Matthew Sims

Prospective, randomized, double-blind, Phase 2 dose-ranging study comparing efficacy and safety of imipenem/cilastatin plus relebactam with imipenem/cilastatin alone in patients with complicated urinary tract infections

Objectives: The &bgr;‐lactamase inhibitor relebactam can restore imipenem activity against imipenem non‐susceptible pathogens. Methods: To explore relebactams safety, tolerability and efficacy, we conducted a randomized (1:1:1), controlled, Phase 2 trial comparing imipenem/cilastatin+relebactam 250 mg, imipenem/cilastatin+relebactam 125 mg and imipenem/cilastatin alone in adults with complicated urinary tract infections (cUTI) or acute pyelonephritis, regardless of baseline pathogen susceptibility. Treatment was administered intravenously every 6 h for 4–14 days, with optional step‐down to oral ciprofloxacin. The primary endpoint was favourable microbiological response rate (pathogen eradication) at discontinuation of intravenous therapy (DCIV) in the microbiologically evaluable (ME) population. Non‐inferiority of imipenem/cilastatin+relebactam over imipenem/cilastatin alone was defined as lower bounds of the 95% CI for treatment differences being above ‐15%. Results: At DCIV, 71 patients in the imipenem/cilastatin+250 mg relebactam, 79 in the imipenem/cilastatin+125 mg relebactam and 80 in the imipenem/cilastatin‐only group were ME; 51.7% had cUTI and 48.3% acute pyelonephritis. Microbiological response rates were 95.5%, 98.6% and 98.7%, respectively, confirming non‐inferiority of both imipenem/cilastatin+relebactam doses to imipenem/cilastatin alone. Clinical response rates were 97.1%, 98.7% and 98.8%, respectively. All 23 ME patients with imipenem non‐susceptible pathogens had favourable DCIV microbiological responses (100% in each group). Among all 298 patients treated, 28.3%, 29.3% and 30.0% of patients, respectively, had treatment‐emergent adverse events. The most common treatment‐related adverse events across groups (1.0%‐4.0%) were diarrhoea, nausea and headache. Conclusions: Imipenem/cilastatin+relebactam (250 or 125 mg) was as effective as imipenem/cilastatin alone for treatment of cUTI. Both relebactam‐containing regimens were well tolerated. (NCT01505634).

Is There a Clinical Association of Vancomycin Mic Creep, agr Group Ii Locus, and Treatment Failure in Mrsa Bacteremia?

BackgroundThe association of vancomycin treatment failure with minimum inhibitory concentration (MIC) creep is concerning, as most isolates are still considered to be in the susceptible range. Several studies have suggested that the accessory gene regulator (agr) group II polymorphism is predictive of vancomycin treatment failure. We assessed the associations between increased vancomycin MIC, agr group II locus, and vancomycin treatment failure in Methicillin-resistant Staphylococcus aureus (MRSA) bacteremias. MethodsMRSA isolates from 99 inpatient bacteremias were studied. Susceptibility testing was conducted by an automated method (MicroScan) and by the gradient diffusion method (E-test). Vancomycin MICs were stratified into 3 groups for analysis: MIC ⩽1, MIC >1 but ⩽2, and MIC >2 &mgr;g/mL. Strains were typed by repetitive-polymerase chain reaction analysis and the agr locus was identified by multiplex polymerase chain reaction. Failure of vancomycin treatment was defined as persistent bacteremia after 72 hours, death at 30 days, or treatment change due to clinical failure. ResultsAmong 99 bacteremic patients, there were 82 agr group II and 15 agr group I isolates. There was no relationship between higher vancomycin MICs and isolate agr II loci (42 of 82) (P=0.59). Earlier vancomycin exposure was significantly associated with increased MIC (P=0.03). Vancomycin treatment failure was observed in 12 patients: 3 required an alternate regimen, 4 had persistent positive cultures, and 5 whose deaths were attributable to MRSA infection. Survival in agr group II was 57 of 82 (69%) versus agr group I in which it was 14 of 15 (93%), (P=0.06). ConclusionsWe did not identify any significant association between MIC creep and vancomycin failure or between higher vancomycin MICs and agr group II. However, a higher mortality was seen in agr group II than agr group I.

An outbreak of Pseudomonas aeruginosa respiratory tract infections associated with intrinsically contaminated ultrasound transmission gel.

We describe an outbreak of Pseudomonas aeruginosa respiratory tract infections related to intrinsically contaminated ultrasound gel used for intraoperative transesophageal echocardiograms in cardiovascular surgery patients. This investigation led to a product safety alert by the Food and Drug Administration and the development of guidelines for appropriate use of ultrasound gel.