By Jake Scott, MD
Clinical Assistant Professor, Infectious Diseases and Geographic Medicine, Stanford University School of Medicine; Antimicrobial Stewardship Program Medical Director, Stanford Health Care Tri-Valley
SYNOPSIS: In a retrospective observational study, transitioning to oral antibiotics was demonstrated to be as effective and safer in solid organ transplant recipients with uncomplicated gram-negative bacteremia as compared with completion of therapy with intravenous antibiotics.
SOURCE: 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;79:208-214.
Nussbaum and colleagues performed a retrospective analysis of solid organ transplant recipients (SOTR) treated for uncomplicated gram-negative bloodstream infection (GNBI) with intravenous (IV) and oral antibiotics who were hospitalized in the Massachusetts General Hospital and Brigham and Woman’s Hospital system between January 2016 and December 2021.1 Uncomplicated GNBI was defined as bacteremia in patients with adequate source control and without complications such as endovascular disease or osteomyelitis. Patients were excluded if the organism isolated from blood cultures was not susceptible to an acceptably bioavailable oral agent, which included fluoroquinolones, trimethoprim-sulfamethoxazole, and metronidazole, as well as certain beta-lactam antibiotics (cefuroxime, cefpodoxime, and amoxicillin-clavulanic acid).
Primary outcomes were mortality, recurrent bacteremia, and reinitiation of IV antibiotics for the same pathogen within 30 days of completion of therapy. Secondary outcomes included the occurrence of Clostridioides difficile colitis within 30 days of completion of therapy, other antimicrobial-related adverse events, hospital length of stay, the need for new central IV access to administer therapy, and the need for tunneled catheter placement. To account for potential selection bias, the investigators generated inverse probability of treatment-weighted models, using propensity scores incorporating various clinical factors.
Study investigators identified 162 bacteremia events in 147 patients who met inclusion criteria; 120 bacteremia events were identified in 107 patients who had been transitioned from IV to oral therapy and 42 events were identified in 40 patients treated with IV therapy only. The median ages in the IV and oral groups were 64.5 years (interquartile range [IQR], 56-70) and 62 years (IQR, 54-70), respectively. The majority of patients in both groups had received kidney transplants (69% in the IV group and 70% in the oral group). Four patients in the oral group (10%) and 13 in the IV only group (11%) had received liver transplants, two patients in the oral group (5%) and seven patients in the IV group (6%) had received lung transplants, three patients in the oral group (7%) and seven patients in the IV group (6%) had received heart transplants, one patient in the IV group (1%) had received a bowel transplant, and four patients in the oral group (10%) and eight patients in the IV group (7%) had received a combined organ type transplant. A total of 36 patients (28 in the oral group and eight in the IV group) with GNBI had received induction immunosuppressive regimens within six months of transplantation. Induction and maintenance immunosuppressive regimens that patients had received were similar between groups. One-third of patients transitioned to oral therapy within one year of transplantation, 30% were within six months, and 15% were within the first three months.
Most bloodstream infections were caused by Escherichia coli (40% in the oral group and 62% in the IV only group), followed by Klebsiella pneumoniae (26% in the oral group and 17% in the IV group). A variety of aerobic and anaerobic gram-negative bacteria made up the rest of the pathogens isolated. The most common source of bacteremia was the urinary tract in both groups (59% in the oral group and 79% in the IV only group). Fluoroquinolones made up the vast majority of oral agents used and were given to 102 patients (86%). Amoxicillin-clavulanic acid was used in six patients (5%), trimethoprim-sulfamethoxazole was used in five patients (4%), cefpodoxime was used in two patients (2%), cefuroxime was used in one patient (1%), metronidazole was used in one patient (1%), and azithromycin was used in one patient (1%).
The median duration of IV therapy prior to transitioning to oral therapy was four days (range, 1-15). Of note, 13 patients (10.8%) who were transitioned to oral antibiotics received more than seven days of IV antibiotics. The median duration of oral antibiotic therapy was 11 days (range, 3-30) and the median duration of combined IV and oral therapy was 15 days (range, 7-36). The median duration of therapy in the IV only group was 16 days (range, 12-28). The difference in median duration of therapy was not statistically significant. However, the median length of hospital stay was significantly shorter in the patients who had been transitioned to oral antibiotics; median length of stay was five days (range, 3-16) in the oral group compared to seven days (range, 4-18) in the IV only group (odds ratio [OR], 1.97 days; 95% confidence interval [CI], 0.4 to 3.6; P = 0.005).
No deaths occurred within 30 days of completion of therapy in either group. Bacteremia recurred in two patients (1.7%) in the oral group and in two patients (4.7%) in the IV only group (OR, 3.1; 95% CI, 0.4 to 23.1; P = 0.27). Both patients who had recurrent bacteremia in the oral therapy group had been transitioned to oral ciprofloxacin and had received lengthy courses of therapy; it was hypothesized that one of the recurrences may have related to seeding of bilateral deep venous thrombi. One of the patients with recurrent bacteremia after oral therapy had previously had recurrent bacteremia after 15 days of IV meropenem for Pseudomonas GNBI. The other individual with recurrent bacteremia after IV therapy was a heart transplant recipient who had recurrent Salmonella bacteremia after 14 days of IV ceftriaxone. There were no significant differences between the groups in the reinitiation of IV antibiotic therapy.
Two patients in the oral group (2%) and five patients in the IV group (12%) developed C. difficile colitis (OR, 8.4; 95% CI, 1.5 to 46.5; P = 0.15). The two patients who developed C. difficile colitis after being transitioned to oral therapy had received fluoroquinolones. Three patients in the oral group (3%) and four patients in the IV group (10%) developed other antibiotic-related adverse events (OR, 6.4; 95% CI, 1.9 to 20.9; P = 0.002). All three patients in the oral group who experienced treatment-related adverse events had received fluoroquinolones (one developed myoclonic jerks and two reported Achilles’ tendon pain).
Of the four patients who experienced adverse events in the IV only group, two patients developed coagulase-negative Staphylococcus catheter-associated bacteremia that required additional therapy, one patient developed a catheter-associated deep vein thrombosis, and one patient developed cefepime-induced neurotoxicity. Thirty-four patients in the IV group (81%) required placement of a new central venous catheter and 23 patients (55%) received a new tunneled catheter to receive antibiotic therapy.
In summary, this retrospective observational study showed that transitioning to oral antimicrobial therapy for the treatment of GNBI in SOTRs was safe and effective as compared with continued IV therapy and was associated with fewer treatment-related adverse events and shorter hospitalizations.
COMMENTARY
This was a retrospective observational study inherently susceptible to confounding, particularly due to selection bias. However, patients who had been transitioned to oral therapy had higher median admission Pitt bacteremia scores (0.92 vs. 0.74) and higher Charlson Comorbidity Index scores (6 vs. 5.5), indicating that these patients may not have been less clinically stable than those who were continued on IV therapy alone. The study included a relatively small population, and a fairly significant portion of those who were transitioned to oral therapy already had received more than seven days of IV therapy, which may have been sufficient. Lastly, the study primarily included kidney transplant recipients with GNBI attributed to the urinary tract, which potentially limits generalizability.
Although clinicians may remain reluctant to treat bacteremic patients with oral antibiotics, multiple studies previously have shown that oral transitional antibiotic therapy can be as effective and even safer than continued IV therapy for patients with GNBI, at least for those who are considered to be immunocompetent. Four randomized controlled trials (RCTs) that included a total of 291 patients evaluated the safety and efficacy of oral vs. IV antibiotics for patients with GNBI.2-5 In the first study, by Amodio-Groton and colleagues, 50 hospitalized patients with GNBI were randomized to receive either oral ciprofloxacin after an initial 72-hour IV antibiotic regimen or to continue IV therapy alone.3 Both regimens were found to be equally effective and safe, and patients in the oral transitional antibiotic group had significantly shorter hospital lengths of stay associated with marked cost savings compared to the IV only group.
Monmaturapoj and colleagues conducted a prospective RCT that compared the clinical and microbiological effectiveness of IV ceftriaxone alone vs. three days of IV ceftriaxone followed by oral cefditoren pivoxil for the treatment of 81 patients with acute pyelonephritis and found no significant differences.2 In an RCT by Park and colleagues, an early switch to oral antibiotic therapy after adequate biliary drainage for patients with acute cholangitis and bacteremia was shown to be noninferior to 10 days of IV therapy in terms of microbiologic cure, recurrence of cholangitis, and 30-day mortality.4 Most recently, a multicenter, open-label, randomized trial conducted by Omrani and colleagues showed that transitioning to oral antibiotic therapy in patients with Enterobacterales bacteremia was noninferior to continued IV therapy.5 Many retrospective studies have shown similar findings.6-8
Since most data are based on the use of the highly bioavailable fluoroquinolones or trimethoprim-sulfamethoxazole, it is less clear whether beta-lactam antibiotics, which are less highly bioavailable, are as effective for the treatment of GNBI. In a systematic review conducted by Punjabi and colleagues, data from eight retrospective studies that reported data on all-cause mortality and/or infection recurrence in patients transitioned to oral antibiotics for GNBI were analyzed.9 Of the 2,289 patients included in the studies, 27% had been transitioned to oral beta-lactam antibiotics. Although there were no significant differences in all-cause mortality, overall rates of infection recurrence were higher among patients transitioned to oral beta-lactams compared to fluoroquinolones (OR, 2.05; 95% CI, 1.17 to 3.61). However, as the authors noted, the dosing of the beta-lactam regimens may have been inadequate.
In conclusion, this was a noteworthy study in that it included highly immunosuppressed patients, and it provides important data for this population that generally is excluded from clinical investigations. RCTs are needed in the future to provide more high-quality data to guide the optimal treatment strategy for immunocompromised patients with GNBIs, which is an important and relatively common issue.
REFERENCES
- 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;79:208-214.
- Monmaturapoj T, Montakantikul P, Mootsikapun P, Tragulpiankit P. A prospective, randomized, double dummy, placebo-controlled trial of oral cefditoren pivoxil 400 mg once daily as switch therapy after intravenous ceftriaxone in the treatment of acute pyelonephritis. Int J Infect Dis 2012;16:e843-e849.
- Amodio-Groton M, Madu A, Madu CN, et al. Sequential parenteral and oral ciprofloxacin regimen versus parenteral therapy for bacteremia: A pharmacoeconomic analysis. Ann Pharmacother 1996;30:596-602.
- Park TY, Choi JS, Song TJ, et al. Early oral antibiotic switch compared with conventional intravenous antibiotic therapy for acute cholangitis with bacteremia. Dig Dis Sci 2014;59:2790-2796.
- 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;30:492-498.
- 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;179:316-323.
- Rieger KL, Bosso JA, MacVane SH, et al. Intravenous-only or intravenous transitioned to oral antimicrobials for Enterobacteriaceae-associated bacteremic urinary tract infection. Pharmacotherapy 2017;37:1479-1483.
- Sutton JD, Stevens VW, Chang NCN, 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:e2020166.
- 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 2019;6:ofz364.
In a retrospective observational study, transitioning to oral antibiotics was demonstrated to be as effective and safer in solid organ transplant recipients with uncomplicated gram-negative bacteremia as compared with completion of therapy with intravenous antibiotics.
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