. SETTING: All 21 hospitals of an integrated healthcare system with 4.4 million members. PATIENTS: All hospitalized patients. INTERVENTIONS: Interventions for high-risk patients included mobilization, upright feeding, swallowing evaluation, sedation restrictions, elevated head of bed, oral care and tube care. RESULTS: HAP rates decreased between 2012 and 2018: from 5.92 to 1.79 per 1,000 admissions (P = .0031) and from 24.57 to 6.49 per 100,000 members (P = .0014). HAP mortality decreased from 1.05 to 0.34 per 1,000 admissions and from 4.37 to 1.24 per 100,000 members. Concomitant antibiotic utilization demonstrated reductions of broad-spectrum antibiotics. Antibiotic therapy per 100,000 members was measured as follows: carbapenem days (694 to 463; P = .0020), aminoglycoside days (154 to 61; P = .0165), vancomycin days (2,087 to 1,783; P = .002), and quinolone days (2,162 to 1,287; P < .0001). Only cephalosporin use increased, driven by ceftriaxone days (264 to 460; P = .0009). Benzodiazepine use decreased between 2014 to 2016: 10.4% to 8.8% of inpatient days. Mortality for patients with HAP was 18% in 2012% and 19% in 2016 (P = .439). CONCLUSION: HAP rates, mortality, and broad-spectrum antibiotic use were all reduced significantly following these interventions, despite the absence of strong supportive literature for guidance. Most interventions augmented basic nursing care. None had risks of adverse consequences. These results support the need to examine practices to improve care despite limited literature and the need to further study these difficult areas of care.

Development and Assessment of Objective Surveillance Definitions for Nonventilator Hospital-Acquired Pneumonia.

Importance: Hospital-acquired pneumonia is the most common health care-associated infection in the United States. Most cases occur in nonventilated patients, but many hospitals track hospital-acquired pneumonia only in ventilated patients because of the complexity and subjectivity of conducting surveillance for large numbers of nonventilated patients. Objective: To propose and assess potentially objective, efficient, and reproducible surveillance definitions for nonventilator hospital-acquired pneumonia (NV-HAP) using routine clinical data stored in electronic health record systems. Design, Setting, and Participants: This cohort study was conducted in 2 tertiary referral and 2 community hospitals in Massachusetts between May 31, 2015, and July 1, 2018. All nonventilated patients aged 18 years or older who were admitted to these hospitals were included (N = 310 651). Exposures: Ten candidate definitions for NV-HAP based on clinically meaningful combinations of 6 potential surveillance criteria were proposed: worsening oxygenation, temperature higher than 38 °C (fever), abnormal white blood cell count of less than 4000/µL or more than 12 000/µL, performance of chest imaging, submission of respiratory specimen for culture, and 3 or more days of new antibiotics. Main Outcomes and Measures: Incidence rates, lengths of stay, hospital mortality rates, and odds ratios (ORs) for time to discharge and mortality compared with those of matched controls were calculated for each candidate definition. The ORs were adjusted for demographics, clinical service, comorbidities, and severity of illness. Results: The study analyzed 310 651 patients with 489 519 admissions, including 205 054 patients with 311 484 admissions of 3 or more days. Among the patients with 311 484 admissions, the mean (SD) patient age was 58.3 (19.3) years and 176 936 (56.8%) were of women. Incidence rates for candidate definitions per 100 admissions ranged from 3.4 events for worsening oxygenation alone to 0.9 event for worsening oxygenation and at least 3 days of new antibiotics to 0.6 event for worsening oxygenation, at least 3 days of new antibiotics, fever, abnormal white blood cell count, and performance of chest imaging. Crude mortality rates ranged from 16.1% (n = 2643) for patients with worsening oxygen alone to 27.7% (n = 868) for patients with worsening oxygenation, at least 3 days of antibiotics, fever or abnormal white blood cell count, and chest imaging. Patients who met NV-HAP candidate definitions remained in the hospital for twice as long as their matched controls (adjusted ORs ranged from 1.8 [95% CI, 1.7-1.8] to 2.1 [95% CI, 2.0-2.1]) and were 4 to 6 times as likely to die in the hospital (adjusted ORs ranged from 3.8 [95% CI, 3.5-4.0] to 6.5 [95% CI, 5.2-8.2]). Agreement between candidate definitions and clinical diagnoses was fair (κ = 0.33). Conclusions and Relevance: These findings suggest that objective surveillance for NV-HAP using electronically computable definitions that incorporate common clinical criteria is feasible and generates incidence, mortality, and adjusted ORs for hospital mortality similar to estimates from manual surveillance. These definitions have the potential to facilitate widespread, automated surveillance for NV-HAP and thus inform the development and evaluation of prevention programs.

A Novel Algorithm to Analyze Epidemiology and Outcomes of Carbapenem Resistance Among Patients With Hospital-Acquired and Ventilator-Associated Pneumonia: A Retrospective Cohort Study.

BACKGROUND: Carbapenem resistance is a growing concern. Applying a novel algorithm, we examined epidemiology and outcomes of carbapenem resistance among gram-negative pathogens in hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP). METHODS: In a retrospective cohort design within the Premier Research database (2009-2016), all hospitalized adult patients with a gram-negative organism in a respiratory or blood culture specimen who fit criteria for HAP/VAP based on International Classification of Diseases, Ninth Revision, Clinical Modification, codes were included in the study. RESULTS: Among 8,969 patients with HAP/VAP, 1,059 isolates (11.8%) were carbapenem-resistant (CR) organisms. Patients with CR organisms were more likely female (41.4% vs 33.2%; P < .001) and medical admissions (33.8% vs 27.4%, P < .001) than those with carbapenem-susceptible (CS) organisms. Patients with carbapenem resistance had higher comorbidity burden than those with carbapenem susceptibility (median [interquartile range] Charlson Comorbidity Index score, 3 [1-4] vs 2 [1-4]; P < .001). Pseudomonas aeruginosa was the most common gram-negative pathogen overall (24.9%) and among CS organisms (23.5%), and was second to Stenotrophomonas maltophilia (44.0%) among CR organisms (35.3%). Acinetobacter baumannii accounted for 11.8% of CR organisms and 2.5% of CS organisms (P < .001). Patients with carbapenem resistance were more likely than those with carbapenem susceptibility to receive inappropriate empiric therapy (25.8% vs 10.0%; P < .001). Carbapenem resistance did not affect adjusted mortality (22.9% CR vs 21.6% CS) or postinfection length of stay (except among survivors of VAP), but it was associated with excess costs ($8,921; 95% CI, 3,864-13,977). CONCLUSIONS: Using administrative data, our novel algorithm identified patients with pneumonia at high risk for death, consistent with HAP/VAP. Among them, carbapenem resistance occurred in 12% of all cases and was associated with substantial excess in hospital costs.

Cost-effectiveness analysis of low versus high dose colistin in the treatment of multi-drug resistant pneumonia in Saudi Arabia.

Background Gram negative pathogens are increasingly resistant to commonly used first line antibiotics and colistin is in most cases the only medicine available. There is very limited information available comparing the effectiveness and costs of low versus high dose colistin with studies showing efficacy with both doses and with variable levels of adverse effects. The absence of a definite dosing strategy makes a model to compare low dose and high dose colistin invaluable in making decisions regarding the appropriate use of colistin. Objective This study was designed to evaluate the cost effectiveness of low versus high dose colistin in the treatment of Pneumonia caused by colistin-only sensitive gram negative bacteria from the perspective of a tertiary care hospital in Saudi Arabia. Setting 300-bed tertiary care hospital in Saudi Arabia. Method A retrospective review was conducted to compare the costs and outcomes of treatment of pneumonia with low versus high dose colistin. The model followed an average patient from initiation of treatment until clinical cure or failure. Main outcome measures The main outcomes were cure, nephrotoxicity, total direct costs per episode, cost per additional cure and cost per nephrotoxicity avoided. Results There was no significant difference between high and low dose colistin with regards to clinical cure (30% vs. 21%; p = 0.292). Significantly more patients experienced nephrotoxicity with high versus low dose colistin (30% vs. 8%; p = 0.004). With low dose colistin the incremental costs per nephrotoxicity avoided was SAR-3056.28. One-way sensitivity analyses did not change the overall results. Conclusion Low dose was not inferior to high dose colistin in terms of clinical cure and had a lower incidence of nephrotoxicity resulting in significant cost avoidance.

Healthcare-associated pneumonia in acute care hospitals in European Union/European Economic Area countries: an analysis of data from a point prevalence survey, 2011 to 2012.

An aim of the ECDC point prevalence survey (PPS) in European Union/European Economic Area acute care hospitals was to acquire standardised healthcare-associated infections (HAI) data. We analysed one of the most common HAIs in the ECDC PPS, healthcare-associated pneumonia (HAP). Standardised HAI case definitions were provided and countries were advised to recruit nationally representative subsets of hospitals. We calculated 95% confidence intervals (CIs) around prevalence estimates and adjusted for clustering at hospital level. Of 231,459 patients in the survey, 2,902 (1.3%; 95% CI: 1.2-1.3) fulfilled the case definition for a HAP. HAPs were most frequent in intensive care units (8.1%; 95% CI: 7.4-8.9) and among patients intubated on the day of the survey (15%; 95% CI: 14-17; n = 737 with HAP). The most frequently reported microorganism was Pseudomonas aeruginosa (17% of 1,403 isolates), followed by Staphylococcus aureus (12%) and Klebsiella spp. (12%). Antimicrobial resistance was common among isolated microorganisms. The most frequently prescribed antimicrobial group was penicillins, including combinations with beta-lactamase inhibitors. HAPs occur regularly among intubated and non-intubated patients, with marked differences between medical specialities. HAPs remain a priority for preventive interventions, including surveillance. Our data provide a reference for future prevalence of HAPs at various settings.

Assessment of the Perceived Acceptability of an Early Enrollment Strategy Using Advance Consent in Health Care-Associated Pneumonia.

Importance: Better treatment options are needed in life-threatening infections, including health care-associated pneumonia. Enrolling patients in antibacterial clinical trials before diagnosis may circumvent existing time-to-enrollment constraints. However, the acceptability of an early enrollment strategy using advance consent is unknown. Objective: To assess the perceived acceptability of an early enrollment strategy for enrolling patients in an antibacterial clinical trial before a pneumonia diagnosis. Design, Setting, and Participants: This qualitative, descriptive study used semistructured telephone interviews. Framed within a planned noninferiority pneumonia antibiotic trial, an early enrollment strategy was described and perceptions were assessed. Using this strategy, patients give consent to enroll before developing pneumonia, to be monitored by study staff, and to be randomly assigned a study antibiotic if pneumonia develops. All interviews were audiorecorded, transcribed verbatim, and analyzed using applied thematic analysis. Fifty-two key stakeholders from across the United States, including 18 patients at risk of pneumonia, 12 caregivers, 10 representatives of institutional review boards, 7 investigators, and 5 study coordinators, were interviewed from June 20 to August 19, 2016. Main Outcomes and Measures: Perceived acceptability of the early enrollment strategy. Results: Among the 52 stakeholders interviewed (ages 29-75 years; 14 women), patients and caregivers expressed no concerns about patients being approached about participation before developing pneumonia; however, some patients may experience anxiety on learning about their risk for pneumonia. No concerns with study staff accessing patients' medical records were expressed. The clarity of consent information was important for understanding the study rather than having the condition under investigation. Among patients, caregivers, and institutional review board representatives, preferences varied regarding opt-out and precedent autonomy procedures. Nearly all patients would be willing to join a trial using the early enrollment strategy and caregivers would be willing to provide proxy consent. Institutional review board representatives were supportive of the strategy and made recommendations for the study protocol, primarily around informed consent. Investigators and study coordinators believed the strategy would not be burdensome and offered suggestions to ensure its feasibility. Conclusion and Relevance: Results of the study suggest that the early enrollment strategy is acceptable. Future research should evaluate whether the strategy improves enrollment rates in registrational pneumonia trials and in trials of other acute infection syndromes with narrow enrollment windows and/or patients with transient decisional incapacity.