Table 2.

Published Studies Describing Oral Antibiotic Therapy for Complicated or “High-risk” S. aureus Bacteremia

Title (Author, Year, Reference)	Study Design	Number and Category of Participants	Study Intervention	Study Outcome	Limitations
Heldman et al. 1996, Oral antibiotic treatment of right-sided staphylococcal endocarditis in infection drug users: prospective randomized comparison with parenteral therapy [10]	A single centre (2 affiliated hospitals) prospective randomised trial.	Of note 61/89 recruited and tested had HIV. Of the total- 87 S. aureus, 5 MRSA, 6 Coagulase negative Staphylococcus (CoNS)	Prospective randomised trial of ciprofloxacin 750 mg BD + rifampicin 300 mg BD for right sided staphylococcal IE in PWID	Similar microbiological and clinical cure rates were noted compared with standard continued IV therapy	The sample size was too small, and confidence intervals too wide for statistical significance due to many patients not completing the protocol. The 2 deaths occurred in those not included, as they did not have right-sided endocarditis- both of whom switched very early at 24 h, and both died within 72 h. The doses used were much lower than those used in similar trials. Resistance to ciprofloxacin is a concern and may not have been adequately observed due to the low numbers of MRSA.
Schrenzel et al. 2004, A randomized clinical trial to compare fleroxacin + rifampicin with flucloxacillin or vancomycin for the treatment of staphylococcal infection. [11]	Multicentre, randomized trial	Deep-seated bacteraemic staphylococcal infections (mostly MSSA). 130 randomised, 127 treated. Not all SAB- CoNS included	Oral fleroxacin 400 mg OD + rifampicin 600 mg OD versus IV treatment for SAB	Similar cure rates, and microbiological/clinical failures were noted in both groups. Less time in hospital was required for the EOS group (12 d vs 23 d)	Fleroxacin is not a widely used drug, as not available in many countries. Extrapolation to newer fluoroquinolones should be valid but is uncertain.
Jorgensen et al. 2019, Sequential intravenous-to oral outpatient antibiotic therapy for MRSA bacteraemia: one step closer. [14]	Retrospective, single-centre study	492 complicated and uncomplicated MRSA-bacteraemia (MRSA-B) patients.	70 participants were switched to oral on discharge after median 8 d of IV treatment. 50% received PO linezolid and 34% PO TMP-SMX (doses not stated)	90-day failure rate non-significantly less in EOS group with significantly lower hospital readmission risk. Selected MRSA-B patients may have at least equivalent clinical outcomes with oral antibiotics versus OPAT	These patients were not part of a closed healthcare setting, limiting the ability to capture data or assess complications and readmissions at other institutions.
Iversen et al 2019, POET: Partial oral versus intravenous treatment of endocarditis. [8]	Randomised controlled trial	87 patients with S. aureus IE, and no MRSA	EOS versus continued IV treatment for IE: 54% switched to oral therapy after median 17 d Dicloxacillin/Amoxicillin (1 g QDS) + rifampicin (600 mg BD) was the most frequently used oral regime for S. aureus infection. IV therapy used a combination amoxicillin/dicloxacillin with another agent.	No difference in the composite primary outcome of all-cause mortality, unplanned cardiac surgery, embolic events, or relapse between the EOS and continued IV groups but not sub analysed for this.	We need to be careful of extrapolating this data, as this was not a planned sub analysis at start of trial.
Pérez-Rodríguez et al 2021, The benefits and safety of oral sequential antibiotic therapy in non-complicated and complicated Staphylococcus aureus bacteraemia. [13]	Retrospective, single-center	201 complicated and uncomplicated SAB patients (17% MRSA). Infective endocarditis (IE_) and endovascular infections were excluded.	62% switched to oral after median 13 d of IV; 66% of whom received TMP-SMX 160/800 mg BD. Others received linezolid (600 mg every 12 h), or levofloxacin (500 mg every 24 h)	No difference in cure rates, recurrence, or mortality were noted between groups. Shorter hospital stays were required for EOS group	Patients who died during their antibiotic therapy were excluded, possibly resulting in a population with less severe infection. Treatment duration was not factored into analysis, and it was noted that the EOS group remained on antibiotics for a greater period of time.
Kouijzer et al 2021, Intravenous to oral switch in complicated Staphylococcus aureus bacteraemia without endovascular infection: a retrospective single-centre cohort study. [16]	Retrospective single-center	106 patients with complicated SAB (96% MSSA), excluding IE/endovascular infection.	61% switched to oral antibiotics after a median 16 d IV; 88.5% of whom received PO clindamycin 600 mg TDS	No significant difference in 3-month mortality EOS versus IV group. No relapses observed among either group; Hospital stay reduced significantly by 12 d in EOS group.	Retrospective study design with a relatively small sample size introduces the inherent risk of confounding bias. Not all countries permit oral dosing of 600 mg clindamycin in each dose. Most applicable to isolates susceptible to clindamycin.
Wildenthal et al 2022, Outcomes of partial oral antibiotic treatment for complicated Staphylococcus aureus bacteremia in people who inject drugs. [19]	Retrospective, single-center, cohort analysis	238 patients with complicated SAB (infective endocarditis, septic arthritis, epidural abscess, and/or vertebral osteomyelitis) and a history of active or recent injection drug use.	69 participants were transitioned to partial oral antibiotic therapy after a median 18 d of IV antibiotics. Doxycycline 100 mg BD was used most frequently, followed by TMP-SMX 160/800 mg BD and Linezolid 600 mg BD; mostly as single-agent therapy.	SOC IV antibiotics and partial oral showed similar levels in microbiological failures. Patients who received at least 10 d of IV antibiotics prior to transition did not have significantly different outcomes. No difference between MRSA and MSSA, however, not powered for this analysis.	Date of discharge was used as the starting point for the follow up period which may have introduced immortal time bias. In addition, those that died before discharge were excluded, potentially biasing towards the IV antibiotic cohort.

Abbreviations: BD, administered twice a day; CoNS, Coagulase negative Staphylococci; EOS, early oral switch; HIV, human immunodeficiency virus; IE, infective endocarditis; IV, intravenous; MRSA, methicillin-resistant Staphylococcus aureus; MRSA-B, MRSA bacteraemia; MSSA, methicillin-susceptible Staphylococcus aureus; OD, administered once a day; OR, odds ratio; QDS, administred four times a day; SAB, S. aureus bacteraemia; SAB-CoNS, S. aureus bacteraemia coagulase negative Staphylococcus; SOC, standard of care; TDS, administered three times a day; TMP-SMX, trimethoprim-sulfamethoxazole.