Oral Step-Down Therapy for Uncomplicated Streptococcal Bloodstream Infections: β-Lactams or Fluoroquinolones?

Highlighted study: Arensman K, Shields M, Beganovic M, Miller JL, LaChance E, Anderson M, et al. Fluoroquinolone versus beta-lactam oral step-down therapy for uncomplicated streptococcal bloodstream infections. Antimicrob Agents Chemother. 2020;64(11)

Bacterial bloodstream infection (BSI) remains a common source of morbidity and mortality in the United States, accounting for approximately 500,000 to 600,000 cases and 70,000 to 80,000 deaths per year.¹ Streptococci rank in the top 10 bacterial pathogens causing BSI, and the ideal treatment for streptococcal BSI remains an important clinical question.²

Traditionally, BSIs are treated with parenteral (intravenous [IV]) antibiotics to achieve the fastest and most reliable therapeutic levels. For decades, the natural clinical course of uncomplicated BSI has generally started with empiric antimicrobial treatment until the pathogen is identified, the targeted narrowing of antimicrobials, then a prolonged hospital stay or outpatient parenteral antibiotic therapy course with medications typically administered via a peripherally inserted central catheter. However, this treatment modality is accompanied by an increased risk of nosocomial infections, procedural complications, and thrombosis, and a higher cost of care. Therefore, there has been a recent trend toward exploring oral (PO) antibiotics after the patient has reached a clinically stable state, so-called oral step-down therapy.^3,4

A growing body of literature supports the efficacy and safety of this simplified approach in appropriately chosen patients. An 8-year multicenter cohort study in Taiwan looked at an early switch from IV to PO antibiotics in community-onset, uncomplicated BSI in noncritically ill patients. The results indicated no significant difference in 30-day clinical failure rates between a short IV course with switch to PO antibiotics compared with IV antibiotics alone.⁵ Data from the POET trial (NCT01375257)suggested that patients with stabilized infective endocarditis fared no worse with oral-step down therapy than patients who completed a full parenteral course.⁶ Other studies have examined the efficacy of oral step-down therapy in other specific settings, such as a randomized study comparing PO versus IV ciprofloxacin to treat bacteremic pyelonephritis or complicated urinary tract infections, generally showing noninferiority with oral therapy.^7-9

A few studies have assessed oral step-down therapy specifically in streptococcal BSI, though mostly in the context of bacteremic pneumococcal pneumonia.^10,11 Investigators in 1 study found no significant difference between early oral step-down versus continued IV therapy among 36 patients with clinically stable bacteremic pneumococcal pneumonia, though the study was underpowered.¹⁰ In another, the authors found no significant difference in clinical failures between nonstaphylococcal gram-positive BSI (of which 75% were streptococci) in patients treated with oral step-down therapy with low versus high bioavailability oral antibiotics; however, this study was also underpowered.¹¹ Although it is premature to say that all BSIs should be treated with oral step-down therapy, increasing literature supports its use in selected patients and clinical scenarios. But more research is needed to elucidate when, precisely, clinicians should offer the therapy.

Arensman et al have helped clarify what to do in treating patients with streptococcal BSI.¹² They conducted a retrospective, multicenter cohort study between January 2014 and June 2019 assessing outcome differences between patients who received oral step-down therapy with either a fluoroquinolone (FQ) or β-lactam (BL) antibiotic. The primary outcome was clinical success, defined as lack of all-cause mortality, recurrent BSI, or infection-related readmission within 90 days. Secondary outcomes included incidence of 90-day Clostridioides difficile infection or an antibiotic-related adverse effect within 30 days.

The investigators conducted the study at 7 sites in Chicago, Illinois. Eligible patients were 18 years or older and had at least 1 blood culture positive for Streptococcus species during the study period, with completion of treatment with oral step-down to an FQ or BL antibiotic. Exclusion criteria included polymicrobial blood cultures, BSI complicated by endocarditis or central nervous system infection, or transition to hospice before completion of BSI therapy.

220 patients of similar demographics participated in the study, with 87 (40%) receiving an FQ and 133 (60%) a BL for step-down therapy. The most common Streptococcus species was Streptococcus pneumoniae (34.1%) followed by Streptococcus pyogenes (17.3%) and Streptococcus agalactiae (16.4%). Patients in the FQ group were most likely to have a respiratory infection (62%), whereas patients in the BL group were most likely to have a skin and soft tissue infection (45%). The most common antibiotic regimens included amoxicillin-clavulanate potassium 875 mg/125 mg every 12 hours (22.3%), moxifloxacin 400 mg every 24 hours (16.4%), and levofloxacin 750 mg every 24 hours (12.7%). The median duration of total antimicrobial treatment was 14 (interquartile range, 13-16) days.

One hundred twenty-two (92.0%) patients of the FQ group and 81(93.2%) of the BL group achieved the primary outcome, with no statistically significant difference (90% CI, -5.2 to 7.8). There was also no statistically significant difference in the secondary outcomes. In a regression analysis, the authors identified that starting oral step-down therapy earlier than day 3 (OR, 5.18; 95% CI, 1.21-22.16) and low-dose oral antibiotics (OR, 2.74; 95% CI, 0.95-7.90) were factors predicting clinical failure (though the latter was not statistically significant).

This is one of the first adequately powered studies to dive into the relative efficacies of oral step-down therapy of FQs and BLs for streptococcal BSI, ultimately showing that no significant difference exists between them. The study results also demonstrated the importance of the initial IV treatment phase, as IV to PO transition earlier than 3 days correlated with clinical failure. This important study gives clinicians treating uncomplicated streptococcal BSI confidence that higher-dose oral BLs, which are generally thought to have fewer adverse effects than FQs, are a safe and efficacious option. Further prospective, randomized trials are needed to solidify the precise role of oral step-down therapy for BSI. Given the risks of complications, cost, and inconvenience of parenteral antibiotic treatment, steps toward a safe transition to oral regimens are welcomed by clinicians and patients alike.

Yu Ting He, MD, is an internal medicine resident at the University of Vermont Medical Center in Burlington.

Andrew J. Hale, MD, is an infectious diseases physician at the University of Vermont Medical Center and an assistant professor of medicine at the University of Vermont Larner College of Medicine in Burlington.

References

1. ^{Goto M, Al-Hasan MN. Overall burden of bloodstream infection and nosocomial bloodstream infection in North America and Europe. Clin Microbiol Infect. 2013;19(6):501-509. doi:10.1111/1469-0691.12195}
2. ^{Diekema DJ, Hsueh PR, Mendes RE, et al. The microbiology of bloodstream infection: 20-year trends from the SENTRY Antimicrobial Surveillance Program. Antimicrob Agents Chemother. 2019;63(7):e00355-19. doi:10.1128/AAC.00355-19}
3. ^{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. doi:10.12788/jhm.2949}
4. ^{Hospenthal DR, Waters CD, Beekmann SE, Polgreen PM. Practice patterns of infectious diseases physicians in transitioning from intravenous to oral therapy in patients with bacteremia. Open Forum Infect Dis. 2019;7(12):ofz386. doi:10.1093/ofid/ofz386}
5. ^{Lee CC, Chen PL, Hsieh CC, Yang CY, Lin CH, Ko WC. Is early oral antimicrobial switch useful for less critically ill adults with community-onset bacteraemia in emergency departments? Antibiotics (Basel). 2020;9(11):807. doi:10.3390/antibiotics9110807}
6. ^{Iversen K, Ihlemann N, Gill SU, et al. Partial oral versus intravenous antibiotic treatment of endocarditis. N Engl J Med. 2019;380(5):415-424. doi:10.1056/NEJMoa1808312}
7. ^{Tamma PD, Conley AT, Cosgrove SE, et al; 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;179(3):316-323. doi:10.1001/jamainternmed.2018.6226}
8. ^{Mercuro NJ, Stogsdill P, Wungwattana M. Retrospective analysis comparing oral stepdown therapy for enterobacteriaceae bloodstream infections: fluoroquinolones versus β-lactams. Int J Antimicrob Agents. 2018;51(5):687-692. doi:10.1016/j.ijantimicag.2017.12.007}
9. ^{Mombelli G, Pezzoli R, Pinoja-Lutz G, Monotti R, Marone C, Franciolli M. Oral vs intravenous ciprofloxacin in the initial empirical management of severe pyelonephritis or complicated urinary tract infections: a prospective randomized clinical trial. Arch Intern Med. 1999;159(1):53-58. doi:10.1001/archinte.159.1.53}
10. ^{Ramirez JA, Bordon J. Early switch from intravenous to oral antibiotics in hospitalized patients with bacteremic community-acquired Streptococcus pneumoniae pneumonia. Arch Intern Med. 2001;161(6):848-850. doi:10.1001/archinte.161.6.848}
11. ^{Quinn NJ, Sebaaly JC, Patel BA, Weinrib DA, Anderson WE, Roshdy DG. Effectiveness of oral antibiotics for definitive therapy of non-Staphylococcal Gram-positive bacterial bloodstream infections. Ther Adv Infect Dis. 2019;6:2049936119863013. doi:10.1177/2049936119863013}
12. ^{Arensman K, Shields M, Beganovic M, et al. Fluoroquinolone versus beta-lactam oral step-down therapy for uncomplicated streptococcal bloodstream infections. Antimicrob Agents Chemother. 2020;64(11):e01515-20. doi:10.1128/AAC.01515-20}