Oritavancin Versus Daptomycin for Osteomyelitis Treatment After Surgical Debridement

Osteomyelitis is an acute or chronic inflammatory process involving the bone and bone structures that occurs from infection with bacteria, fungi, and/or mycobacteria [1]. It is estimated that the annual incidence of osteomyelitis is approximately 22 cases per 100,000 person-years with the higher prevalence among those with comorbid conditions including diabetes mellitus and peripheral vascular disease [2]. In the United States, as many as 50,000 annual hospital admissions may occur due to osteomyelitis [1].

Non-hematogenous osteomyelitis occurs from the introduction of a large inoculum of bacteria or other pathogens into bone or bone structures associated with trauma, ischemic conditions, or a foreign body, which renders bone susceptible to infection [3]. Bacteria, particularly Staphylococcus aureus, adhere to bone and creates a protective biofilm coating that encompasses underlying surfaces, and the biofilm is associated with phenotypic resistance to antibiotic therapy [3]. Formation of biofilms may explain the persistence of bone infections and high failure rates of short-term treatment with antibiotics [4]. Staphylococcus aureus is the most common cause of acute and chronic hematogenous osteomyelitis in adults and children, and methicillin-resistant S. aureus (MRSA) is increasingly a cause for one-third of osteomyelitis infections [5, 6]. Other pathogens less frequently causing osteomyelitis include coagulase-negative Staphylococci, beta-hemolytic Streptococci, Enterococci, aerobic Gram-negative bacilli (Pseudomonas species, Enterobacter species, Escherichia coli), and anaerobic bacteria (Peptostreptococcus, Clostridium species, Bacteroides species) [6]. A mainstay of osteomyelitis management involves surgical debridement of the infection site [5]. These procedures may have varying success rates and depend largely on the amount of infected material excised from bone and surrounding tissue, which may also help determine the duration of treatment with active antibiotics [5]. However, prolonged antibiotic therapy for 4–6 weeks guided by culture and sensitivity information may be essential for effective treatment and cure of osteomyelitis, especially when surgical debridement is limited.

Oritavancin is a lipoglycopeptide antibiotic with a half-life of approximately 245 h that permits single-dose administration for treatment of acute skin and skin structure infections [7]. In vitro, oritavancin demonstrates activity against a broad spectrum of Gram-positive organisms including MRSA, methicillin-susceptible S. aureus (MSSA), various Streptococcus sp., vancomycin-susceptible Enterococcus faecalis, and vancomycin-resistant enterococci including E. faecium [8‐13]. While no randomized controlled trials have been conducted with oritavancin for treating osteomyelitis, the safety, tolerability, and effectiveness of oritavancin have been reported in a number of case series and retrospective studies with high response rates [14‐16]. This study was undertaken to further evaluate oritavancin for treating osteomyelitis in a cohort of patients undergoing surgical debridement.

This was a retrospective case series of patients with osteomyelitis treated with oritavancin or daptomycin by Metro Infectious Disease Consultants (MIDC), the largest infectious disease group in the U.S. providing physician services in ambulatory care facilities, long-term acute-care hospitals and long-term care facilities, and outpatient infusion services. Western Institutional Review Board (WIRB) was utilized as the central institutional review board for all study locations. The retrospective study was approved for analysis and publication by WIRB and patient consent was waived. Patients were treated between October 2020 and January 2022.

All patients were identified from the MIDC electronic medical record though traditional reports and tracking. All information was collected by infectious disease clinicians, but final analysis and tracking of patients through the case records was performed by the principal investigator, with subsequent review and validation of information by the co-primary investigator.

The chart review identified 150 consecutive outpatients at seven geographically diverse MIDC sites who met study criteria and were treated with either oritavancin (n = 73, two doses 1 week apart; n = 2, single dose) or daptomycin (n = 75) following surgical debridement. The two single-dose patients were included in the analysis. One patient experienced an adverse event (see safety section) while the other received the first dose but did not return for the second dose. This patient was not readmitted to any surrounding area hospitals for care. Patients generally were comparable for baseline characteristics (Table 1). Three (4.0%) patients prescribed daptomycin and two (2.7%) prescribed oritavancin were culture negative at baseline (Table 2). At baseline, no significant differences (p = 0.096) were observed between daptomycin and oritavancin treatment groups for diagnosis or infection source (Table 3). The average daptomycin dose was 6.2 mg/kg and the mean duration of therapy was 27.5 days. At baseline, no patient had received antibiotic therapy within the previous 30 days, was hospitalized within 90 days prior or had a history of prior surgery for osteomyelitis at the current infection site. A history of C. difficile infection in the last 6 months was present in 24 (32.0%) patients with daptomycin and 17 (22.7%) with oritavancin. A history of a multidrug-resistant infection unrelated to the current osteomyelitis infection was reported in 66 (88.0%) patients with daptomycin and 63 (84.0%) with oritavancin. These included infections with carbapenem-resistant Enterobacterales; extended-spectrum beta-lactamase Gram-negative pathogens; methicillin-resistant S. aureus; or vancomycin-resistant enterococci. Chronic kidney disease (creatinine clearance < 30 ml/min) was noted in seven (9.3%) patients with daptomycin and 21 (28.0%) with oritavancin. Three of the seven patients in the daptomycin group and seven of the 21 patients in the oritavancin group were undergoing hemo- or peritoneal dialysis. Two patients in the oritavancin arm received single 1200-mg IV doses.

The results of this study demonstrate a significantly higher rate of clinical success with oritavancin compared to daptomycin among patients with osteomyelitis following surgical debridement, with lower rates of all-cause and infection-related readmissions, repeat surgical debridement, and need for post discharge antibiotics. The high rate of clinical success with oritavancin is consistent with findings from previous case series and other retrospective studies in patients with osteomyelitis [15, 16]. All patients classified as having infection-related readmission were managed for worsening osteomyelitis and underwent additional surgery and received 1 or 2 days of vancomycin and an agent which covers Gram-negatives. A low rate of AEs was reported with both antibiotics in this study. While no cases of C. difficile infection occurred with oritavancin, three patients experienced infection with daptomycin. In animal models of C. difficile, oritavancin was found to reduce bacterial counts and spore formation suggesting a low risk of developing C. difficile [20‐22]. However, the elimination of oritavancin into the human intestinal lumen and the impact on microbiota has not been thoroughly investigated when administered IV [7].

Bone and joint infections including osteomyelitis represent a complex of conditions that are characterized by inflammation and destruction of bone [4]. Recommended treatment includes surgical debridement and based on the extent of the surgical debridement, antibiotic treatment up to 6 weeks or longer is often needed to eradicate and prevent recurrence of infection [3, 23]. Unfortunately, no antibiotic is approved for treating bone and joint infections, including osteomyelitis, in part because of the absence of evidence from randomized, controlled clinical trials. Conducting randomized, controlled, clinical trials in patients with osteomyelitis is challenging because of the prolonged course of therapy required to demonstrate efficacy. In addition, the Food and Drug Administration provides no guidance for industry for developing drugs to treat osteomyelitis.

Long-acting lipoglycopeptides are approved for treating acute bacterial skin and skin structure infections. While not approved for treating osteomyelitis, these long-acting antibiotics represent promising treatment options because of their long half-lives that permit treatment with extended dosing intervals, excellent in vitro activity against Gram-positive pathogens that are the most common causes of osteomyelitis, and excellent activity in the presence of biofilms, which is a major contributor to treatment failure [4]. Oritavancin, a long-acting lipoglycopeptide, represents an important consideration for treating osteomyelitis because of its microbiological, pharmacological, and safety and tolerability profile [23‐25]. In an animal model, oritavancin showed excellent bone penetration [26], which contrasts with many of the beta-lactam antibiotics that exhibit low penetration into bone tissue [27, 28]. In vitro, oritavancin demonstrates potent activity against biofilms produced by Gram-positive pathogens [11, 12, 29, 30] with a low minimum biofilm eradication concentration (MBEC) that is similar to or comparable to its minimum inhibitory concentration in some instances [11‐13]. Oritavancin is not appreciably excreted in the urine and requires no dosage adjustment for patients with mild or moderate renal or hepatic impairment. A paucity of data exist in patients with severe renal dysfunction including those on hemodialysis or peritoneal dialysis.

The largest experience with oritavancin was from a retrospective study of 134 patients with acute osteomyelitis where the majority of infections were caused by MRSA [16]. A number of published case reports describe beneficial outcomes with oritavancin for treatment of osteomyelitis and prosthetic joint infections [14, 31‐35]. A compilation of the findings from 23 patients included in these case series reported clinical cure or improvement in 87% with only mild AEs in two patients [36].

Strengths of our study include minimization of prior antibiotic exposure, identification of infecting pathogen, similarity in patient demographics and characteristics, and assessment of patient outcomes by trained infectious disease clinicians with internal validation. Also, patients who accounted for all-cause readmission were the same patients readmitted for infection and also subjected to repeated surgical intervention. Clinical failure could be driven by the definition used in this study, which includes all three outcomes, but these occurred in the same patients and more frequently in the daptomycin arm.

Limitations of this study were its retrospective and observational nature, and the potential for selection bias in decisions by prescribers to select a specific treatment. In this study, MIDC physicians favored daptomycin in patients with a subjectively assessed higher potential for clinical failure and rehospitalization thereby leading to daily dosing with daptomycin to improve monitoring of clinical progress. In addition, reasons to select oritavancin rather than daptomycin in MIDC practice and applicable to the patients enrolled here included patient preference not to insert PICC line, risk factors for PICC complications; patient mobility issues preventing daily OPAT visits, resides in remote locations, and current or history of recent substance abuse. The importance of this is partly negated by patients in the oritavancin arm having similar Charlson Comorbidity scores and more co-morbidities. Another limitation is the lack of evaluating patients for IV drug use and thereby not assessing the influence of specific challenges presented by this subpopulation.

Data not collected and evaluated in this study may have confounded our results. First, the role of peripherally inserted central line catheter (PICC) placement, which occurred in all daptomycin recipients, was not examined as causes of complications, adverse events, or hospital readmissions. Also, antibiotic susceptibilities were not gathered during the study period. Since susceptibilities are infrequently measured for long-acting lipoglycopeptides, we chose not to assess the potential role of resistance in these unfavorable outcomes observed in the comparator arm. However, among 7498 S. aureus bloodstream isolates collected in the SENTRY program between 2010 and 2019, oritavancin and daptomycin susceptibilities were ≥ 99.8% [9]. The high susceptibilities against the major pathogen S. aureus in this study suggests that phenotypic resistance would not have influenced these outcomes. Also, patients with a history of MDR-S. aureus were low in both groups.

Most literature on daptomycin therapy of osteomyelitis derives from the CORE registry [37, 38] which demonstrated higher clinical success rates with doses greater than 4 mg/kg [39‐42]. Several studies demonstrate overall clinical success in at least 75% of patients with osteomyelitis (Gallagher [43], 209 patients, 2007–2008, 94% clinical resolution; Gonzalez-Ruiz [44], 432 patients, 2006–2012, 80.3% clinical success; Seaton [41], 994 patients, 2004–2012, 77.7% clinical success; Seaton [39], 220 patients, 2006–2010, 75% clinical success) but dosing, duration, presence of prosthesis, pathogen, prior antibiotics, surgical intervention and other patient characteristics make definitive conclusions regarding clinical resolution difficult. For example, one study found a relationship between treatment duration and dose, and amongst several patient groups the highest clinical success rate of 74.4% was associated with surgical debridement [45]. Another study by Malizos et al. [42] included 421 patients with either osteomyelitis or orthopedic device infections who underwent surgical debridement of tissue or bone. The clinical success rate of 224 patients with non-prosthetic device osteomyelitis was 79.9%, and although unclear in the study, many of these patients likely endured surgical debridement. Also, almost 15% of these patients were non-evaluable.

In our study, the daptomycin clinical success rate of 33.3% contrasts with the published findings of the studies cited above but is generally consistent with the findings of Delate et al. [45] who found success rates in 168 patients of 22.0–74.4% depending on patient characteristics, daily dose (mean, 5.7 mg/kg), treatment duration (< 6 weeks or ≥ 6 weeks), and use of surgical debridement. These findings necessitate more detailed exploration of patient factors and developing a method for assessing the extent of surgical debridement, achievement of clean margins, and pathology which accurately identifies residual infected bone and tissue. As such, we were unable to assess the completeness of surgical debridement and residual infected or devitalized soft tissue and bone.

This study adds to the body of evidence that long-acting lipoglycopeptides play an important option in the management of the post-surgical osteomyelitic patient. A single randomized, open-label trial with two 1500 mg doses of dalbavancin administered on post-surgical days 1 and 8 was compared to vancomycin and reported clinical success in 97% with dalbavancin versus 88% with standard of care [46]. This is similar to the design of our study using daptomycin as the comparator. However, there are some notable differences between these two studies. Only 6% of patients were infected with MRSA which contrasts with the almost one-third of patients in our study. Also, the comparator vancomycin was used in a small number of patients which contrasts with our study which had a similar number of patients in both treatment arms which strengthens comparison of outcomes. Additionally, a recent study by Moenster et al. [47] of a national cohort of veterans treated for Gram-positive bloodstream infection with either oritavancin or standard of care showed between group differences in the primary outcomes of clinical success, all-cause mortality, and all-cause readmission in the full cohort in favor of oritavancin, although not statistically significant.

In summary, this real-world retrospective study of osteomyelitis outcomes suggests that oritavancin provides a viable treatment option, especially with its long half-life permitting extended dosing intervals, in vitro activity against common Gram-positive pathogens causing osteomyelitis, and consistent demonstration of effectiveness and tolerability from observational data. Our findings should be verified in larger randomized studies, especially in light of the outcomes for daptomycin.