Oral antimicrobial therapy for Gram-negative bacteremia: Have We Hit the “Target”?

Reviewed by David Cluck, PharmD, University of Virginia and Cindy Noyes, MD, University of Vermont Medical Center

Using causal inference methods, Alzaidi and colleagues describe a large multicenter observational cohort study of adult patients to compare effectiveness of step-down to oral antibiotics to complete treatment for E. coli or Klebsiella species bacteremia secondary to a urinary tract infection (UTI) from January 2016 through December 2022.1  Patients were excluded if they were deemed to be complicated defined by any of the following: polymicrobial bacteremia, infected kidney stones, abscesses or prostatitis.1  Patients were stratified into 1 of 3 comparator groups: highly bioavailable β-lactams (HBBL: amoxicillin, amoxicillin/clavulanic acid, cephalexin), fluoroquinolones (FQ: ciprofloxacin or levofloxacin) or trimethoprim-sulfamethoxazole (TMP-SMX).1  Dosing strategies for oral regimens were determined by the treating physician.1 The primary outcome measured recurrence free days for 60 days following treatment—defined as a symptomatic UTI and/or bacteremia.1  Of the 2571 patients screened, 648 met inclusion criteria—248 received FQ, 99 received TMP-SMX, 201 received HBBL.1  Sixty-day recurrence, driven primarily by recurrent symptomatic UTI, was lowest in the FQ group.1  Recurrence was similar in patients treated with TMP-SMX or a FQ.1  Patients in the HBBL group had the highest odds of recurrence, with an adjusted hazard ratio of 2.19 (0.95-5.01), though not statistically significant.1 In sub-analyses, short course FQ therapy, defined as ≤8 days, was associated with a higher recurrence rate than a long course (>8 days), with risk factors of history of recurrent UTI and nephrolithiasis being significant.1  Most importantly, however, mortality and C difficile onset were low in all groups, suggesting these to be reasonable strategies to pursue.1 

The use of trial emulation can be utilized to reduce potential bias which may occur in observational studies. Knowing this, Tingsgård and colleagues used a target trial emulation framework from the INVEST trial protocol to evaluate 90-day mortality when de-escalating from intravenous to oral antibiotics for Gram-negative bacteremia.2 One treatment arm switched to oral antibiotics within 4 days whereas the other maintained IV antibiotics for ≥5 days. Choice of IV, oral antibiotic and treatment duration after availability of the susceptibility report was at the discretion of the treating physician but had to align with the susceptibility result. Notably, most patients received oral β-lactams in the oral switch arm. The proportion of individuals who died was higher in the group receiving prolonged IV treatment (69 of 481 [14.3%] vs 3 of 433 [6.9%]).

The findings from both studies which are more rigorous in study design reinforce the outcomes from other available observational data – oral β-lactams in addition to other oral agents are reasonable stepdown therapies for uncomplicated Gram-negative bacteremia.


  1. Alzaidi S, et al.  Oral B-lactams, fluoroquinolones or trimethoprim-sulfamethoxazole for definitive treatment of uncomplicated E coli or klebsiella species bacteremia from a urinary tract source.  Open Forum Infect Dis.  2024; 11(2).  https://doi.org/10.1093/ofid/ofad657
  2. Tingsgård S, Bastrup Israelsen S, Jørgensen HL, Østergaard C, Benfield T. Early Switch From Intravenous to Oral Antibiotics for Patients With Uncomplicated Gram-Negative Bacteremia. JAMA Netw Open. 2024;7(1):e2352314. doi:10.1001/jamanetworkopen.2023.52314
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