Impact of intensive care unit relocation and role of tap water on an outbreak of Pseudomonas aeruginosa expressing OprD-mediated resistance to imipenem.

BACKGROUND: To assess the impact of the incidental relocation of an intensive care unit (ICU) on the risk of colonizations/infections with Pseudomonas aeruginosa exhibiting OprD-mediated resistance to imipenem (PA-OprD). AIM: The primary aim was to compare the proportion of PA-OprD among P. aeruginosa samples before and after an incidental relocation of the ICU. The role of tap water as a route of contamination for colonization/infection of patients with PA-OprD was assessed as a secondary aim. METHODS: A single-centre, observational, before/after comparison study was conducted from October 2013 to October 2015. The ICU was relocated at the end of October 2014. All P. aeruginosa-positive samples isolated from patients hospitalized ≥48 h in the ICU were included. Tap water specimens were collected every three months in the ICU. PA-OprD strains isolated from patients and tap water were genotyped using pulse-field gel electrophoresis. FINDINGS: A total of 139 clinical specimens of P. aeruginosa and 19 tap water samples were analysed. The proportion of PA-OprD strains decreased significantly from 31% to 7.7% after the relocation of the ICU (P = 0.004). All PA-OprD clinical specimens had a distinct genotype. Surprisingly, tap water was colonized with a single PA-OprD strain during both periods, but this single clone has never been isolated from clinical specimens. CONCLUSION: Relocation of the ICU was associated with a marked decrease in P. aeruginosa strains resistant to imipenem. The polyclonal character of PA-OprD strains isolated from patients and the absence of tap-water-to-patient contamination highlight the complexity of the environmental impact on the endogenous colonization/infection with P. aeruginosa.

A phase I, pharmacokinetic and pharmacodynamic study of GSK2256098, a focal adhesion kinase inhibitor, in patients with advanced solid tumors.

BACKGROUND: Focal adhesion kinase (FAK) is important in cancer growth, survival, invasion, and migration. The purpose of this study was to determine the maximum tolerated dose (MTD), safety, pharmacokinetics (PK), and pharmacodynamics (PD) of the FAK inhibitor, GSK2256098, in cancer patients. PATIENTS AND METHODS: The dose of GSK2256098 was escalated, in cohorts of patients with advanced cancer, from 80 to 1500 mg, oral twice daily (BID), until the MTD was determined. Serial blood samples were obtained from all patients, and the PK was determined. Paired tumor biopsies were obtained in select patients, and the level of phospho-FAK (pFAK) was determined. RESULTS: Sixty-two patients (39 males, 23 females; median age 61 y.o., range 21-84) received GSK2256098. Dose-limiting toxicities of grade 2 proteinuria (1000 mg BID), grade 2 fatigue, nausea, vomiting (1250 mg BID), and grade 3 asthenia and grade 2 fatigue (1500 mg BID) were reported with the MTD identified as 1000 mg BID. The most frequent adverse events (AEs) were nausea (76%), diarrhea (65%), vomiting (58%), and decreased appetite (47%) with the majority of AEs being grades 1-2. The PK was generally dose proportional with a geometric mean elimination half-life range of 4-9 h. At the 750, 1000, and 1500 mg BID dose levels evaluated, the pFAK, Y397 autophosphorylation site, was reduced by ∼80% from baseline. Minor responses were observed in a patient with melanoma (-26%) and three patients with mesothelioma (-13%, -15%, and -17%). In the 29 patients with recurrent mesothelioma, the median progression-free survival was 12 weeks with 95% CI 9.1, 23.4 weeks (23.4 weeks merlin negative, n = 14; 11.4 weeks merlin positive, n = 9; 10.9 weeks merlin status unknown, n = 6). CONCLUSIONS: GSK2256098 has an acceptable safety profile, has evidence of target engagement at doses at or below the MTD, and has clinical activity in patients with mesothelioma, particularly those with merlin loss.