#PharmToExamTable: Oral Therapy for Gram-Negative Rod (GNR) Bacteremia: Can We Go PO?

The following post exploring a switch from IV to oral antibiotics for treatment of bacteremia was written by Molly Miller, PharmD, ID Pharmacist at Nebraska Medicine.

How do we usually treat bloodstream infections?

Standard management of bloodstream infections (BSIs) due to Gram-negative rods (GNRs) is empiric IV therapy with an active antimicrobial agent (typically a third or fourth generation cephalosporin, piperacillin-tazobactam, a fluoroquinolone, or a carbapenem) followed by eventual narrowing to definitive therapy based on culture results and susceptibilities. In addition to antibiotic therapy, perhaps the most important aspect of management is source control, which is accomplished by eliminating any nidus of infection (i.e., removing infected catheters/devices, draining abscesses or fluid collections). Treatment of GNR bacteremia is generally recommended for a duration of 7-14 days, but this can be extended for longer durations if the infection is complicated and source control is not achieved.

There has been recent interest in using oral therapy for many serious infections which were traditionally treated exclusively with IV therapy. Recent studies include the POET and OVIVA trials for endocarditis and bone and joint infections, respectively.^1,2 Current evidence shows that there are several potential benefits to using oral therapy over extended courses of IV therapy, including reduction in catheter-related complications such as infection and thrombosis, reduction in length of stay (LOS), improvement in patient satisfaction and comfort, and reduction in healthcare costs.^1-5

What specifically is the evidence for the use of oral antibiotics in this infection?

Though there have been no prospective, randomized, controlled trials published thus far regarding the use of oral therapy for GNR bacteremia (the SOAB trial is in progress), there is a growing body of observational data supporting this approach. In 2019, Tamma and colleagues published a multicenter, propensity-matched, retrospective cohort study comparing outcomes between adults with monomicrobial bacteremia due to Enterobacterales species who received oral step-down therapy versus continued IV therapy.³ Eligible patients had source control, clinical improvement on initial therapy, an active oral agent available to treat the causative organism, and the ability to take and absorb oral medication. Of the patients transitioned to oral therapy, most (84%) received a “highly bioavailable” antibiotic (fluoroquinolone or trimethoprim-sulfamethoxazole). The median time to oral switch was 3 days of IV therapy. There was no difference in all-cause mortality or recurrent bacteremia at 30 days between the oral and IV therapy groups; however, there was a shorter median time to discharge (5 days vs 7 days) in the oral step-down group.³ A number of smaller retrospective studies have shown similar results, with transition to oral therapy resulting in similar clinical outcomes with reductions in hospital LOS and IV line-associated complications.^4,5

In 2016, a retrospective study was published by Kutob and colleagues, which included patients with GNR BSI and compared outcomes between patients receiving high, moderate, and low bioavailability agents.⁶ This study found that high bioavailability oral agents were effective definitive therapy; however, a higher failure rate was observed in patients receiving a moderate to low bioavailability agent compared to a high bioavailability agent (12-14% vs 2%). This poses the question: which oral antibiotics are suitable for use as step-down therapy in GNR BSI? A recent meta-analysis compared outcomes of oral step down to fluoroquinolones (FQs) or trimethoprim-sulfamethoxazole (TMP-SMX) versus oral beta-lactams (OBLs) for Enterobacterales BSI.⁷ This meta-analysis pooled a population of 2,289 patients, of whom 65% received FQs, 7.7% received TMP-SMX, and 27.2% received OBL therapy. Across the studies, patients were transitioned to oral therapy after a median of 3-5 days of IV therapy. There was no difference in mortality noted between groups receiving FQ or TMP-SMX compared to OBL (5.1% vs 3.5%, p = 0.63); however, patients receiving OBLs had a 2x higher odds of recurrent infection versus FQs. An important thing to note, however, is that bioavailability is only part of the equation, and other pharmacokinetic and pharmacodynamic (PK/PD) principles are important to consider when dosing oral antibiotics to treat serious infections. One specific concern the authors of this meta-analysis had was that 30-50% of patients in the included studies received suboptimal doses of OBLs. Another concern is that OBLs require every 6-8 hour dosing to attain target levels compared to every 12-24 hour dosing for TMP-SMX or FQs, which may introduce adherence issues and therefore increase the risk of treatment failure as well.

Though FQs and TMP-SMX have benefits compared to OBLs for the reasons discussed above, note that these therapies have significant toxicities, and it is important to consider drug- and patient-specific factors when choosing an oral antibiotic. FQs have many boxed warnings for serious adverse events, including tendon rupture, aortic aneurysm rupture, central nervous system effects, QT prolongation, dysglycemias, and increased risk of C. difficileinfection. TMP-SMX may cause blood dyscrasias, severe dermatologic reactions, hyperkalemia, and increased serum creatinine, and it also carries some drug-drug interactions, particularly with warfarin and other agents causing increased serum potassium. In comparison, OBLs are fairly well-tolerated, with rash and gastrointestinal side effects being most common. As always, patient co-morbidities, allergies/intolerances, and drug-drug interactions should be taken into account when choosing appropriate therapy.

In summary…

Patients who have achieved effective source control and are clinically stable (including hemodynamically stable and afebrile) who are able to tolerate and absorb oral antibiotics with no contraindications can be considered for transition to oral therapy if there is assurance of good adherence and close monitoring and follow-up. Oral antibiotics with high bioavailability have the most supportive evidence for use in these circumstances. While most often this is a FQ or potentially TMP-SMX, there is emerging evidence that some OBLs may be acceptable if dosed appropriately. Other considerations include patient-specific factors (allergies, co-morbidities, and drug-drug interactions), antibiotic penetration to the site of infection, and antimicrobial susceptibility. By transitioning patients to oral therapy when possible, we can reduce the risk of IV line-related complications, reduce length of stay, and improve patient satisfaction and comfort.

References:

1. Iversen K, Ihlemann N, Gill SU, et al. Partial Oral versus Intravenous Antibiotic Treatment of Endocarditis. New Engl J Med. 2019;380(5):415-24.
2. Li H-K, Rombach I, Zambellas R, et al. Oral versus Intravenous Antibiotics for Bone and Joint Infection. New Engl J Med. 2019;380(5):425-36.
3. Tamma PD, Conley AT, Cosgrove SE, Harris AD, Lautenbach E, Amoah J, Avdic E, Tolomeo P, Wise J, Subudhi S, Han JH; Antibacterial Resistance Leadership Group. Association of 30-Day Mortality With Oral Step-Down vs Continued Intravenous Therapy in Patients Hospitalized With Enterobacteriaceae Bacteremia. JAMA Intern Med. 2019 Mar 1;179(3):316-323. doi: 10.1001/jamainternmed.2018.6226. Erratum in: JAMA Intern Med. 2019 Nov 1;179(11):1607. PMID: 30667477; PMCID: PMC6439703.
4. Rieger KL, Bosso JA, MacVane SH, Temple Z, Wahlquist A, Bohm N. Intravenous-only or intravenous transitioned to oral antimicrobials for Enterobacteriaceae-associated bacteremic urinary tract infection. Pharmacotherapy. 2017;37(11): 1479-1483. doi:10.1002/phar.2024
5. Thurber KM, Arnold JR, Narayanan PP, Dierkhising RA, Sampathkumar P. Comparison of intravenous and oral definitive antibiotic regimens in hospitalised patients with Gram-negative bacteraemia from a urinary tract infection. J Glob Antimicrob Resist. 2019 Sep;18:243-248. doi: 10.1016/j.jgar.2019.03.013. Epub 2019 Mar 26. PMID: 30926468.
6. 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.
7. Punjabi C, Tien V, Meng L, et al. Oral Fluoroquinolone or Trimethoprim-Sulfamethoxazole vs beta-lactams as step-down therapy for Enterobacteriaceae Bacteremia: Systematic Review and Meta-analysis. Open Forum Infect Dis. 2019; 6(10): ofz364.