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What literature is available on oral beta-lactam therapy for gram-negative bacteremia?

Introduction

The current management of gram-negative bacteremia is highly variable with regard to oral step-down therapy,1,2 although available guidance generally recommends a transition to oral antibiotic therapy when possible.3,4 Patients with gram-negative bacteremia traditionally received intravenous (IV) antibiotic therapy for the full treatment duration, although recent practice changes suggest approximately 40% of patients with bacteremia are now being transitioned to oral therapy.5,6 The transition from IV to oral therapy has been associated with reduced hospital stays, lower healthcare costs, quality of life improvements, and reduced risks associated with IV catheters.7 Treatment options for oral step-down therapy may include fluoroquinolones (FQ), trimethoprim-sulfamethoxazole (TMP-SMX), or beta-lactams,5 although concerns have been raised about the bioavailability of certain oral beta-lactam agents.5,8,9 Because of these concerns, Delphi consensus guidance has recommended exerting caution with oral beta-lactams for bacteremia, and recommend oral beta-lactams only in clinical scenarios where pharmacokinetic and pharmacodynamic target attainment are high.3 The recommended dosing of oral agents for bacteremia due to Enterobacterales based on Delphi consensus guidance along with pharmacokinetic and pharmacodynamic factors are described in the Table. Agents that cannot be routinely recommended that are not included in the table are cefadroxil, cefpodoxime, and cefdinir.

Table. Delphi Consensus Dosing Recommendations for Management of Uncomplicated Gram-Negative Bacteremia3,10
DrugBioavailabilityPK/PD TargetSuggested DosingaCLSI Breakpoint for EnterobacteralesTarget Attainment
Ciprofloxacin70%fAUC24/MIC ≥ 72750 mg orally every 12 hours≤0.25High likelihood of attainment for MIC values up to 0.25 mcg/mL
Levofloxacin99%fAUC24/MIC ≥ 72750 mg orally every 24 hours≤0.5High likelihood of attainment for MIC values up to 0.5 mcg/mL
TMP-SMXNear 100%Not well characterized; possibly AUC/MIC and fT >MIC5 mg/kg orally every 12 hoursb≤2/38Not well characterized, regardless of route
Amoxicillin70 to 80%40% fT > MIC1000 mg orally every 8 hours≤8High likelihood of attainment for MIC values up to 2 mcg/mL
Amoxicillin/clavulanate70 to 80% (based on amoxicillin component)40% fT > MIC875 to 1000 mg orally every 8 hours≤8/4High likelihood of attainment for MIC values up to 2 mcg/mL
Cephalexin95%60% fT > MIC1000 mg orally every 6 hoursN/AcHigh likelihood of attainment for MIC values up to 2 mcg/mL
Abbreviations: AUC=area under the curve; CLSI=Clinical and Laboratory Standards Institute; fAUC=free area under the curve; fT=free drug concentration; MIC=minimum inhibitory concentration; N/A=not available; PK/PD=pharmacokinetic/pharmacodynamic; TMP-SMX=trimethoprim-sulfamethoxazole
aAssuming normal renal function
bApproximately 2 double-strength tablets every 12 hours for a 70 kg patient
c≤16 cefazolin surrogate test for uncomplicated cystitis; cannot apply to systemic infections

Literature Review

A 2019 meta-analysis of 8 observational studies by Punjabi and colleagues found that oral step down therapy for gram-negative bacteremia with an oral beta-lactam versus FQ or TMP-SMX had no effects on all-cause mortality, although oral beta lactams were associated with a greater infection recurrence versus FQ therapy (odds ratio [OR], 2.05; 95% confidence interval [CI], 1.17 to 3.61).11 This finding was not replicated in the comparison between beta-lactams and TMP-SMX (OR, 0.96; 95% CI, 0.30 to 3.06); however, this analysis was limited by the small number of patients who received TMP-SMX. The authors noted that sub-optimal dosing of beta-lactams used in several studies likely contributed to the finding of greater infection recurrence.

Since the 2019 meta-analysis, numerous observational studies, and 1 randomized controlled trial (RCT) have been published on oral beta-lactams for step-down therapy.7,8,12-23,25 Although a second RCT recently evaluated step-down therapy from an antipseudomonal beta-lactam to a non-antipseudomonal agent, the study did not investigate outcomes for the subgroup of patients descalated to oral therapy only.13 In the open-label RCT conducted by Omrani and colleagues, the noninferiority of oral step-down therapy after 3 to 5 days of parenteral treatment was assessed versus the continuation of IV therapy.12 The most common source of infection was the urinary tract (60%), and the most common pathogens were Escherichia coli (67%) and Klebsiella species (24%). Following randomization, the most common oral agents were cephalosporins and beta-lactam/beta-lactamase inhibitor combinations (e.g., amoxicillin/clavulanate), and the most common parenteral agents were cephalosporins and carbapenems. The median duration of treatment was 12 days (interquartile range: 10 to 15). The primary outcome of treatment failure within 90 days was the composite of: death from any cause, need for additional antibiotic therapy, microbiological relapse, or infection-related readmission in the modified intent-to-treat (mITT) population, which occurred in 25.6% of 82 patients receiving IV therapy, and 21.7% of 83 patients receiving oral therapy (absolute risk difference, -3.7%; 95% CI, -16.6% to 9.2%). Based on a noninferiority margin of 10%, the transition to oral therapy was determined to be noninferior to the continuation of IV therapy in clinically stable patients with adequate source control.

Observational studies that address the comparative efficacy between oral beta-lactam, FQ, and TMP-SMX therapy in gram-negative bacteremia have yielded mixed findings.7,8,14-23 Across the included studies, bacteremia primarily originated from a urinary source and E. Coli was the predominant gram-negative organism. Two studies found that patients receiving a FQ, TMP-SMX, or a high-bioavailability beta-lactam agent (e.g., amoxillicin, amoxicillin/clavulanate, cephalexin) had an increased risk of infection recurrence with beta-lactams, although suboptimal beta-lactam dosing was used in both studies.14,15 Another study by Mponponsuo and colleagues in older adults (>66 years of age), found that patients who received FQ or TMP-SMX at discharge had reduced rates of the composite outcome (adjusted OR, 0.76; 95% CI, 0.60 to 0.93) compared to beta-lactam therapy, which consisted of mortality, recurrent bacteremia, or all-cause readmission within 90 days.16 Of note, patients receiving FQ or TMP-SMX had a mean total treatment duration of 8.1 ± 4.4 days, while patients receiving beta-lactam therapy were treated for an average duration of 7 ± 4.3 days.

In contrast, other observational studies have shown no differences in treatment outcomes with beta-lactam therapy, with varying durations of follow-up.7,8,17-23 In a study conducted by Mack and colleagues, no difference was shown between oral agents for hospital readmission or recurrent bacteremia after 48 hours of parenteral treatment, although oral beta-lactam therapy was associated with a greater risk of repeat hospital admission with recurrent urinary tract infection (UTI) versus FQ or TMP-SMX (5% versus 0%; p=0.037).19 Of the patients readmitted with bacteremia or UTI, the authors noted that 25% of bacteremia readmissions and 33% of recurrent UTI were associated with cefdinir use, which has lower urinary penetration than other beta-lactam agents. Three observational studies have shown no increase in the risk of recurrent bacteremia or mortality at 30 days with oral beta-lactam therapy.20-22 In a study conducted by Saad and colleagues that compared oral beta-lactams to oral FQ, no difference was also shown in rates of clinical cure at 30 days.21 In a study by Bjork and colleagues, comparable rates of treatment failure, bacteremia recurrence, and all cause mortality at 90 days were observed with oral beta-lactam therapy versus FQs.8 In a study by Tingsgård and colleagues that evaluated an early switch to oral antibiotics in clinically stable patients within 4 days of the blood culture, 90-day all-cause mortality was similar between those who switched to oral antibiotics compared to those who continued treatment (risk ratio, 0.78; 95% CI, 0.60 to 1.10).7 Oral beta-lactam therapy was prescribed to the majority of patients (63.1%), followed by oral ciprofloxacin (16.6%). Compared to patients who received extended IV treatment, patients who received oral antibiotic therapy were more likely to have a urinary tract source of infection.

In the first study of patients with low-risk occult bacteremia initiated with oral beta-lactam therapy on an outpatient basis, outcomes were similar to other febrile patients with bacteremia managed on an outpatient basis.24 Additionally, a retrospective study of solid organ transplant recipients found the continuation of IV therapy versus switching to oral therapy in uncomplicated gram negative bacteremia resulted in no differences in mortality, bacteremia recurrence, or reinitiation of IV antibiotics at 30 days.25

Conclusion

The current literature has yielded mixed findings with regard to oral beta-lactams as step-down therapy in patients with uncomplicated gram-negative infection, although studies with negative outcomes often used suboptimal dosing. The majority of patients in these studies developed bacteremia from a urinary tract source, which may limit the generalizability of study findings. According to Delphi consensus guidance, use of the oral beta-lactams amoxicillin, amoxicillin/clavulanate, and cephalexin at recommended doses for uncomplicated gram negative bacteremia due to Enterobacterales provides a high likelihood of attaining minimum inhibitory concentration (MIC) values up to 2 mcg/mL. The use of these antibiotic agents for step-down therapy should be considered on a case-by-case basis, and must also take into account the organism, microbiological susceptibilities, source control, and pharmacokinetics/pharmacodynamics of the antibiotic, among other patient factors.

References

  1. Thaden JT, Tamma PD, Doi Y, et al; Antibacterial Resistance Leadership Group (ARLG). Variability in oral antibiotic step-down therapy in the management of Gram-negative bloodstream infections. Int J Antimicrob Agents. 2021;58(6):106451. doi:10.1016/j.ijantimicag.2021.106451
  2. Thaden JT, Tamma PD, Pan Q, et al. Survey of infectious diseases providers reveals variability in duration of antibiotic therapy for the treatment of Gram-negative bloodstream infections. JAC Antimicrob Resist. 2022;4(1):dlac005. doi:10.1093/jacamr/dlac005
  3. Heil EL, Bork JT, Abbo LM, et al. Optimizing the management of uncomplicated gram-negative bloodstream infections: Consensus guidance using a modified delphi process. Open Forum Infect Dis. 2021;8(10):ofab434. doi:10.1093/ofid/ofab434
  4. Pranita D. Tamma, Emily L. Heil, et al, Infectious Diseases Society of America Antimicrobial-Resistant Treatment Guidance: Gram-Negative Bacterial Infections. Infectious Diseases Society of America 2024; Version 4.0. Available at https://www.idsociety.org/practice-guideline/amr-guidance/. Accessed July 19, 2024.
  5. Tamma PD, Cosgrove SE. Which trial do we need? Early oral antibiotic therapy for the treatment of gram-negative bloodstream infections. Clin Microbiol Infect. 2023;29(6):670-672. doi:10.1016/j.cmi.2023.02.012
  6. 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. doi:10.1001/jamanetworkopen.2023.49864
  7. Tingsgård S, Bastrup Israelsen S, Jørgensen HL, et al. 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
  8. Bjork L, Hopkins T, Yang L, et al. Comparative-effectiveness of oral beta-lactams and fluoroquinolones for stepdown therapy in patients with Enterobacterales bloodstream infections: A retrospective cohort study. Int J Med Sci. 2023;20(4):437-443. doi:10.7150/ijms.80621
  9. Kutob LF, Justo JA, Bookstaver PB, et al. Effectiveness of oral antibiotics for definitive therapy of Gram-negative bloodstream infections. Int J Antimicrob Agents. 2016;48(5):498-503. doi:10.1016/j.ijantimicag.2016.07.013
  10. Berry AV, Kuti JL. Pharmacodynamic thresholds for beta-lactam antibiotics: a story of mouse versus man. Front Pharmacol. 2022;13:833189. doi:10.3389/fphar.2022.833189
  11. Punjabi C, Tien V, Meng L, et al. Oral fluoroquinolone or trimethoprim-sulfamethoxazole vs. ß-lactams as step-down therapy for Enterobacteriaceae bacteremia: systematic review and meta-analysis. Open Forum Infect Dis. doi:10.1093/ofid/ofz364
  12. Omrani AS, Abujarir SH, Ben Abid F, et al. Switch to oral antibiotics in Gram-negative bacteraemia: a randomized, open-label, clinical trial. Clin Microbiol Infect. 2024;30(4):492-498. doi:10.1016/j.cmi.2023.10.014.
  13. López-Cortés LE, Delgado-Valverde M, Moreno-Mellado E, et al. Efficacy and safety of a structured de-escalation from antipseudomonal β-lactams in bloodstream infections due to Enterobacterales (SIMPLIFY): an open-label, multicentre, randomised trial. Lancet Infect Dis. 2024;24(4):375-385. doi:10.1016/S1473-3099(23)00686-2.
  14. Veillette JJ, May SS, Alzaidi S, et al. Real-world effectiveness of intravenous and oral antibiotic stepdown strategies for gram-negative complicated urinary tract infection with bacteremia. Open Forum Infect Dis. 2024;11(4):ofae193. doi:10.1093/ofid/ofae193
  15. Alzaidi S, Veillette JJ, May SS, et al. Oral β-Lactams, fluoroquinolones, or trimethoprim-sulfamethoxazole for definitive treatment of uncomplicated Escherichia coli or Klebsiella species bacteremia from a urinary tract source. Open Forum Infect Dis. 2023;11(2):ofad657. doi:10.1093/ofid/ofad657
  16. Mponponsuo K, Brown KA, Fridman DJ, et al. Highly versus less bioavailable oral antibiotics in the treatment of gram-negative bloodstream infections: a propensity-matched cohort analysis. Clin Microbiol Infect. 2023;29(4):490-497. doi:10.1016/j.cmi.2022.10.004
  17. McAlister MJ, Rose DT, Hudson FP, et al. Oral β-lactams vs fluoroquinolones and trimethoprim/sulfamethoxazole for step-down therapy for Escherichia coli, Proteus mirabilis, and Klebsiella pneumoniae bacteremia. Am J Health Syst Pharm. 2023;80(Suppl 1):S33-S41. doi:10.1093/ajhp/zxac202
  18. Nisly SA, McClain DL, Fillius AG, et al. 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. doi:10.1016/j.jgar.2019.07.026
  19. Mack T, Hiles JJ, Wrin J, et al. Use of fluoroquinolones or sulfamethoxazole-trimethoprim compared to Β-Lactams for oral step-down therapy in hospitalized patients with uncomplicated Enterobacterales bacteremia. Ann Pharmacother. 2023;57(3):251-258. doi:10.1177/10600280221106789
  20. Sutton JD, Stevens VW, Chang NN, et al. Oral β-Lactam antibiotics vs fluoroquinolones or trimethoprim-sulfamethoxazole for definitive treatment of Enterobacterales bacteremia from a urine source. JAMA Netw Open. 2020;3(10):e2020166. doi:10.1001/jamanetworkopen.2020.20166
  21. Geyer AC, VanLangen KM, Jameson AP, et al. Outcomes of high-dose oral beta-lactam definitive therapy compared to fluoroquinolone or trimethoprim-sulfamethoxazole oral therapy for bacteremia secondary to a urinary tract infection. Antimicrob Steward Healthc Epidemiol. 2023;3(1):e148. doi:10.1017/ash.2023.435
  22. 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. JAMA Intern Med. 2019;179(3):316-323. doi:10.1001/jamainternmed.2018.6226
  23. Saad S, Mina N, Lee C, et al. Oral beta-lactam step down in bacteremic E. coli urinary tract infections. BMC Infect Dis. 2020;20(1):785. doi:10.1186/s12879-020-05498-2
  24. Casado A, Gimeno A, Aguilar-Guisado M, et al. Safety of early oral ambulatory treatment of adult patients with bloodstream infections discharged from the emergency department. Antimicrob Agents Chemother. 2023;67(11):e0078023. doi:10.1128/aac.00780-23
  25. Nussbaum EZ, Koo S, Kotton CN. Oral antibiotics for treatment of gram-negative bacteremia in solid organ transplant recipients: A propensity score weighted retrospective observational study. Clin Infect Dis. 2024;79(1):208-214. doi:10.1093/cid/ciae007

Prepared by:
Christie Denton, PharmD, BCPS
Clinical Assistant Professor, Drug Information Specialist
University of Illinois at Chicago College of Pharmacy

July 2024

The information presented is current as of July 17, 2024. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.