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

Abstract

BackgroundHospital-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.MethodsA 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 All unpublished RCTs recorded on the ClinicalTrials.gov registry were also screened.ResultsFrom the 93 abstracts reviewed, 39 potentially relevant studies were inspected,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 This variability slightly improved over time but remained significant in the 13 registered but currently unpublished RCTs that we screened.ConclusionOur study provides a description of populations and endpoints of RCTs evaluating antimicrobials for treatment of HAP/VAP in the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.Electronic supplementary materialThe online version of this article (doi:10.1186/s13054-017-1755-5) contains supplementary material, which is available to authorized users.

Exebacase for patients with Staphylococcus aureus bloodstream infection and endocarditis

“…Overall, the 30-day all-cause mortality rate was 9.7% in the exebacase-treated group and 12.8% in the antibiotics-alone group, with a greater difference in the MRSA subgroup (3.7% vs. 25.0%). These findings are important, considering that 28-day mortality has been used as a standard for assessment of survival in hospitalized patients with serious infections (e.g., hospitalacquired and ventilator-associated bacterial pneumonia [HABP/ VABP]) (29,30), and is an FDA-recommended endpoint in HABP/ VABP trials (31). All-cause mortality rates in both groups were higher at the TOC time point, which varied widely between patients (up to 180 days after dosing) allowing time for mortality due to medical events unrelated to the infection under study.…”

The time‐dependent “cure‐death” model investigating two equally important endpoints simultaneously in trials treating high‐risk patients with resistant pathogens

“…However, we can make inferences about one timepoint only and, consequently, the result strongly depends on this selected time point. These timepoints are quite heterogeneous amongst trials; see the systematic review of Weiss et al() By not considering the time‐dynamic process, much valuable information that may be highly relevant from the patient perspective can get lost. Using transition probabilities, time‐dependent effects as, eg, in simulation, Scenario 5, can be made transparent.…”

“…The appropriate primary endpoint to be used in trials including hospitalised patients with HAP or VAP is still a subject of debate. Weiss et al() provide a systematic review of characteristics of enrolled populations, inclusion/exclusion criteria, and endpoints addressing the efficacy of antimicrobial treatments. The Foundation for the National Institutes of Health states that future studies must determine which outcomes are most important to patients and should incorporate short‐term as well as long‐term outcomes.…”

Aerosol Therapy for Pneumonia in the Intensive Care Unit

“…With current standard-of-care therapy, clinical success rates are often less than 60%, related to the many challenges that encompass antibiotic therapy in critically ill patients, including alterations in pharmacokinetics (PK) and pharmacodynamics (PD), relative low penetration of most antibiotics into the lung tissue, and the frequency of difficult-to-treat or highly resistant pathogens in that setting. 1 Aerosol antibiotic administration offers the theoretic advantages of achieving high drug concentrations at the infection site, considerably more than the minimal inhibitory concentration (MIC) of most causative microorganisms, and low systemic absorption, thereby avoiding toxicity, particularly the renal toxicity of aminoglycosides or colistin. The poor development of this potentially advantageous technique in patients on mechanical ventilation (MV) is caused partly by high amounts of the particles dispersed by conventional nebulizers depositing in the ventilatory circuits and the tracheobronchial tree during MV, therefore not reaching the distal lung, and hence less drug is available in the alveolar compartment.…”