Use of Oral Antibiotic Therapy for Prosthetic Joint Infections: Considerations for Implementation of Interdisciplinary Practice Changes

Introduction

Bone and joint infections have traditionally been treated with prolonged courses of intravenous antibiotic therapy. Recent evidence, however, suggests that highly bioavailable oral antibiotic therapy is noninferior to intravenous (IV) antibiotic therapy for the treatment of these infections (1–3). The use of oral antibiotic therapy presents several advantages, including avoidance of vascular catheter placement and its associated complications (occlusion, thrombosis, and infection), improved patient quality of life, and reduced health care utilization (4,5).

Prosthetic joint infections (PJIs) complicate about 0.5%–2% of all joint arthroplasty surgeries. Effective treatment of PJIs requires a multidisciplinary approach between orthopedic surgeons, infectious diseases (ID) specialists, and microbiologists. Despite evidence supporting the use of highly bioavailable oral antibiotic therapy for treatment of these infections, significant practice variation continues to exist (6,7).

A previous retrospective study found that the majority of ID and orthopedic surgeons are supportive of using highly bioavailable oral antibiotics for PJI, but that some clinical, as well as system-level, barriers prevent incorporation of this evidence into practice (8). This Practice Point article is intended to draw on lessons learned to inform implementation for institutions adopting an oral antibiotic approach to the treatment of PJIs.

Rationale for Practice Change

Significant practice variation exists globally in the surgical and medical management of PJIs, shaped by clinician knowledge and experience and clinical dogma (6,7). Engrained practice patterns relating to the use of IV therapy for PJIs may pose a barrier to evolution of practice. Therefore, it is crucial that clinical trial and real-world data supporting the use of oral antibiotic therapy for PJIs be presented to relevant stakeholders involved in the diagnosis and management of PJIs (orthopedic surgeons, ID specialists, microbiologists, and hospitalist medicine specialists). The rationale for the practice change should be framed in the context of quality measures relevant to management of PJIs (Table 1).

Table 1:

Impact of oral antibiotic therapy on domains of health care quality

Domains of quality	Impact
Safe	Avoidance of venous catheter-related complications
Timely	Reduced length of hospital stay (waiting for venous catheter insertion) Reduced need for emergency department visits for venous catheter-related complications
Efficient	Reduction in medical waste and equipment associated with outpatient parenteral antibiotic therapy (9)
Patient-centred	Avoidance of additional vascular procedures for intravenous access (reinsertion of venous catheters) Reduced need for laboratory monitoring of relevant intravenous antibiotics (eg, creatinine, vancomycin levels during vancomycin treatment)
Effective	Oral antibiotic therapy shown to be noninferior to intravenous antibiotic therapy

Use of oral antibiotic therapy for the treatment of PJIs can reduce the need for placement and maintenance of venous access devices. Complications (occlusion, thrombosis, infection) associated with venous catheter use in the outpatient parenteral therapy setting result in additional health care visits, interruptions in antimicrobial therapy, and decreased patient quality of life (4,5) and have been shown to occur in up to a one quarter of patients with peripherally inserted central catheters. Furthermore, arranging for venous catheter insertions may result in delays in hospital discharge, further contributing to health care costs, as well as delays in catheter placement for the management of patients with other conditions, where oral therapies are not an option. Clinical trial and real-world studies have shown that the use of oral antibiotic therapy for bone and joint infections result in decreased hospital length of stays (1,3).

How to Standardize Management of Prosthetic Joint Infection

With relevant stakeholder engagement, standardization of the process of PJI management should be pursued. The following sections describe the processes of care that should be implemented in collaboration between ID specialists, microbiologists, and other stakeholders. Although there are no data to suggest that oral antibiotic therapy is less effective in recurrent PJIs, or in PJIs where a hardware retention strategy is pursued, early practice change beginning with patients experiencing a first episode PJI may be most feasible due to their lower complexity. While clinical trial data support the use of empiric IV therapy for up to 7 days before transition to oral therapy, (1) there is no requirement for a minimum duration of IV therapy when the use of highly bioavailable oral antibiotic therapy provides comparable drug levels at the site of infection. Furthermore, prolonging the initial IV course of therapy may introduce complexity to disposition planning and outpatient antibiotic therapy, as many patients will be ready for hospital discharge soon after their revision surgery.

Early involvement of infectious diseases specialists

Early involvement of the ID specialist in the management of PJIs is essential to ensuring appropriate antibiotic treatment is initiated in a timely and efficient manner. ID consultation should ideally be obtained when PJI is first suspected perioperatively. This allows the ID specialist to provide advice to the primary team regarding appropriate specimen acquisition and testing, the potential suitability of oral antibiotic therapy, and the need for, or potential avoidance, of long-term venous access catheter insertion. Early involvement of the ID specialist will also facilitate collaboration with the microbiology laboratory to facilitate accurate pathogen identification, antimicrobial susceptibility testing, and release of antibiotic susceptibilities that may facilitate oral therapy.

Susceptibility testing for oral antibiotic agents

Use of highly bioavailable oral antimicrobial therapy may require extended antimicrobial susceptibility testing beyond what is routinely performed and reported by the microbiology laboratory. Delays in this testing were reported to be one of the reasons that IV treatment is selected over highly bioavailable antibiotics (8). Timely additional susceptibility results facilitate treatment decisions without incurring additional hospital days and may require refinements of the preanalytic, analytic, and postanalytic phases of microbiologic testing. Preanalytic considerations include collection of tissue or aspirates during surgery as opposed to swabs, submitting the appropriate number of samples from a variety of potentially infected tissues, provision of appropriate clinical information (ie, that PJI is suspected), and appropriate labeling of sample type (bone, synovium, periprosthetic tissue, fluid, etc.). Laboratory analytic considerations include appropriate verification and validation of specimen processing for optimal recovery of potential pathogens, instruments, or methods used for susceptibility testing, and interpretation of breakpoints for highly bioavailable oral agents. Finally, postanalytical considerations include appropriate reporting by cascading of antibiotic susceptibility results for bone and joint cultures, which include reporting of highly oral bioavailable oral agents. Table 2 outlines the highly bioavailable oral agents that can be considered for the treatment of PJI and that have available laboratory testing standards (10).

Table 2:

Highly bioavailable oral agents which can be considered for treatment of PJI when demonstrated to be susceptible

Bacteria	Antibiotic*
Staphylococcus spp	Cephalexin Ciprofloxacin or levofloxacin or moxifloxacin Clindamycin Doxycycline Linezolid Rifampin† Trimethoprim-sulfamethoxazole
Streptococcus spp β-hemolytic group	Amoxicillin Clindamycin Levofloxacin‡
Cutibacterium acnes	Amoxicillin Doxycycline
Enterococcus spp	Amoxicillin Doxycycline Linezolid
Enterobacterales	Amoxicillin Ciprofloxacin or levofloxacin Doxycycline Trimethoprim-sulfamethoxazole
Pseudomonas aeruginosa	Ciprofloxacin

^*Antibiotics listed in this table are based on the availability of laboratory susceptibility testing standards (10) and should not be considered comprehensive

^†Use of rifampin is generally considered an adjunctive therapy (see Areas of Controversy) and should not be used as monotherapy

^‡Breakpoints are not available for other fluoroquinolones for this organism (10)

Choosing a patient for oral antibiotic therapy

Not every patient with PJI is suitable for oral antibiotic therapy, and as many as 40% may not be eligible (8). Following empiric or directed intravenous therapy in the immediate postoperative period, transition to highly bioavailable therapy should only be instituted if the following criteria are met:

• the patient has undergone appropriate source control, if applicable (ie, washout with revision arthroplasty, incision, debridement, and drainage);

• a pathogen is isolated that it is confirmed to be susceptible to a highly bioavailable oral agent or there is an understanding of local common causes of PJI and their antimicrobial susceptibility patterns in cases of culture-negative infections;

• there is no other focus of infection that requires intravenous antibiotic therapy;

• the patient has a functioning gastrointestinal tract;

• there is no allergy or drug interactions related to the chosen oral agent that would contraindicate its use;

• the patient is expected to be able to adhere to an oral antibiotic regimen; and

• payment for a 6–12-week course of oral antibiotic therapy is not a barrier.

Choosing an oral antibiotic regimen

To maximize the chances of clinical cure, an orally administered antibiotic should achieve adequate concentrations at the site of infection in the joint and periprosthetic tissues. As a result, the most commonly used oral agents are ones that possess high oral bioavailability with adequate bone and joint space penetration. In the largest randomized controlled trial demonstrating noninferiority of oral antibiotic therapy versus parenteral antibiotic therapy for the treatment of bone and joint infections, the most commonly used antibiotic classes were the following: quinolones (43.8%), penicillins (13.9%), macrolides/lincosamides (11.4%), and tetracyclines (8.9%) (1). Table 3 summarizes common highly bioavailable oral antibiotics and their associated adverse effects.

Table 3:

Summary of antibiotic classes, oral bioavailability, and important adverse effects (23,24)

Antibiotic class	Oral bioavailability	Important adverse effects
β-lactams	Cephalexin: 90% Amoxicillin: 70%–80%	Hypersensitivity reactions, acute kidney injury
Clindamycin	90%	Gastrointestinal upset, Clostridioides difficile infection
Fluoroquinolones	Ciprofloxacin: 70%–80% Levofloxacin: 99% Moxifloxacin: 90%	Tendinopathy, QT prolongation, hypoglycemia, Clostridioides difficile infection
Linezolid	100%	Cytopenias, neuropathy, serotonin syndrome
Rifampin*	70%–90%	Red-orange discoloration of bodily fluids, drug interactions (CYP3A inducer), cytopenias, rash, hepatitis
Tetracyclines	Doxycycline: >90%	Photosensitivity, pill esophagitis
Trimethoprim-sulfamethoxazole	100%	Rash, acute kidney injury, hyperkalemia, hypoglycemia, hepatitis

^*Use of rifampin is generally considered an adjunctive therapy (see Areas of Controversy) and should not be used as monotherapy

Hospital discharge planning considerations

Throughout the in-hospital postoperative period, the ID specialist should be apprised of the patient’s disposition plan and expected date of discharge. Figure 1 outlines an approach that takes into account hospital disposition planning. Some patients may be ready for discharge, while operative cultures results are pending, and discharge should never be delayed to await decisions about definitive therapy. Use of a rapid follow-up clinic for those discharged home on empiric intravenous or oral therapy, can facilitate early reassessment based on final operative cultures (11).

Figure 1: Consideration in discharge planning for patients with prosthetic joint infections.

*In culture-negative cases, an oral antibiotic regimen should be chosen on the basis of local epidemiology and organism susceptiblity data in order to provide >90% coverage of suspected organisms

Areas of Uncertainty

Culture-negative prosthetic joint infections

Clinicians will encounter culture-negative cases of PJIs, where the empiric choice of oral antibiotic therapy may be challenging to determine. Broad-spectrum intravenous antibiotic therapy has historically been used to empirically cover common causes of acute and delayed PJIs (eg, a combination of vancomycin and ceftriaxone). A comparable spectrum of coverage can be achieved using a combination oral antibiotics for eligible patients (eg, a combination of a fluoroquinolone and doxycycline). Clinicians should choose a comparable oral antibiotic regimen based on local knowledge of the most common microbial aetiologies and their susceptibility patterns to provide >90% coverage of suspected organisms.

Oral beta-lactam therapy

While beta-lactam antibiotics are generally felt to have lower bioavailability than agents listed above, some agents (such as amoxicillin and cephalexin) possess high oral bioavailability. However, it is unclear whether the doses prescribed orally can achieve appropriate levels at the target site. Clinical and pharmacokinetic studies focused on gram-negative bacteremia and infective endocarditis have supported the use of high-dose beta-lactam therapy (12–14). Bone and joint penetration of high-dose amoxicillin and cephalexin appear to be adequate based on single- and multiple-dose pharmacokinetic studies involving patients without infection undergoing joint arthroplasty (15). Furthermore, in the paediatric population, cephalexin prescribed using weight-based dosing has been used successfully in the treatment of osteoarticular infections (16,17). Based on the available data, clinicians may consider the use of high-dose amoxicillin or cephalexin for treatment of PJIs caused by highly susceptible bacteria, although evidence supporting this practice in the adult population continues to evolve.

Adjunctive rifampin therapy for staphylococcal PJI

The Infectious Diseases Society of America clinical practice guidelines for the management of prosthetic joint infections recommend rifampin as a companion drug for rifampin-susceptible staphylococcal PJIs treated with debridement and retention or single-stage revision arthroplasty (18). However, definitive data on its effectiveness are missing. Recent observational studies appear to support the addition of rifampin (19,20). It is unclear whether the potential benefits of rifampin are limited to combination therapy with fluoroquinolones, or extend to combination with other drug classes (21). In the OVIVA trial, approximately one half of all patients in the oral therapy arm were treated with adjunctive rifampin (1). In a subgroup analysis, the use of rifampin was not associated with a decreased risk of treatment failure in either arm; however, the study was not adequately powered to evaluate such an effect (1). Two small randomized controlled trials studying the use of adjunctive rifampin have been conducted to date, which have shown mixed results (21,22). Based on the limited data available, clinicians can consider rifampin as adjunctive therapy in select staphylococcal PJIs.

Conclusions

Nearly a decade ago, members of the Association of Medical Microbiology and Infectious Disease (AMMI) Canada, collaborated to create five Choosing Wisely statements within the clinical purview of its members through a consensus method (22). The top ranked statement was “Do not routinely prescribe intravenous forms of highly bioavailable antimicrobial agents for patients who can reliably take and absorb oral medications.” (22) The evidence supporting this statement has only increased since development of this list, where management of bone and joint infections, including PJIs, represent a clear opportunity to improve the value of health care that is based on high-quality evidence. Given that not all patients are candidates to receive highly bioavailable oral therapy for treatment of PJI, the involvement of ID and microbiology specialists is essential to ensuring appropriate use of these agents, in collaboration with orthopedic surgeons. Many of the known barriers to using these agents can be addressed through changes in system-design to support early ID involvement, appropriate labelling of relevant specimens, and changes in microbiology testing and reporting.

Funding Statement

No funding was received for this article.

Contributors:

Conceptualization, P Lam, J Leis; Writing – Original Draft, P Lam; Writing – Review & Editing, P Lam, P Lagacé-Wiens, W Gold, S Peermohamed, L Matukas, S Poutanen, M-F Granger, D Yamamura, J Leis.

Ethics Approval:

Ethics approval was not required for this article.

Informed Consent:

N/A

Registry and the Registration No. of the Study/Trial:

N/A

Data Accessibility:

N/A

Funding:

No funding was received for this article.

Disclosures:

The authors have nothing to disclose.

Animal Studies:

N/A