Increased role of oral antibiotics in the management of deep-seated infections

INTRODUCTION The management of deep-seated infections remains a major challenge. Typically, prolonged intravenous (IV) antibiotic therapy is considered necessary to ensure adequate drug delivery and efficacy.1 However, there has been a shift towards oral (per oral PO) therapy for these infections. The shift has been in part driven by logistical difficulties with administration of IV antibiotics and the need to reduce the burden on step-down facilities such as community hospitals and home-based healthcare services (e.g. hospital at home) due to rising costs of care. In many countries, there are also active concerns with placing indwelling catheters in persons who inject drugs.2 Interest in oral antibiotics for therapy has grown, with a three-fold increase in annual publications pertaining to 'oral antibiotics' indexed on PubMed in 2024 compared to 2000. Since 2019, there have been more than 3000 publications annually on 'oral antibiotics' Figure 1.Figure 1: Publications on 'oral antibiotics' indexed in PubMed annually from year 2000 to 2024.Oral antibiotics with good bioavailability have shown efficacy as alternatives to IV antibiotics. Several recent large studies suggest that oral antibiotics may offer comparable outcomes in select cases, providing benefits such as reduced complications, shorter hospital stays and lower healthcare costs.1 This article briefly reviews the evidence for oral therapy of three common deep-seated infections that were traditionally treated with prolonged IV antibiotics: (a) bone and joint infections, (b) bacteraemia (Gram-negative bacteraemia and Staphylococcus aureus bacteraemia SAB) and (c) endocarditis. Table 1 shows an overall summary and our recommendations.Table 1: Summary of clinical trials for early oral antibiotic switch in deep-seated infections.ORAL ANTIBIOTICS FOR BONE AND JOINT INFECTIONS Bone and joint infections remain challenging to treat and have traditionally been treated with extended IV antibiotic courses to ensure adequate antibiotic penetration into bone tissue. The Oral Versus Intravenous Antibiotics (OVIVA) trial — the largest study to date with 1054 enrolled patients — demonstrated the non-inferiority of early oral therapy in managing bone and joint infections. This multicentre, open-label randomised controlled trial (RCT) included patients with native osteomyelitis and prosthesis-related bone and joint infections, randomising them to receive either IV or oral antibiotics within the first 7 days of treatment. The primary outcome of definite treatment failure within 1 year showed no significant difference between groups (PO 13.3% vs. IV 14.7%).3 A majority of the pathogens were Gram positive, including methicillin-susceptible S. aureus (MSSA; 27.7%), methicillin-resistant S. aureus (MRSA; ~10%), coagulase-negative staphylococci (CONS) and Streptococcus spp. Importantly, the PO group experienced fewer IV catheter-related complications Table 1. However, the study population remained heterogeneous, and several different effective oral regimens were used, including fluoroquinolones (FQ), trimethoprim–sulfamethoxazole (TMP–SMX), clindamycin and linezolid, often with the adjunctive agent rifampicin. These agents have excellent bioavailability and are able to penetrate biofilm, which poses a particular problem in deep-seated bone and joint infections.6 Similar to OVIVA, most of the earlier and smaller published studies showed efficacy data with FQ or TMP–SMX, with or without adjunctive rifampicin.7,8,9 The OVIVA trial added to this existing body of knowledge in terms of scale and rigour, enrolling over a thousand patients across 26 hospitals. This led to real-world implementation of early oral antibiotic strategies that have demonstrated cost savings and reduction in length of hospital stay and catheter-related complications, without an increase in treatment failure or recurrence of infection.10,11,12 In terms of antibiotic choice, the addition of rifampicin may be important when treating S. aureus. Combination therapy may help due to the pre-existing high rates of FQ resistance, as well as the potential for FQ resistance to emerge while on monotherapy.13,14 Due to the high rates of FQ resistance, in addition to concerns for FQ toxicity, alternative agents could also be considered. Depending on the pathogen, these include TMP–SMX, amoxicillin, cephalosporins, and even linezolid or tedizolid. Toxicity from linezolid (e.g. myelosuppression) is common when used for prolonged durations.15 In such settings, tedizolid may be a more costly but better tolerated alternative.16 Close monitoring is still required for clinical response to the infection and adherence to oral therapy. In addition, there may be interindividual variability in bioavailability and bone penetration of certain oral β-lactams, which therefore, requires monitoring for treatment response. Nevertheless, from a practical perspective, oral antibiotics allow for earlier hospital discharge and reduce IV-related complications. Many outpatient parenteral antibiotic therapy (OPAT) programmes have transitioned to complex outpatient antibiotic therapy, which now includes patients on prolonged oral antibiotics for close monitoring of adherence, treatment response and side effects.17 ORAL ANTIBIOTICS FOR BACTERAEMIA Gram-negative bacteraemia There is now growing evidence that oral antibiotics for Gram-negative bacteraemia are effective, with studies demonstrating that oral therapy achieves outcomes comparable to those of IV regimens in select patients. A meta-analysis of RCTs showed non-inferiority in terms of treatment failure as an outcome, when comparing oral to IV antibiotics. These included bacteraemia (most commonly, Escherichia coli and Klebsiella pneumonia), in which the source was controlled.18 Common sources included pyelonephritis, biliary tract infections and pneumonia. Evidence for this comes from RCTs as well as large retrospective cohorts.18,19,20 Of note, higher treatment success may be observed with agents that have higher bioavailability.21 Effective oral options often included FQs, TMP–SMX and beta-lactam/beta-lactamase inhibitor combinations, when susceptible. Several limitations remain. The included studies were heterogeneous in terms of patient profile, type of infections and antibiotic choice. In addition, most of these infections were urinary, which may limit their applicability to other sites of infection and specific patient profiles.18 In particular, future work is warranted to define the role of oral antibiotics in the critically ill and immunocompromised hosts such as solid organ transplant recipients.22,23 S. aureus bacteraemia The role of oral antibiotics in SAB remains controversial. The Staphylococcus Aureus Bloodstream Infection Antibiotic Treatment Options (SABATO) trial provided some insight by exploring early switch to oral antibiotics in patients with 'low-risk' SAB.4 This international, open-label RCT evaluated early oral step-down after 5–7 days of initial IV treatment versus standard IV therapy, and reported non-inferiority in terms of SAB-related complications, the primary outcome. However, the study had significant limitations, including being underpowered, possibly due to the strict inclusion and exclusion criteria. The trial also specifically excluded injection drug use, recurrent or complicated SAB, and presence of prosthetic or deep vascular grafts, thus limiting its generalisability. The trial screened 5063 patients with SAB, but only 213 (4.2%) were recruited, suggesting patients with truly 'low-risk' SAB may be difficult to identify in a real-world setting. In addition, the oral antibiotic regimens and doses used in SABATO may be difficult for patients to tolerate. For MSSA, TMP–SMX 960 mg BD or clindamycin 600 mg 8 h was suggested, both of which have prominent gastrointestinal side effects. Comparatively, for MRSA, TMP–SMX 960 mg BD or linezolid 600 mg BD was suggested, both of which cause myelosuppression.15 Similar to earlier, close monitoring is required for toxicity and tolerability while on these agents, as side effects such as nausea and vomiting may adversely affect adherence to oral therapy. Early oral switch for SAB may only be reserved for a very limited population of patients with 'low-risk' SAB due to limited clinical experience. ORAL ANTIBIOTICS FOR INFECTIVE ENDOCARDITIS Infective endocarditis (IE) is increasingly common, possibly related to the placement of indwelling medical devices, central catheters and prosthetic devices, which can serve as a nidus for infection.24 Furthermore, it is a common complication among persons who inject drugs, which poses a challenge for continuing long-term IV antibiotics.2 The Partial Oral Endocarditis Treatment (POET) trial evaluated oral step-down therapy for stable patients with left-sided IE caused by Streptococcus species, Enterococcus faecalis, CONS and MSSA. Patients received at least 10 days of IV antibiotics before transitioning to high-dose dual oral therapy.5 Importantly, although eligible, no patients with MRSA IE were enrolled in this trial. The trial demonstrated non-inferiority of oral therapy for the composite primary outcomes of mortality, unplanned surgery, embolic events and relapse. Long-term follow-up (5 years) also demonstrated significantly lower mortality in the oral therapy group.25 Real-world application of the POET clinical criteria outside of a clinical trial setting demonstrated feasibility and efficacy of early oral antibiotics compared to IV therapy in managing IE in a select group of patients.26 However, a potential limitation to this approach is that a negative transoesophageal echocardiography (TOE) for abscesses was required for early oral switch in the POET trial. In resource-limited settings, or in situations where patients may decline TOE, it is unclear whether an early oral antibiotic switch would be safe. In addition, antibiotic regimens need to be carefully selected. The regimens used in POET generally required dual oral antibiotic therapy with high pill burdens, which may limit adherence and tolerability. Beyond the POET trial, a review by Brown and Gould27 highlighted that key pharmacokinetic and pharmacodynamic factors could influence the feasibility of oral antibiotics for IE. One major consideration is achieving adequate peak serum concentrations and maintaining effective levels above the minimum inhibitory concentration for the duration of treatment. Several oral antibiotics, such as amoxicillin and flucloxacillin, can achieve plasma concentrations sufficient for antimicrobial activity against common IE pathogens. Importantly, factors such as bioavailability, protein binding and time-dependent killing characteristics must be considered when selecting oral agents.27 Therefore, careful patient selection, antibiotic choice and close monitoring for adherence, tolerability and toxicity of these agents would be critical while administering oral therapy for IE. FUTURE DIRECTION Despite promising data, several important considerations pertaining to the optimal use of oral antibiotics for deep-seated infections remain. More real-world data are needed outside of clinical trial settings, involving more diverse patient populations to ensure generalisability of the findings. Additionally, newer methods to track patient progress over time may be needed. Specific novel biomarkers, or advanced imaging modalities like fluorodeoxyglucose positron emission tomography–computed tomography may enhance risk stratification and better identify patients who will benefit most from early oral antibiotics.28 Finally, cost-effectiveness analyses comparing oral and IV therapies, factoring in drug costs, hospital stays and patient complications, would be important to inform clinical and policy decisions. CONCLUSION Oral antibiotics are emerging as a safe and effective alternative to prolonged IV therapy for certain deep-seated infections. This paradigm shift can help to reduce length of hospital stay and the strain on resources required to deliver IV antibiotics. Careful patient selection and close monitoring for adherence, clinical response and toxicity remain critical when administering oral antibiotics. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.