The Shorter the Better!

Clin Infect Dis. 2018 Dec 11

Contributed by Dr Abi Manesh

Accumulating evidence suggests shorter one-week therapy is probably as efficacious as two weeks therapy for gram-negative Enterobacteriaceae bacteremia. This has been supported by few retrospective data and one metaanalysis. This was examined in a recent RCT conducted in Israel and Italy. They proposed that shortening the duration may reduce unnecessary antibiotic use, drug related adverse events, duration of hospitalization, emergence of antibacterial resistance and superinfections, including fungal and Clostridium difficile infection.

The authors randomized 600 patients in an open-label/ analyst-blinded non-inferiority (10% margin), 1:1 parallel group trial. The patients had a gram-negative bacteremia with optimal source control and at least 7 days of effective therapy (empirical or directed). Importantly patients who remained febrile or hemo-dynamically unstable 48 hours before randomization and neutropenic patients were excluded. The primary outcome at 90 days from randomization was a composite of all-cause mortality; clinical failure, including either relapse of the bacteremia, local suppurative complications or distant complications; and re-admission or extended hospital stay (>14 days).

Of 4807 patients with Gram-negative bacteremia surviving to day 7, 2169 potentially-eligible patients were assessed and 604 patients were included (306 in the short duration arm and 298 in the long duration arm) between 1 Jan 2013 to 31 Aug 2017. The primary composite outcome of mortality, clinical failure, readmissions or extended hospitalization at 90 days occurred in 140 of 306 patients in the short duration group (45.8%) compared with 144 of 298 in the long duration group (48.3%) (Risk difference [RD] -2.6%, 95% confidence interval [CI], -10.5% to 5.3%), establishing non-inferiority.

The strengths of this trial include non-restrictive inclusion criteria allowing a large population of elderly patients (404/604, 66.9% ≥65 years) and immunocompromised patients (150/604, 24.8%; mainly solid organ transplanted patients and patients treated for malignancy). The trial results are valid for 7-day survivors of Gram-negative Enterobacteriaceae bacteremia achieving hemodynamic stability and afebrile for at least 48 hours before day 7 with no uncontrolled source of infection and have no severe immune-compromising conditions. This RCT provides additional confidence to make shorter therapy as the standard of care in a select group of patients.