Intra-abdominal infections (IAI) are an important cause of morbidity and are frequently associated with poor prognosis, particularly in high-risk patients. The cornerstones in the management of complicated IAIs are timely effective source control with appropriate antimicrobial therapy. Empiric antimicrobial therapy is important in the management of intra-abdominal infections and must be broad enough to cover all likely organisms because inappropriate initial antimicrobial therapy is associated with poor patient outcomes and the development of bacterial resistance. The overuse of antimicrobials is widely accepted as a major driver of some emerging infections (such as C. difficile), the selection of resistant pathogens in individual patients, and for the continued development of antimicrobial resistance globally. The growing emergence of multi-drug resistant organisms and the limited development of new agents available to counteract them have caused an impending crisis with alarming implications, especially with regards to Gram-negative bacteria. An international task force from 79 different countries has joined this project by sharing a document on the rational use of antimicrobials for patients with IAIs. The project has been termed AGORA (Antimicrobials: A Global Alliance for Optimizing their Rational Use in Intra-Abdominal Infections). The authors hope that AGORA, involving many of the world's leading experts, can actively raise awareness in health workers and can improve prescribing behavior in treating IAIs.

This article is one of ten reviews selected from the Annual Update in Intensive Care and Emergency Medicine 2015 and co-published as a series in Critical Care. Other articles in the series can be found online at http://ccforum.com/series/annualupdate2015. Further information about the Annual Update in Intensive Care and Emergency Medicine is available from http://www.springer.com/series/8901.

Catheter suctioning of respiratory secretions in intubated subjects is limited to the proximal airway and associated with traumatic lesions to the mucosa and poor tolerance. “Mechanical insufflation-exsufflation” exerts positive pressure, followed by an abrupt drop to negative pressure. Potential advantages of this technique are aspiration of distal airway secretions, avoiding trauma, and improving tolerance. We applied insufflation of 50 cmH2O for 3 s and exsufflation of − 45 cmH2O for 4 s in patients with an endotracheal tube or tracheostomy cannula requiring secretion suctioning. Cycles of 10 to 12 insufflations-exsufflations were performed and repeated if secretions were aspirated and visible in the proximal artificial airway. Clinical and laboratory parameters were collected before and 5 and 60 min after the procedure. Subjects were followed during their ICU stay until discharge or death. Mechanical insufflation-exsufflation was applied 26 times to 7 male and 6 female subjects requiring suctioning. Mean age was 62.6 ± 20 years and mean Apache II score 23.3 ± 7.4 points. At each session, a median of 2 (IQR 1; 2) cycles on median day of intubation 11.5 (IQR 6.25; 25.75) were performed. Mean insufflation tidal volume was 1043.6 ± 649.9 ml. No statistically significant differences were identified between baseline and post-procedure time points. Barotrauma, desaturation, atelectasis, hemoptysis, or other airway complication and hemodynamic complications were not detected. All, except one, of the mechanical insufflation-exsufflation sessions were productive, showing secretions in the proximal artificial airway, and were well tolerated. Our preliminary data suggest that mechanical insufflation-exsufflation may be safe and effective in patients with artificial airway. Safety and efficacy need to be confirmed in larger studies with different patient populations. EudraCT 2017-005201-13 (EU Clinical Trials Register).

Pseudomonas aeruginosa (PA) pneumonia is associated with morbidity and mortality in mechanically ventilated, intensive care unit (MV ICU) patients despite best clinical care. We assessed efficacy, PK, and safety of MEDI3902 in MV ICU subjects in the placebo-controlled, randomized Phase 2 EVADE study (NCT02696902; EudraCT 2015-001706-34). Subjects with PCR-confirmed PA colonization of the lower respiratory tract were randomized to either a single IV infusion of 1,500 mg MEDI3902 (n = 85) or placebo (n = 83). Primary Efficacy endpoint was Endpoint Adjudication Committee-determined relative risk reduction (RRR) of PA pneumonia incidence in MEDI3902 vs. placebo recipients within 21 days post dose (2-sided α = 0.2). Serum MEDI3902 PK levels were measured through 49 days post dose. Treatment-emergent adverse events (TEAEs) and serious AEs (SAEs) were assessed through 49 days post dose. Baseline characteristics were similar between groups. MEDI3902 did not meet the primary endpoint of PA pneumonia vs. placebo (22.4% vs. 18.1%; RRR -23.7%, P = 0.491). Mean serum MEDI3902 level was 9.46 µg/mL (target 1.7µg/mL) at 21 days post dose, with a t½ 5.6 days. Proportion of subjects with TEAEs was similar between groups: ≥1 TEAE (98.8% MEDI3902; 97.6% placebo); ≥1 serious; and/or ≥grade 3 severity SAE (70.6% MEDI3902; 66.3% placebo). Deaths were numerically higher, although not statistically significant (24 (28.2%) MEDI3902 vs 19 (22.9%) Placebo; RRR -23.3%, P 0.429). Post-hoc analyses suggested RRR 47% among ~70% of the study population who had baseline Procalcitonin levels < 0.55 µg/L (12.5% MEDI3902 vs 23.7% placebo; 80%CI 6.1%-69.9%; P 0.135). Similarly, RRR 83% was observed among 50% of study subjects with baseline absolute neutrophil count (ANC) of < 8170 /µL (2.8% MEDI3902 vs 17.0% placebo; 80%CI 39.5%-95.5%; P 0.038). Subjects with Procalcitonin < 0.55 µg/L and ANC < 8170/ µL also had higher serum PK exposure. A single IV dose of MEDI3902 provided PK exposure above the target level but did not achieve primary efficacy endpoint of reduction in PA pneumonia. Efficacy trends were observed in subjects with lower levels of baseline inflammatory biomarkers. MEDI3902 may have a path forward in certain patient populations such as ICU patients with lower baseline inflammation. Jean Chastre, MD, AstraZeneca (Scientific Research Study Investigator) Marc Bourgeois, MD, AstraZeneca (Scientific Research Study Investigator) Apostolos Komnos, MD, PhD, AstraZeneca (Scientific Research Study Investigator) Ricard Ferrer, MD, PhD, Shionogi B.V. (Advisor or Review Panel member) Galia Rahav, MD, AstraZeneca (Scientific Research Study Investigator) Nicolas De Schryver, MD, AstraZeneca (Scientific Research Study Investigator) Alain Lepape, MD, AstraZeneca (Scientific Research Study Investigator) Miguel Sanchez Garcia, MD, PhD, AstraZeneca (Scientific Research Study Investigator) Antoni Torres, MD, PhD, AstraZeneca (Scientific Research Study Investigator) Omar Ali, PhD, AstraZeneca (Employee) Kathryn Shoemaker, MS, AstraZeneca (Employee) Alexey Ruzin, PhD, AstraZeneca (Employee, Shareholder) Yu Jiang, PhD, AstraZeneca (Employee) Susan Colbert, BSN, AstraZeneca (Employee) Drieke Vandamme, PhD, AstraZeneca (Scientific Research Study Investigator) Terramika Bellamy, n/a, AstraZeneca (Employee) Colin Reisner, MD, AstraZeneca (Employee) Filip Dubovsky, MD, MPH, AstraZeneca (Employee) Hasan S. Jafri, MD, FAAP, AstraZeneca (Employee)