Duration of Antibiotic Therapy for Uncomplicated Gram-Negative Bacteremia: Seven Is the New Fourteen

The treatment duration for uncomplicated gram-negative bloodstream infections (BSIs) has traditionally ranged from 7 to 14 days.^1-2 However, recent retrospective studies and meta-analyses have observed no differences in clinical outcomes in patients treated with shorter courses compared with prolonged courses, especially with urinary sources of infection.^1-2 In addition, the role of oral stepdown for defini­tive therapy for gram-negative BSIs has been explored with similar clinical outcomes regard­less of duration.³ These recent studies have led to an increased interest in stewardship efforts to optimize antibiotic utilization and promote appropriate oral stepdown therapy for gram-negative BSIs.

Yahav and colleagues conducted the first prospective, randomized, controlled, noninfe­riority trial to compare short-course (7 days) versus long-course (14 days) antibiotic therapy for uncomplicated gram-negative BSIs.⁴ Patients were included if they were hemodynami­cally stable and normothermic for 48 hours by day 7 of effective antibiotic therapy and were excluded if an uncontrolled source of infection was present. Overall, 604 patients were random­ized to receive either short-course (n = 306) or long-course (n = 298) therapy. The primary outcome was a composite of all-cause mortality; clinical failure defined as relapse, suppurative, or distant complications; and re-admission or extended hospitalization by 90 days. The first day of effective empiric or definitive antibiotics was considered day 1 of therapy. Most patients (92%) received the protocol-specific treatment durations (± 2 days), and about 73% of patients were switched to oral stepdown therapy (fluo­roquinolones: 74%; β-lactams: 18%; sulfamethox­azole/trimethoprim: 8%). Patients were generally older than 65 years (67%) and immunocom­petent (75%). The most common pathogens identified were Enterobacteriaceae, and the primary sources of infection were urinary (68%) and intraabdominal (12%).

Short-course therapy was noninferior to long-course therapy for the primary outcome (45.8% vs 48.3%, respectively; 95% CI, —10.5 to 5.3) or in any of its individual components. No significant differences were observed in any of the secondary outcomes, including resistance development, adverse effects, or Clostridium difficile infections, with the exception of func­tional capacity needs at 30 days favoring short-course therapy. The authors concluded that 7 days of antibiotic therapy was nonin­ferior to 14 days in patients who had gram-negative BSIs with adequate source control and were clinically stable by day 7 of therapy.

This robustly powered study addresses stewardship efforts in the management of uncomplicated BSIs. The findings from this study support the trend of shorter antibiotic courses for infections with adequate source control. In addition, the high rate of use of oral stepdown therapy without clinical compromise demonstrates the ability to avoid placement of central lines and ultimately prevent unneces­sary catheter-related adverse effects.^3,5 Finally, obtaining repeat blood cultures to confirm microbiological clearance is not necessary for clinical success and provides an opportunity for diagnostic stewardship. This landmark study provides high-quality evidence that promotes the duration of 7 days as the correct duration for uncomplicated BSIs. Conversely, caution should be practiced when applying these results in the immunocompromised or BSIs caused by non-Enterobacteriaceae (Table).

Dr. Cho is currently a PGY2 infectious diseases pharmacy resident at Allegheny General Hospital in Pittsburgh, Pennsylvania. He received his PharmD from the Philadelphia College of Pharmacy, also in Philadelphia.

References:

1. Havey TC, Fowler RA, Daneman N. Duration of antibiotic therapy for bacteremia: a systematic review and meta-analysis. Crit Care. 2011;15(6):R267. doi: 10.1186/cc10545.
2. Chotiprasitsakul D, Han JH, Cosgrove SE, et al. Antibacterial Resistance Leadership Group. Comparing the outcomes of adults with Enterobacteriaceae bacteremia receiving short-course versus prolonged-course antibiotic therapy in a multicenter, propensity score-matched cohort. Clin Infect Dis. 2017;66(2):172-177. doi: 10.1093/cid/cix767.
3. Mercuro N, Stogsdill P, and Wungwattana M. Retrospective analysis comparing oral stepdown therapy for enterobacteriaceae bloodstream infections: fluoroquinolones versus β-lactams. Int J Antimicrob Agents. 2018;51(5):687-692. doi: 10.1016/j.ijantimicag.2017.12.007.
4. Yahav D, Franceshini E, Koppel F, et al. Bacteremia Duration Study Group. Seven versus fourteen days of antibiotic therapy for uncomplicated gram-negative bacteremia: a non-inferiority randomized controlled trial [published online December 11, 2018]. Clin Infect Dis. doi: 10.1093/cid/ciy1054.
5. Underwood J, Marks M, Collins S, Logan S, Pollara G. Intravenous catheter-related adverse events exceed drug-related adverse events in outpatient parenteral antimicrobial therapy [published online November 20, 2018]. J Antimicrob Chemother. doi: 10.1093/jac/dky474.