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• W4366751004 abstract "Ventilator-associated pneumonia (VAP) is a significant cause of morbidity and mortality in critically ill patients. The emergence of drug-resistant gram-negative bacteria (GNB) as causative organisms has limited the available treatment options. Although there is guidance on treatment duration for VAP [[1]Kalil A.C. Metersky M.L. Klompas M. Muscedere J. Sweeney D.A. Palmer L.B. et al.Management of adults with hospital-acquired and ventilator-associated pneumonia: 2016 clinical practice guidelines by the Infectious Diseases Society of America and the American Thoracic Society.Clin Infect Dis. 2016; 63: e61-e111https://doi.org/10.1093/cid/ciw353Crossref PubMed Scopus (1934) Google Scholar,[2]Torres A. Niederman M.S. Chastre J. Ewig S. Fernandez-Vandellos P. Hanberger H. et al.International ERS/ESICM/ESCMID/ALAT guidelines for the management of hospital-acquired pneumonia and ventilator-associated pneumonia: guidelines for the management of hospital-acquired pneumonia (HAP)/ventilator-associated pneumonia (VAP) of the European Respiratory Society (ERS), European Society of Intensive Care Medicine (ESICM), European Society of Clinical Microbiology and Infectious Diseases (ESCMID) and Asociación Latinoamericana del Tórax (ALAT).Eur Respir J. 2017; 501700582https://doi.org/10.1183/13993003.00582-2017Crossref Scopus (645) Google Scholar], there continues to exist a debate about the treatment duration of VAP because of non-fermenter GNB and an uncertainty about the treatment duration of VAP because of highly resistant GNB. This debate stems from the fact that previous studies have shown a high recurrence rate of VAP caused by non-fermenting (NF) GNB, including Pseudomonas aeruginosa, if treated for 7 days. Despite the limitations and controversy of recurrence definitions used in previous trials, this concern has persisted [[3]Albin O.R. Kaye K.S. McCreary E.K. Pogue J.M. Less is more? Antibiotic treatment duration in Pseudomonas aeruginosa ventilator-associated pneumonia.Clin Infect Dis. 2023; 76: 745-749https://doi.org/10.1093/cid/ciac784Crossref PubMed Scopus (6) Google Scholar,[4]Metersky M.L. Klompas M. Kalil A.C. Less is more: a 7-day course of antibiotics is the evidence-based treatment for Pseudomonas aeruginosa ventilator-associated Pneumonia.Clin Infect Dis. 2023; 76: 750-752https://doi.org/10.1093/cid/ciac809Crossref PubMed Scopus (4) Google Scholar]. In the most recent up-to-date systematic review [[5]Daghmouri M.A. Dudoignon E. Chaouch M.A. Baekgaard J. Bougle A. Leone M. et al.Comparison of a short versus long-course antibiotic therapy for ventilator-associated pneumonia: a systematic review and meta-analysis of randomized controlled trials.EClinicalMedicine. 2023; 58101880https://doi.org/10.1016/j.eclinm.2023.101880Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar] that included five randomized controlled trials (RCTs) involving a total of 1069 patients, there was no statistically significant difference between short- and long-course antibiotic therapy for recurrence and relapses of VAP including those because of (NF)-GNB, 28-day mortality, mechanical ventilation duration, number of extra-pulmonary infections and length of intensive care unit stay. Nevertheless, pooled OR for different outcomes were >1 and their CIs barely crossed one (in favour of long-course therapy). For example, the pooled 28-day mortality OR = 1.24, 95% CI [0.92, 1.67], p = 0.16; thus, raising the concern that if additional studies were included, a worse outcome may have been seen with short-course therapy. Several guidelines are available for the management of VAP [[1]Kalil A.C. Metersky M.L. Klompas M. Muscedere J. Sweeney D.A. Palmer L.B. et al.Management of adults with hospital-acquired and ventilator-associated pneumonia: 2016 clinical practice guidelines by the Infectious Diseases Society of America and the American Thoracic Society.Clin Infect Dis. 2016; 63: e61-e111https://doi.org/10.1093/cid/ciw353Crossref PubMed Scopus (1934) Google Scholar,[2]Torres A. Niederman M.S. Chastre J. Ewig S. Fernandez-Vandellos P. Hanberger H. et al.International ERS/ESICM/ESCMID/ALAT guidelines for the management of hospital-acquired pneumonia and ventilator-associated pneumonia: guidelines for the management of hospital-acquired pneumonia (HAP)/ventilator-associated pneumonia (VAP) of the European Respiratory Society (ERS), European Society of Intensive Care Medicine (ESICM), European Society of Clinical Microbiology and Infectious Diseases (ESCMID) and Asociación Latinoamericana del Tórax (ALAT).Eur Respir J. 2017; 501700582https://doi.org/10.1183/13993003.00582-2017Crossref Scopus (645) Google Scholar]. The Infectious Diseases Society of America recommends a 7-day course of antibiotic therapy for VAP, irrespective of the causative organisms (strong recommendation, moderate-quality evidence) [[1]Kalil A.C. Metersky M.L. Klompas M. Muscedere J. Sweeney D.A. Palmer L.B. et al.Management of adults with hospital-acquired and ventilator-associated pneumonia: 2016 clinical practice guidelines by the Infectious Diseases Society of America and the American Thoracic Society.Clin Infect Dis. 2016; 63: e61-e111https://doi.org/10.1093/cid/ciw353Crossref PubMed Scopus (1934) Google Scholar]. On the other hand, the European and Latin American guidelines recommend 7–8-day course of antibiotic therapy in patients with VAP (weak recommendation, moderate quality of evidence) [[2]Torres A. Niederman M.S. Chastre J. Ewig S. Fernandez-Vandellos P. Hanberger H. et al.International ERS/ESICM/ESCMID/ALAT guidelines for the management of hospital-acquired pneumonia and ventilator-associated pneumonia: guidelines for the management of hospital-acquired pneumonia (HAP)/ventilator-associated pneumonia (VAP) of the European Respiratory Society (ERS), European Society of Intensive Care Medicine (ESICM), European Society of Clinical Microbiology and Infectious Diseases (ESCMID) and Asociación Latinoamericana del Tórax (ALAT).Eur Respir J. 2017; 501700582https://doi.org/10.1183/13993003.00582-2017Crossref Scopus (645) Google Scholar]. Both guidelines suggest that certain patients should be excluded from this recommendation and treatment durations should be individualized [[1]Kalil A.C. Metersky M.L. Klompas M. Muscedere J. Sweeney D.A. Palmer L.B. et al.Management of adults with hospital-acquired and ventilator-associated pneumonia: 2016 clinical practice guidelines by the Infectious Diseases Society of America and the American Thoracic Society.Clin Infect Dis. 2016; 63: e61-e111https://doi.org/10.1093/cid/ciw353Crossref PubMed Scopus (1934) Google Scholar,[2]Torres A. Niederman M.S. Chastre J. Ewig S. Fernandez-Vandellos P. Hanberger H. et al.International ERS/ESICM/ESCMID/ALAT guidelines for the management of hospital-acquired pneumonia and ventilator-associated pneumonia: guidelines for the management of hospital-acquired pneumonia (HAP)/ventilator-associated pneumonia (VAP) of the European Respiratory Society (ERS), European Society of Intensive Care Medicine (ESICM), European Society of Clinical Microbiology and Infectious Diseases (ESCMID) and Asociación Latinoamericana del Tórax (ALAT).Eur Respir J. 2017; 501700582https://doi.org/10.1183/13993003.00582-2017Crossref Scopus (645) Google Scholar]. Patients in whom short duration of therapy may not be possible include those who received discordant empirical antibiotic therapy, the severely immunocompromised patients, and VAP because of multidrug-resistant (MDR) and extensively drug-resistant (XDR) GNB. MDR and XDR are defined as acquired non-susceptibility to at least one agent in three or more antimicrobial categories, or non-susceptibility to at least one agent in all but two or fewer antimicrobial categories (i.e. bacterial isolates remain susceptible to only one or two categories), respectively. The desirable goals of a 7-day antibiotic regimen are to decrease antibiotic exposure, the emergence of antibiotic resistance, costs, and side effects without negatively affecting patients' outcomes or increasing the rate of recurrent infection. Nevertheless, clinicians tend to treat resistant organisms for a longer duration because of the perception that these organisms are more virulent and difficult to cure or the limited availability of new antibiotics in many hospitals. In fact, there exists a complex interplay between acquiring drug resistance and (an increase or decrease) in virulence among GNB, which depends on the mechanisms of resistance [[6]Cepas V. Soto S.M. Relationship between virulence and resistance among gram-negative bacteria.Antibiotics (Basel). 2020; 9: 719https://doi.org/10.3390/antibiotics9100719Crossref PubMed Scopus (41) Google Scholar]. Treating nosocomial pneumonia because of resistant organisms for a longer duration was reflected in important clinical trials testing novel antibiotics. For example, the ASPECT-NP trial [[7]Kollef M.H. Nováček M. Kivistik Ü. Réa-Neto Á Shime N. Martin-Loeches I. et al.Ceftolozane-tazobactam versus meropenem for treatment of nosocomial pneumonia (ASPECT-NP): a randomised, controlled, double-blind, phase 3, non-inferiority trial.Lancet Infect Dis. 2019; 19: 1299-1311https://doi.org/10.1016/S1473-3099(19)30403-7Abstract Full Text Full Text PDF PubMed Scopus (190) Google Scholar] that compared ceftolozane-tazobactam vs. meropenem for the treatment of nosocomial pneumonia, the RESTORE-IMI 2 Study [[8]Titov I. Wunderink R.G. Roquilly A. Gonzalez D.R. David-Wang A. Boucher H.W. et al.A randomized, double-blind, multicenter trial comparing efficacy and safety of imipenem/cilastatin/relebactam versus piperacillin/tazobactam in adults with hospital-acquired or ventilator-associated bacterial pneumonia (RESTORE-IMI 2 Study).Clin Infect Dis. 2021; 73: e4539-e4548https://doi.org/10.1093/cid/ciaa803Crossref PubMed Scopus (82) Google Scholar] that compared imipenem/cilastatin/relebactam vs. piperacillin/tazobactam in hospital-acquired pneumonia or VAP, and the APEKS-NP [[9]Wunderink R.G. Matsunaga Y. Ariyasu M. Clevenbergh P. Echols R. Kaye K.S. et al.Cefiderocol versus high-dose, extended-infusion meropenem for the treatment of gram-negative nosocomial pneumonia (APEKS-NP): a randomised, double-blind, phase 3, non-inferiority trial.Lancet Infect Dis. 2021; 21: 213-225https://doi.org/10.1016/S1473-3099(20)30731-3Abstract Full Text Full Text PDF PubMed Scopus (204) Google Scholar] trial that examined cefiderocol vs. high-dose, extended-infusion meropenem for the treatment of GNB nosocomial pneumonia: all three trials protocols used the 7–14-day treatment duration. In the RESTORE-IMI 2 Study [[8]Titov I. Wunderink R.G. Roquilly A. Gonzalez D.R. David-Wang A. Boucher H.W. et al.A randomized, double-blind, multicenter trial comparing efficacy and safety of imipenem/cilastatin/relebactam versus piperacillin/tazobactam in adults with hospital-acquired or ventilator-associated bacterial pneumonia (RESTORE-IMI 2 Study).Clin Infect Dis. 2021; 73: e4539-e4548https://doi.org/10.1093/cid/ciaa803Crossref PubMed Scopus (82) Google Scholar], more than 40% of patients received more than 8-day course, and in the ASPECT-NP [[7]Kollef M.H. Nováček M. Kivistik Ü. Réa-Neto Á Shime N. Martin-Loeches I. et al.Ceftolozane-tazobactam versus meropenem for treatment of nosocomial pneumonia (ASPECT-NP): a randomised, controlled, double-blind, phase 3, non-inferiority trial.Lancet Infect Dis. 2019; 19: 1299-1311https://doi.org/10.1016/S1473-3099(19)30403-7Abstract Full Text Full Text PDF PubMed Scopus (190) Google Scholar], 14 days' therapy was recommended for patients infected with P. aeruginosa. The median course duration was 10 days in the APEKS-NP study [[9]Wunderink R.G. Matsunaga Y. Ariyasu M. Clevenbergh P. Echols R. Kaye K.S. et al.Cefiderocol versus high-dose, extended-infusion meropenem for the treatment of gram-negative nosocomial pneumonia (APEKS-NP): a randomised, double-blind, phase 3, non-inferiority trial.Lancet Infect Dis. 2021; 21: 213-225https://doi.org/10.1016/S1473-3099(20)30731-3Abstract Full Text Full Text PDF PubMed Scopus (204) Google Scholar]. Despite guideline recommendations, the debate on how long to treat VAP caused by NF-GNB or MDR and XDR GNB continues. Whether a second week of therapy has any additional benefit in patients who have a favourable initial clinical response to treatment at 7 days represents a clinical equipoise. I propose to conduct a parallel design non-inferiority pragmatic RCT that enrols patients with VAP because of MDR and XDR GNB and who have a favourable response on day 7 to either receive an extra week of placebo or to continue the antibiotics course for an extra week (Table 1). Empirical and targeted antibiotic choices in this trial will be guided by international guidelines while considering the local epidemiology of GNB-resistance patterns [[1]Kalil A.C. Metersky M.L. Klompas M. Muscedere J. Sweeney D.A. Palmer L.B. et al.Management of adults with hospital-acquired and ventilator-associated pneumonia: 2016 clinical practice guidelines by the Infectious Diseases Society of America and the American Thoracic Society.Clin Infect Dis. 2016; 63: e61-e111https://doi.org/10.1093/cid/ciw353Crossref PubMed Scopus (1934) Google Scholar,[2]Torres A. Niederman M.S. Chastre J. Ewig S. Fernandez-Vandellos P. Hanberger H. et al.International ERS/ESICM/ESCMID/ALAT guidelines for the management of hospital-acquired pneumonia and ventilator-associated pneumonia: guidelines for the management of hospital-acquired pneumonia (HAP)/ventilator-associated pneumonia (VAP) of the European Respiratory Society (ERS), European Society of Intensive Care Medicine (ESICM), European Society of Clinical Microbiology and Infectious Diseases (ESCMID) and Asociación Latinoamericana del Tórax (ALAT).Eur Respir J. 2017; 501700582https://doi.org/10.1183/13993003.00582-2017Crossref Scopus (645) Google Scholar,10Tamma P.D. Aitken S.L. Bonomo R.A. Mathers A.J. van Duin D. Clancy C.J. Infectious Diseases Society of America 2022 Guidance on the treatment of extended-spectrum β-lactamase producing enterobacterales (ESBL-E), carbapenem-resistant enterobacterales (CRE), and Pseudomonas aeruginosa with difficult-to-treat resistance (DTR-P. aeruginosa).Clin Infect Dis. 2022; 75: 187-212https://doi.org/10.1093/cid/ciac268Crossref PubMed Scopus (111) Google Scholar, 11Tamma P.D. Aitken S.L. Bonomo R.A. Mathers A.J. van Duin D. Clancy C.J. Infectious Diseases society of America guidance on the treatment of AmpC β-lactamase-producing enterobacterales, carbapenem-resistant Acinetobacter baumannii, and Stenotrophomonas maltophilia infections.Clin Infect Dis. 2022; 74: 2089-2114https://doi.org/10.1093/cid/ciab1013Crossref PubMed Scopus (159) Google Scholar, 12Paul M. Carrara E. Retamar P. Tängdén T. Bitterman R. Bonomo R.A. et al.European society of clinical microbiology and infectious Diseases (ESCMID) guidelines for the treatment of infections caused by multidrug-resistant gram-negative bacilli (endorsed by European society of intensive care medicine).Clin Microbiol Infect. 2022; 28: 521-547https://doi.org/10.1016/j.cmi.2021.11.025Abstract Full Text Full Text PDF PubMed Scopus (183) Google Scholar]. Enrolment in the trial should start on day 7 of treatment for patients with a favourable response [[13]von Dach E. Albrich W.C. Brunel A.S. Prendki V. Cuvelier C. Flury D. et al.Effect of C-reactive protein-guided antibiotic treatment duration, 7-day treatment, or 14-day treatment on 30-day clinical failure rate in patients with uncomplicated gram-negative bacteremia: a randomized clinical trial.JAMA. 2020; 323: 2160-2169https://doi.org/10.1001/jama.2020.6348Crossref PubMed Scopus (107) Google Scholar]. A favourable response on day 7 is defined clinically and with the use of procalcitonin monitoring [[1]Kalil A.C. Metersky M.L. Klompas M. Muscedere J. Sweeney D.A. Palmer L.B. et al.Management of adults with hospital-acquired and ventilator-associated pneumonia: 2016 clinical practice guidelines by the Infectious Diseases Society of America and the American Thoracic Society.Clin Infect Dis. 2016; 63: e61-e111https://doi.org/10.1093/cid/ciw353Crossref PubMed Scopus (1934) Google Scholar,[2]Torres A. Niederman M.S. Chastre J. Ewig S. Fernandez-Vandellos P. Hanberger H. et al.International ERS/ESICM/ESCMID/ALAT guidelines for the management of hospital-acquired pneumonia and ventilator-associated pneumonia: guidelines for the management of hospital-acquired pneumonia (HAP)/ventilator-associated pneumonia (VAP) of the European Respiratory Society (ERS), European Society of Intensive Care Medicine (ESICM), European Society of Clinical Microbiology and Infectious Diseases (ESCMID) and Asociación Latinoamericana del Tórax (ALAT).Eur Respir J. 2017; 501700582https://doi.org/10.1183/13993003.00582-2017Crossref Scopus (645) Google Scholar,[14]Scott J. Deresinski S. Use of biomarkers to individualize antimicrobial therapy duration: a narrative review.Clin Microbiol Infect. 2023; 29: 160-164https://doi.org/10.1016/j.cmi.2022.08.026Abstract Full Text Full Text PDF PubMed Scopus (4) Google Scholar]. Enrolment will be stratified by the centre and by fermenting and NF-GNB. The trial should be a pragmatic trial that reflects the phenotypes of patients commonly seen in the intensive care unit, by also enrolling patients with severe critical illness, including the immunocompromised [[15]Imlay H. Laundy N.C. Forrest G.N. Slavin M.A. Shorter antibiotic courses in the immunocompromised: the impossible dream?.Clin Microbiol Infect. 2023; 29: 143-149https://doi.org/10.1016/j.cmi.2022.08.007Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar] that were excluded from previous trials. The pragmatic design of this RCT, which requires an international multicentre collaboration, the inclusion of all GNB-related VAPs, the high incidence of resistance among GNBs worldwide, and the use of composite outcomes should minimize challenges of patients' enrolment that were experienced with the recent iDIAPASON trial [[16]Bouglé A. Tuffet S. Federici L. Leone M. Monsel A. Dessalle T. et al.Comparison of 8 versus 15 days of antibiotic therapy for Pseudomonas aeruginosa ventilator-associated pneumonia in adults: a randomized, controlled, open-label trial.Intensive Care Med. 2022; 48: 841-849https://doi.org/10.1007/s00134-022-06690-5Crossref PubMed Scopus (23) Google Scholar]. This proposed trial as detailed in Table 1 will provide important answers to what remains an unresolved clinical dilemma.Table 1Trial design considerationsTrial design considerationsRationalePragmatic design1.Slow enrolment in previous RCTs2.Treatment and, therefore, outcomes of VAP depend on the complexity of factors such as local bacterial resistance patterns, novel antibiotic availability, ICU care, and physicians' expertise in each hospital. Results of a pragmatic trial will be more generalizable3.Previous trials excluded a large group of patients with VAP such as the immunocompromised or the severely ill patient. Given that randomization will start on day 7 of treatment based on a favourable clinical response, minimal exclusion criteria will be applied4.Informed consent will be easier to obtain because of the favourable response on day 7 and because 7-day course is consistent with current international guidelinesRandomization on day 7 of treatment restricted to patients with favourable clinical response and biochemical profile1.Previous trials randomly assigned patients early on and without consideration of a favourable response on day 7 (the duration of short-course therapy). The important question is whether an extra week of antibiotics in patients with good response provides any additional benefitsDouble-blind placebo controlled1.To avoid performance and outcome assessment bias (whether because of differential time at risk in the two arms because of different follow-up durations or outcome ascertainment bias)2.Because all antimicrobials are administered intravenously, the use of placebo will be feasibleFollow-up duration: 90 d1.To limit differential time at risk between short-course and long-course treatment arms for the ascertainment of recurrent VAPPrimary outcome (patient centred): a composite of all-cause mortality or failure to wean from mechanical ventilation at 28 d1.Both endpoints are important to patients and clinicians2.Objective and not susceptible to assessment bias3.Previous composite outcomes combined endpoints of mortality and recurrent VAP that are not of equal importance to patients4.The use of composite outcome will require a smaller sample sizeSecondary outcomes:1.Incidence rate of clinical recurrence of VAP (relapse or superinfection) at 90 d2.Length of ICU and hospital stay3.Duration of mechanical ventilation4.Number of antibiotic-free days5.Emergence of resistant organisms6.Safety outcomes1.To avoid differential follow-up bias for VAP recurrence: (a) time zero will be the day of randomization and (b) incidence rates (not cumulative incidence) will be calculatedSample size calculation1.Non-inferiority margin at 10%, with a power of 80% (1-β) and a one-sided significance level (α) of 5%2.Estimated proportion with primary outcome (all-cause mortality or failure to wean from mechanical ventilation) on day 28: 40% to 50% based on my literature review3.Using the Farrington-Manning method for sample size calculation in non-inferiority trials with binary outcomes, an estimated sample size of approximately 600–800 participants would be required (as per primary outcome estimated range of values)ICU, intensive care unit; RCT, randomized controlled trial; VAP, ventilator-associated pneumonia. Open table in a new tab ICU, intensive care unit; RCT, randomized controlled trial; VAP, ventilator-associated pneumonia. The author declares no conflicts of interest. No financial support was provided relevant to this article." @default.
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• W4366751004 title "Which trial do we need? Comparison of 7 versus 14 days of antibiotic therapy for ventilator-associated pneumonia due to highly resistant gram-negative bacteria" @default.
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