Dalbavancin Use in Vulnerable Patients Receiving Outpatient Parenteral Antibiotic Therapy for Invasive Gram-Positive Infections

Invasive gram-positive infections, particularly those caused by methicillin-resistant Staphylococcus aureus (MRSA), are a therapeutic challenge and significant burden on the health care system [1‐3]. Often, optimal treatment requires long-term intravenous antibiotic therapy, which poses a particular challenge for treating patients classified as vulnerable or high-risk for complications such as persons who inject drugs (PWID) or those who lack social support such as the elderly, homeless or patients with an underlying psychiatric illness [4, 5]. These patients are at higher risk for drug-related adverse events (ADEs), line-associated complications, nonadherence and hospital re-admission [6, 7].

Dalbavancin, a novel second-generation lipoglycopeptide antibiotic with an extended half-life was approved by the Food and Drug Administration in 2014 for acute gram-positive bacterial soft tissue and skin structure infections (ABSSSIs). Dalbavancin’s half-life of approximately 14 days has the potential to obviate the need for long-term intravenous access [8].

There are limited data on the use of dalbavancin for indications other than 1–2 doses for treatment of ABSSSI. Case reports have demonstrated success in treating more complicated infections such as MRSA pneumonia, osteomyelitis and endovascular infections [9‐11]. Dalbavancin for treatment of catheter-related bloodstream infections demonstrated efficacy in a small phase 2 open-label study with overall success of 87% (95% CI 73.2–100%) [12]. Recently, a randomized control trial for dalbavancin in the treatment of osteomyelitis versus standard of care demonstrated clinical efficacy with overall success of 97% (95% CI 89.6–99.6%) [13]. In addition, both studies demonstrated safety with mild ADEs that were similar to comparators.

Herein, we describe characteristics and outcomes of off-label use of dalbavancin for invasive gram-positive infections as primarily sequential treatment in patients with high risk for complications.

A total of 45 patients received dalbavancin at UMMC and VAMHCS from March 2014 to March 2017. Twenty-eight patients met the inclusion criteria for further review (Fig. 1). Table 1 describes the overall patient characteristics. Most patients were male, and the median age was 52 years old. Underlying substance use disorder (SUD) (68%) was the most common comorbidity followed by hepatitis C (25%) and diabetes mellitus (21%). The most common indications for antibiotics included osteomyelitis (46%), endovascular infection (25%) and uncomplicated bacteremia (14%). PWID (54%) was the predominant reason for dalbavancin (over standard therapy) followed by patient refusal of long-term intravenous access (25%). Dalbavancin was initiated in 22 patients (79%) in the inpatient and 6 patients (21%) in the outpatient setting. The median number of doses, including loading doses, in total was three. Median duration of prior antibiotic was 13.5 days. Sixty-eight percent (19/28) were on prior antibiotics for 1 week or longer before switching to dalbavancin. Twenty-eight percent (8/28) had completed ≥ 50% of the therapy prior to dalbavancin.

MRSA and mixed gram-positive organisms were the most common cultures targeted followed by methicillin-susceptible S. aureus (MSSA) and coagulase-negative staphylococci (CoNS) (Table 1). Mixed gram-positive organisms included Enterococcus faecalis, MRSA, MSSA and CoNS. One patient had Propionibacterium acnes isolated. In six patients, dalbavancin was used in combination with an oral fluoroquinolone to treat a concomitant gram-negative organism, three of which were for definitive therapy against Pseudomonas aeruginosa (n = 2) and Escherichia coli (n = 1), in addition to one requiring oral metronidazole to cover Bacteroides fragilis. In the remaining three patients, an oral fluoroquinolone was used as part of empiric therapy.

This study evaluated clinical outcomes of dalbavancin use for non-ABSSI indications in two different medical centers with high prevalence of SUD (68%). Dalbavancin successfully treated 15/28 of patients with invasive gram-positive infections, though 7 patients were lost to follow-up, conferring a 71% (15/21) success rate in the treatment of evaluable patients.

There is significant interest in the use of dalbavancin for off-label indications. Dalbavancin offers the potential for line-sparing treatment, which can facilitate outpatient treatment of serious infections, enable hospital discharge for patients disqualified from facility placement and long-term intravenous access due to active substance use, and prevent line-related complications. Several published case reports demonstrate clinical success of dalbavancin for off-label indications including the treatment of septic phlebitis with secondary MRSA bacteremia, MRSA pneumonia and Corynebacterium striatum native septic arthritis [9, 10, 14]. Most recently, larger case series and comparative studies have been published and are described in Table 3. Dalbavancin treatment success ranged from 71 to 92%, but populations and infectious syndromes were fairly heterogenous [12, 13, 15‐20]. For comparison, daptomycin real-world experience from a large registry of 6075 patients and mixed infection revealed a clinical success of 81% [21].

There are published failures and shortcomings of dalbavancin. In one case report, dalbavancin was used for MRSA endocarditis, which resulted in infection relapse and breakthrough bacteremia with vancomycin-intermediate S. aureus (VISA) [22]. The development of VISA was thought to be related to sub-inhibitory dalbavancin exposure and high inoculum infection. Comparatively, in vitro studies have demonstrated increased MICs of S. aureus and CoNS in the presence of sub-inhibitory dalbavancin [23]. It is unclear how this translates to clinical use of dalbavancin, specifically if dosing strategies should be revised based on etiology, but further studies are needed to evaluate the risk of relapse infection in high inoculum infections.

Osteomyelitis was the most common infection type encountered in our study with the lowest 30-day clinical cure (46%), equally owing to the poor follow-up and failures. Lack of source control was the primary reason for failure, as documented by persistently positive margins, wound dehiscence and persistent elevation of inflammatory markers. Dalbavancin has been shown to have high concentrations through day 14 in bone in rat studies, which is promising for clinical application [11]. Rappo et al. performed a randomized clinical trial of dalbavancin in first-episode osteomyelitis treatment and found that patients treated with dalbavancin (1500 mg, 2 doses 1 week apart) had clinical cure at day 42 in 65/67 (97%) versus 7/8 (88%) in standard-of-care patients [13]. These are encouraging data for expanding options for treating osteomyelitis. However, this study had few patients with diabetes mellitus in the dalbavancin group (14.3%) and no patients with underlying substance use disorder. Furthermore, all patients had some degree of debridement. The outcomes of our study suggest that dalbavancin may be a suitable option for osteomyelitis; however, as with many antimicrobials in the setting of osteomyelitis, it is more likely to fail if concomitant source control is not achieved [24].

Low clinical cure rates were also seen for endovascular infections (50%) owing to one patient with failure and two patients who were lost to follow-up; however, there were no relapse infections at day 90. Clinical success was high (93%) in a comparable study in Italy looking at 27 patients with infective endocarditis [15]. Dalbavancin has been shown to have in vitro activity against biofilms of Staphylococci, and there are data to suggest that dalbavancin may be an effective agent in frequent biofilm infections such as endocarditis [25].

A potential niche for dalbavancin is as an alternative therapeutic option to long-term intravenous access and institutional placement. However, if patients fail to return for maintenance dosing or fail to follow up to assess for clinical response as treatment is ongoing, dalbavancin will fall short in filling this therapeutic niche. Brysom-Cohn et al. focused only on the PWID population and described a high loss to follow-up with only 53% (17/32) completing treatment, comparable to our SUD population follow-up of 32% (6/19); however, most of our patients completed the intended treatment course. Nonetheless, these patients had infectious etiologies that traditionally require long-term intravenous antibiotic therapy (> 2 weeks) such as osteomyelitis. As such, the lack of follow-up is problematic given the absence of observation for clinical cure, drug toxicities and recrudescent infection that would determine extension, discontinuation or re-initiation of therapy. It is, therefore, important to recognize nonadherence with therapy and loss to follow-up as significant barriers to successful use of dalbavancin.

SUD and PWID were the most common comorbidities and reason for dalbavancin, respectively. PWIDs are an especially vulnerable patient population that carries a high morbidity risk and places a significant burden on the health care system [26]. Most of the patients lost to follow-up had SUD. Despite this setback, 77% of the clinically evaluable patients with active or history of SUD achieved clinical cure. Thus, dalbavancin offers an alternative treatment option for high-risk patient populations who otherwise are poor candidates for conventional parenteral therapy, provided they followed with treatments. There is much needed improvement in PWID outcomes by applying a multi-disciplinary and co-location strategy that has been successfully used in the treatment of coincident opioid use disorder with hepatitis C and/or HIV infection [27].

In this study, dalbavancin mostly functioned as a bridge to discharge patients who otherwise would have stayed in the hospital receiving parenteral antibiotics. When compared with a study evaluating the health care cost and utilization of patients with MRSA infection, the length of stay for our study population was lower (8.0 days versus 22.4 days) [28]. Although no formal cost analysis was done, the data from these two centers suggest that this strategy may potentially help to alleviate some health care costs including costs of hospital stay and prolonged subacute rehabilitation stays. Despite these obvious cost savings, access to dalbavancin for off-label use does present a challenge; obtaining insurance coverage can be time consuming and, at times, may lead to interruption in therapy. This was exemplified by one case for which a patient received one dose of the two planned doses of dalbavancin because of a gap in insurance coverage.

The two cases of nephrotoxicity raise some concerns about renal toxicity with use of dalbavancin. However, conclusions regarding this relationship cannot be made based on these two complicated cases with other contributing causes of AKI. A cumulative effect of doses greater than two and up to seven were otherwise well tolerated. There was no evidence of hepatotoxicity or cytopenias. These study results reinforce that weekly outpatient laboratory monitoring, to include renal function, is recommended.

Based on our experience with dalbavancin at these two different medical centers, we offer criteria for use (Table 4) that have been adapted into our clinical decision support by antimicrobial stewardship and OPAT programs. Dalbavancin offers alternative treatment for select circumstances that should be carefully considered. Infection determinants are required for dalbavancin candidacy, followed by either a drug determinant (i.e., drug-drug interaction with an alternative) or social determinant (i.e., PWID). By following these criteria for use, inappropriate prescribing of dalbavancin can be limited. Implementation and validation of these proposed criteria for use need to be conducted.

This study has several advantages, including a predominant representation of the PWID and SUD population and the high prevalence of MRSA. We also provide an example of criteria for use that can be adapted by other institutions and summary of the literature. However, due to the small sample size and study design, the overall generalizability is low. There are several other limitations of our study. As a retrospective study, there can be information bias leading to differential misclassification. There is no comparator group, and therefore we are unable to make any conclusions regarding effectiveness against standard of care. Additionally, most patients were on standard of care therapy before starting dalbavancin with the majority completing at least 1 week of antibiotics prior to dalbavancin. Clinical response during that time was not evaluated in our study. Thus, the impact of dalbavancin on clinical cure could not be evaluated separately from the clinical benefits provided by previous antimicrobials. Retention of care was another limitation of our study. Notably, patients at UMMC had higher loss to follow-up at 30 days compared with VAHMCS (42% versus 12%). This may be in part because OPAT at UMMC is newly established and has less coordinated care and oversight compared with VAHMCS. The difference in coordinated care and follow-up between the two OPAT programs further highlights the importance of OPAT programs for all long-term parenteral antibiotic therapies including dalbavancin. Multidisciplinary OPAT coordination is an integral component of successful dalbavancin treatment in these high-risk patients.

In conclusion, this study describes two centers’ experience with dalbavancin, suggesting a possible role for dalbavancin in the treatment of non-ABSSSI invasive gram-positive infections. In carefully selected patients and with OPAT oversight, we propose dalbavancin as an alternative to long-term daily intravenous antibiotic therapy in invasive gram-positive infections, but more experience and investigation are needed.