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: Completion of therapy with oral antibiotics was shown to be non-inferior to continued intravenous therapy in patients considered to have low-risk Staphylococcus aureus bacteremia.
SOURCE: Kaasch AJ, López-Cortés LE, Rodríguez-Baño J, et al. Efficacy and safety of an early oral switch in low-risk Staphylococcus aureus bloodstream infection (SABATO): An international, open-label, parallel-group, randomised, controlled, non-inferiority trial. Lancet Infect Dis 2024; Jan 17:S1473-3099(23)00756-9. doi: 10.1016/S1473-3099(23)00756-9. [Online ahead of print].
Patients with uncomplicated, or low-risk, Staphylococcus aureus bacteremia (SAB) historically have been treated with 14 days of intravenous (IV) antibiotics.1,2 However, this practice has been based primarily on observational data and expert opinion rather than high-quality studies, which have been lacking. Kaasch and colleagues conducted the SABATO trial, which was an international, open-label, randomized, controlled non-inferiority trial that evaluated the efficacy and safety of an early switch to oral antibiotic therapy compared with standard IV antibiotic therapy in adult patients with low-risk SAB.3
The study was conducted at 31 tertiary care centers in four European countries (Germany, France, the Netherlands, and Spain). Patients were included in the study if they had been given appropriate IV antibiotic therapy within 72 hours after the first positive blood culture for S. aureus and if they had at least one negative follow-up blood culture obtained within 24-96 hours after the initiation of appropriate antibiotics. Patients were excluded if there were any signs or symptoms of complicated SAB prior to enrollment, which included a deep-seated focus (e.g., endocarditis, pneumonia, infected implant, undrained abscess, empyema, and osteomyelitis), septic shock within four days of randomization, prolonged bacteremia (defined as a positive blood culture obtained more than 72 hours after initiation of adequate antibiotic therapy), and a temperature greater than 38 degrees Celsius on two separate days within 48 hours before randomization.
Additional exclusion criteria included polymicrobial bloodstream infection, recent history (within three months) of SAB, the presence of non-removable foreign bodies (e.g., prosthetic heart valve, deep-seated vascular graft), the presence of an intravascular catheter when the first positive blood culture was drawn (if not removed within four days), severe immunosuppression, and injection drug use. Patients with prosthetic joints and pacemakers were eligible for the study, as long as the devices had been implanted more than six months before enrollment and if the source of infection was a removable intravascular catheter or a skin or soft-tissue infection.
All participants initially were treated with five to seven days of IV antibiotic therapy and were randomized in a 1:1 ratio to switch to oral therapy or to continue IV therapy for a total duration of 14 days. Oral regimens were selected based on susceptibility results and suspected allergy or intolerance in the following order: co-trimoxazole (160 mg trimethoprim plus 800 mg sulfamethoxazole every 12 hours) for methicillin-susceptible S. aureus (MSSA) and methicillin-resistant S. aureus (MRSA), or clindamycin 600 mg every eight hours for MSSA, or linezolid 600 mg every 12 hours for MRSA infections. Intravenous regimens included flucloxacillin or cloxacillin 2 g every six hours, cefazolin 2 g every eight hours, or vancomycin 1 g every 12 hours (to be adjusted as needed based on a target trough of 10 mcg/mL to 20 mcg/mL) for MSSA, or vancomycin or daptomycin 6 mg/kg to 10 mg/kg every 24 hours for MRSA.
Follow-up began at the end of therapy and ended 90 days after the first positive blood culture. The primary endpoint was a composite outcome of 90-day SAB-related complications, defined as relapsing SAB, deep-seated infection with S. aureus, or mortality attributable to SAB. Secondary outcomes consisted of hospital length of stay (starting from the date of first positive blood culture to hospital discharge or death); complications attributed to IV administration (caused by a study medication or not); Clostridioides difficile infection; 14-day, 30-day, and 90-day survival; and adverse events.
A total of 5,063 participants were screened between 2013 and 2019, and 213 were enrolled in the intention-to-treat (ITT) population, with a recruitment rate of 4.2%; 108 were assigned to the oral switch group and 105 to the IV group. Of these 213 participants, 165 were clinically evaluable (86 in the oral switch group and 79 in the IV group). Slow enrollment led to termination of the trial before reaching the initial target population of 430 participants and the decision to convert the planned interim analysis into a final analysis. With a smaller sample size, the initial non-inferiority margin of 5% was changed to 10%.
Baseline characteristics between groups were well balanced. The mean age of participants was 63.5 years (standard deviation [SD], 17.5). The majority of participants in both groups were male (66% in the oral group and 73% in the IV group). More participants in the oral group (44 [41%]) had diabetes compared to those in the IV group (28 [27%]). The number of days spent in the hospital prior to randomization was 10 (interquartile range [IQR], 7-14) in the oral group and 11 (IQR, 7-15) in the IV group. The most common source of infection was a peripheral venous catheter (44% in both groups), followed by a central venous catheter (22% in the oral group and 24% in the IV group), and skin and soft-tissue infection (24% in the oral group and 21% in the IV group).
Participants in both groups received a median of six days of IV antibiotics prior to randomization and participants in both groups received a median of eight days (IQR, 7-9) of the study medication, resulting in a medial total duration of antibiotics of 14 days (IQR, 14-15). In the ITT population, 63 of the 108 participants (58%) in the oral switch group received co-trimoxazole, 35 (32%) received clindamycin, nine (8%) received linezolid, and one (1%) did not receive any study medication. Forty-six of the 105 participants (44%) in the IV group received cefazolin, 45 (43%) received IV flucloxacillin or cloxacillin, seven (7%) received vancomycin, five (5%) received daptomycin, and two (2%) did not receive any study medication. The rates of MRSA infections were rare in both groups (6% in the oral switch group and 10% in the IV group).
In the ITT population, the trial demonstrated that an oral switch was non-inferior to continued IV therapy for the treatment of low-risk SAB, based on the primary composite outcome of complications related to SAB within 90 days, which occurred in 14 (13%) of 108 participants in the oral switch group and in 13 (12%) of 105 participants in the IV standard therapy group (treatment difference of 0.7 percentage points; 95% confidence interval [CI], -7.8 to 9.1; P = 0.013). In the clinically evaluable population, SAB-related complications within 90 days occurred in three (4%) of 86 participants in the oral switch group and in four (5%) of 79 participants in the IV group (treatment difference of -2.9 percentage points; 95% CI, -9.6 to 3.9; P < 0.0001).
Non-inferiority was shown in both the ITT and clinically evaluable populations (upper bound of the 95% CI was < 10 percentage points for the ITT population and < 5 percentage points for the clinically evaluable population). Of note, the majority of the SAB-related complications were detected early; 11 (76%) of the 14 complications in the oral group and nine (69%) of the 13 complications in the IV group were reported within the first week of the intervention phase. These early complications may have been unidentified yet present at the time of enrollment, which would make them unlikely to have been related to the study treatment.
Mortality attributable to SAB occurred in two (2%) of the 108 participants in the oral switch group and in none of the participants in the IV group. The length of hospital stay, starting from the first positive blood culture, was significantly shorter in the oral switch group than in the IV group (median stay of 12 days [IQR, 9-19] vs. 16 days [IQR, 10-19], respectively, with a median difference of -2 days; 95% CI, -4 to 0; P = 0.043). Fewer patients in the oral switch group experienced complications related to IV administration than in the IV group (treatment difference of -7.9 percentage points; 95% CI, -17.6 to 1.9). Only two participants in each of the groups developed C. difficile infection during the study period.
Overall survival rates at 14, 30, and 90 days were numerically lower in the oral switch group, but the differences were not statistically significant. Although more adverse events were reported in the oral switch group (49%) than in the IV group (41%), they were not statistically significant differences, and most of these were infections that were unlikely related to the study drugs. Drug-related serious adverse events occurred in three (3%) of 107 participants in the oral switch group and in none of the participants in the IV group; the three drug-related events were cardiac failure, C. difficile colitis, and fever.
COMMENTARY
Although SAB tends to be one of the most common infections treated by infectious diseases specialists, the evidence for the most optimal treatment strategies has remained poor. It has long been assumed that the successful treatment of SAB requires that the entire course of therapy be with IV antibiotics. However, this assumption has been based largely on uncontrolled case series conducted more than 75 years ago, and we now have evidence from better quality and more recent studies that suggests that patients with SAB can be safely and effectively treated with oral antibiotics, at least after an initial IV lead-in phase while patients are more acutely ill.4
Despite a small sample size, infrequent event rates, and a relatively wide non-inferiority margin, the SABATO trial makes an important contribution to this controversial subject, and the investigators should be commended for their extraordinary efforts. In addition to demonstrating non-inferiority, the SABATO trial showed that transitioning to oral therapy can significantly shorten hospital length of stay and lead to fewer complications associated with IV therapy. Other randomized controlled trials (RCTs) of patients with SAB also showed that patients who were transitioned from IV to oral therapy had a significantly shorter hospital length of stay.4,5 In the POET trial, which was a randomized, noninferiority study that included 400 adult patients with left-sided endocarditis treated with either IV antibiotics alone or IV antibiotics followed by a transition to oral antibiotics, the median length of stay after randomization was three days (IQR, 1-10) in the oral group compared to 19 days (IQR, 14-25) in the IV group (P < 0.0001).5 The POET trial also found that switching stable patients to oral therapy was non-inferior to continued IV therapy for the treatment of left-sided endocarditis, based on a primary composite outcome within six months after antibiotic treatment was completed.
The SABATO trial attempted to strictly enroll patients considered to have low-risk, or uncomplicated, SAB, which may be less and less common these days, and this is a challenging population to classify accurately.6 Indeed, in this study, the majority of patients who were found to have SAB-related complications were diagnosed during the first week of the intervention phase, which suggests that the complications may have developed regardless of the particular agent used, perhaps due to an uncontrolled source of infection. Metastatic complications may not be clinically apparent early on and can pose a significant diagnostic challenge. As the authors pointed out, another study of patients with “uncomplicated” SAB found that a third of patients were later diagnosed with “complicated” SAB.7 Advancements in diagnostic strategies to detect SAB-related complications earlier and methods for more accurately identifying risk factors for complications are needed.
In addition to careful selection of patients for whom oral antibiotic therapy may be considered, it also is important that antibiotic selection be judicious and based on published data and in vitro susceptibility. It also is critical that the optimal dose be given. Patients in the SABATO trial were given a relatively low dose of oral co-trimoxazole (160 mg trimethoprim and 800 mg sulfamethoxazole), which is lower than doses used in other studies that include patients with SAB.8,9 Whether higher doses are needed for the successful treatment of uncomplicated SAB remains unclear.
All of the patients included in the SABATO trial had been diagnosed with SAB after several days of being hospitalized, and the source of infection was most commonly a peripheral or central venous catheter or skin and soft-tissue infection. Whether the results of this study can be generalized to a population with SAB stemming from other causes, or with community-onset SAB, remains unknown and warrants further investigation.
There also was only a small number of patients (16) in the study with MRSA infection, which was attributed to low prevalence rates of MRSA in the participating countries. Other studies that evaluated the use of oral antibiotics for serious S. aureus infections also lacked a sufficient number of patients with MRSA infection. In the POET trial, all 87 patients with S. aureus endocarditis had MSSA. In the OVIVA trial, a large RCT that demonstrated that the treatment of complex orthopedic infections with oral antibiotic therapy was non-inferior to IV antibiotic therapy, only 19 (10.2%) of 186 S. aureus cases for which antimicrobial susceptibilities were available were MRSA. The SNAP trial, which is a large, adaptive platform trial that currently is enrolling patients, is expected to include a more diverse range of patients with SAB treated with a wider variety of antibiotic regimens, and it is hoped will provide more generalizable data soon to address some of these important questions.10
REFERENCES
- Holland TL, Arnold C, Fowler VG Jr. Clinical management of Staphylococcus aureus bacteremia: A review. JAMA 2014;312:1330-1341.
- Liu C, Bayer A, Cosgrove SE, et al. Clinical practice guidelines by the Infectious Diseases Society of America for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children. Clin Infect Dis 2011;52:e18-55.
- Kaasch AJ, López-Cortés LE, Rodríguez-Baño J, et al. Efficacy and safety of an early oral switch in low-risk Staphylococcus aureus bloodstream infection (SABATO): An international, open-label, parallel-group, randomised, controlled, non-inferiority trial. Lancet Infect Dis 2024; Jan 17:S1473-3099(23)00756-9. doi: 10.1016/S1473-3099(23)00756-9. [Online ahead of print].
- Schrenzel J, Harbarth S, Schockmel G, et al. A randomized clinical trial to compare fleroxacin-rifampicin with flucloxacillin or vancomycin for the treatment of staphylococcal infection. Clin Infect Dis 2004;39:1285-1292.
- Iversen K, Ihlemann N, Gill SU, et al. Partial oral versus intravenous antibiotic treatment of endocarditis. N Engl J Med 2019;380:415-424.
- Mathé P, Göpel S, Hornuss D, et al. Increasing numbers and complexity of Staphylococcus aureus bloodstream infection — 14 years of prospective evaluation at a German tertiary care centre with multi-centre validation of findings. Clin Microbiol Infect 2023;29:1197.e9-1197.e15.
- Holland TL, Raad I, Boucher HW, et al. Effect of algorithm-based therapy vs usual care on clinical success and serious adverse events in patients with staphylococcal bacteremia: A randomized clinical trial. JAMA 2018;320:1249-1258.
- Paul M, Bishara J, Yahav D, et al. Trimethoprim-sulfamethoxazole versus vancomycin for severe infections caused by meticillin resistant Staphylococcus aureus: Randomised controlled trial. BMJ 2015;350:h2219.
- Tissot-Dupont H, Gouriet F, Oliver L, et al. High-dose trimethoprim-sulfamethoxazole and clindamycin for Staphylococcus aureus endocarditis. Int J Antimicrob Agents 2019;54:143-148.
- Tong SYC, Davis JS, Eichenberger E, et al. Staphylococcus aureus infections: Epidemiology, pathophysiology, clinical manifestations, and management. Clin Microbiol Rev 2015;28:603-661.
Completion of therapy with oral antibiotics was shown to be non-inferior to continued intravenous therapy in patients considered to have low-risk Staphylococcus aureus bacteremia.
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