What: Bacteriemia, more commonly known as a bloodstream infection, is one of the leading causes of hospitalization, with the incidence of gram-negative bacteremia (GNB) having increased in recent years.¹ Gram-negative bacteremia are not only associated with devastating morbidity and mortality, but also carry significant treatment costs—around $44,000 per patient with GNB—mainly because of inpatient hospital cost and increased length of hospital stay.² Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Acinetobacter baumannii are the typical offenders because of their shared distinctive pathogenic mechanisms: capsule production, adhesion, and flexibility. Empiric treatment of GNB depends on the source of infection—given that bacteria can enter the blood through multiple routes or primary infections (eg, untreated UTIs that spread to the blood)—and the patient’s clinical presentation.³ Following susceptibilities and antibiotic stewardship best practices, many patients remain on intravenous antibiotic therapy, given that multiple practice facets exist; however, oral antibiotics can be considered after the patient has achieved clinical stability and adequate source control.⁴

Why: Historically, intravenous antibiotic therapy has been the treatment mainstay for GNB; however, this is partly because of the lack of consistent evidence addressing the optimal transitioning period.¹ The controversy stems from whether intravenous antibiotics are necessary for the entire treatment—extending to transitioning timelines from intravenous to oral antibiotic therapy. Other GNB treatment practice variabilities are influenced through multiple avenues, such as antibiotic allergies, illness severity, source of infection, and organism susceptibilities.⁴ All of these facets influence practical transitioning to oral antibiotics and the overall treatment course. Oral antibiotic therapy can offer advantages (decreased health care expenditures) over traditional intravenous antibiotic therapy while also reducing the risk associated with prolonged intravenous antibiotics. For extended intravenous therapy, patients must have a long-term intravenous catheter, exposing them to procedural complications, secondary infections, and increased risk of thrombosis.⁵ By offering oral antibiotic therapy or earlier transitioning—especially to patients with uncomplicated GNB or who have achieved clinical stability—we are eliminating these additional health care expenditures and patient risks.⁴ Finally, oral antibiotics concur with antimicrobial stewardship by reducing exposure to broad-spectrum intravenous agents.⁵

When: Based on the Engers et al study,⁴ investigators identified that transitioning to oral antibiotic therapy by treatment day 7 had occurred in 43% of the 4581 episodes identified at the 24 hospital sites in North America. They acknowledged that patients maintained on intravenous antibiotics past treatment day 7 had more severe illness and/or more comorbidities; however, they did report that most of the patients, 89.7%, were clinically stable within 5 days, with a 2-day median for adequate infection source control.⁴ The authors also cited the Tamma et al study, which found efficacy and safety with oral transition similar to continued intravenous therapy—reporting no difference in 30-day all-cause mortality or recurrence of bacteremia.⁶ Based on the Hale et al study,⁵ they identified a treatment failure rate of only 2% among patients treated with a highly bioavailable oral antibiotic if the GNB was of the Enterobacteriaceae family and susceptible to oral agents. They further discussed a trial comparing oral with intravenous ciprofloxacin for pyelonephritis with a secondary bacteremia occurrence rate of 38%—finding no significant differences in treatment failure or unsatisfactory clinical responses between groups.

Who: Another point of controversy among oral antibiotic use in GNB is placed on proper selection. Oral versus intravenous antibiotic selection, though patient-specific, depends on 3 main principles: organism susceptibility, antibiotic bioavailability, and barrier to resistance. We mention patient-specific to reemphasize that not all patients may be candidates for oral antibiotic therapy or early transitioning because of these specific patient factors. Fluoroquinolones—ciprofloxacin and levofloxacin—have been the nonofficial first-line agents because of their high oral bioavailability and ideal coverage of the most common causative pathogens; however, there have been no well-established effectiveness studies comparing fluoroquinolones with other agents.¹ Nisly et al aimed to decrease this gap by analyzing the relative effectiveness of oral fluoroquinolones, β-lactams, and trimethoprim-sulfamethoxazole. They found that most patients, 66.7%, received oral fluoroquinolones, and the composite primary end point—30-day mortality, 30-day recurrent bacteremia, and transition back to intravenous antibiotics—occurred in only 7.4% of patients, with no statistical difference (P = .523) in the treatment arms consisting of β-lactams and trimethoprim-sulfamethoxazole.¹ Kutob et al found that among patients with GNB receiving definitive antimicrobials with moderate bioavailability, defined as 75% to 94% bioavailability, or low bioavailability, defined as less than 75% bioavailability, oral antibiotics were associated with higher rates of treatment failure (P = .005 and P = .003, respectively) than high oral bioavailability.⁷ Although differences exist between the 2 studies regarding exclusion criteria, both support transitioning to oral antibiotic therapies for uncomplicated GNB with a highly bioavailability antibiotic.^1,7 Finally, fluroquinolones are the only oral antibiotic with antipseudomonal activity; however, they may not achieve adequate blood concentrations for P aeruginosa at standard dosing regimens; thus, conservative intravenous approaches should be taken in these patient populations.⁵

Pearl Takeaway: With more clinical data becoming available, antimicrobial teams should consider earlier transition therapy on the basis of the patient’s stability and bacterial susceptibilities. In these patients, oral antibiotic step-down therapy should be considered—specifically with a highly bioavailable antibiotic, like fluoroquinolones.

References

1. Nisly SA, McClain DL, Fillius AG, Davis KA. Oral antibiotics for the treatment of gram-negative bloodstream infections: a retrospective comparison of three antibiotic classes. J Glob Antimicrob Resist. 2020;20:74-77. https://doi.org/10.1016/j.jgar.2019.07.026

2. Thaden JT, Li Y, Ruffin F, et al. Increased costs associated with bloodstream infections caused by multidrug-resistant gram-negative bacteria are due primarily to patients with hospital-acquired infections. Antimicrob Agents Chemother. 2017;61(3):e01709-16. https://doi.org/10.1128/AAC.01709-16

3. Holmes CL, Anderson MT, Mobley HLT, Bachman MA. Pathogenesis of gram-negative bacteremia. Clin Microbiol Rev. 2021;34(2):e00234-20. https://doi.org/10.1128/CMR.00234-20

4. Engers DW, Tamma PD, Fiawoo S, et al. Transition to oral antibiotic therapy for hospitalized adults with gram-negative bloodstream infections. JAMA Netw Open. 2024;7(1):e2349864. https://doi.org/10.1001/jamanetworkopen.2023.49864

5. Hale AJ, Snyder GM, Ahern JW, Eliopoulos G, Ricotta D, Alston WK. When are oral antibiotics a safe and effective choice for bacterial bloodstream infections? An evidence-based narrative review. J Hosp Med. 2018;13(5):328-335. https://doi.org/10.12788/jhm.2949

6. Tamma PD, Conley AT, Cosgrove SE, et al. Association of 30-day mortality with oral step-down vs continued intravenous therapy in patients hospitalized with Enterobacteriaceae bacteremia [published correction appears in JAMA Intern Med. 2019;179(11):1607]. JAMA Intern Med. 2019;179(3):316-323. https://doi.org/10.1001/jamainternmed.2018.6226

7. Kutob LF, Justo JA, Bookstaver PB, Kohn J, Albrecht H, Al-Hasan MN. Effectiveness of oral antibiotics for definitive therapy of gram-negative bloodstream infections. Int J Antimicrob Agents. 2016;48(5):498-503. https://doi.org/10.1016/j.ijantimicag.2016.07.013