Long-Acting Lipoglycopeptides for the Treatment of Bone and Joint Infections

Abstract

Background:

The long-acting lipoglycopeptides dalbavancin and oritavancin possess excellent microbiologic activity against gram-positive bacteria and provide prolonged tissue exposure at sites of infection. Moreover, these antibiotics are well tolerated and do not require therapeutic drug monitoring.

Methods:

Pharmacokinetic/pharmacodynamic experiments ascertained that one to two doses of these long-acting agents can provide an extended period (≥6 weeks) of antimicrobial therapy.

Results:

Clinical studies subsequently found that microbiologic and clinical response rates with these agents were comparable to standard antibiotic agents used in the treatment of bone and joint infections. In addition, pharmacoeconomic analyses have discovered cost savings with the use of these antimicrobial agents in the treatment of serious deep-seated bacterial infections.

Conclusions:

Thus, these long-acting lipoglycopeptides offer potential for cost-effective outpatient parenteral antibiotic therapy of difficult to treat infections, such as osteomyelitis.

The management of bone and joint infections is difficult and often necessitates prolonged courses of antibiotic therapy [1]. The optimal route and duration of treatment regimens remains ill-defined because of limited prospective randomized trials. Furthermore, the selection of the most appropriate agent has been made more challenging in that no antimicrobial has been U.S. Food and Drug Administration (FDA)-approved for this indication in more than 30 years. An agent of choice should have potent antimicrobial activity against the causative pathogen, stable pharmacokinetics, minimal drug interactions and adverse effects, and acceptable medical costs.

Staphylococcus aureus is the leading causative organism of osteomyelitis, with identification in 44%–54% of patients [2]. Furthermore, the development of methicillin-resistant Staphylococcus aureus (MRSA) isolates has become problematic across the United States and Europe. Vancomycin has been a mainstay for treatment of MRSA osteomyelitis because of its extensive clinical experience compared with other antibiotic agents. Unfortunately, for vancomycin to be given as outpatient parenteral antibiotic therapy (OPAT), long-term intravenous access and frequent laboratory monitoring are required. Substantial nephrotoxicity is also associated with extended use of vancomycin [3]. Alternatively, newer antibiotics used for OPAT can be effective but their role and optimal dose for treating bone and joint infections have not been well defined. Oral antibiotic agents can also be effective, but patient adherence with oral antibiotic agents is often low and associated with a poor clinical response [4,5].

The long-acting lipoglycopeptide antibiotic agents dalbavancin and oritavancin are currently approved in both the United States and Europe for treating acute bacterial skin and skin structure infections (ABSSSI) among adult patients [6]. Both agents demonstrate bactericidal activity against many gram-positive organisms including MRSA and enterococcal species. Furthermore, these antibiotic agents have a promising pharmacokinetic profile that includes a prolonged elimination half-life and good penetration into bone and synovial fluid [7]. These drugs are also well tolerated and do not require therapeutic drug monitoring. Thus, these long-acting antimicrobial agents offer potential for “lineless” OPAT of patients with a variety of serious deep-seated bacterial infections such as bone and joint infections.

Microbiology

Lipoglycopeptides do not cross the gram-negative cell wall and are only active against gram-positive bacteria. These agents kill gram-positive bacteria by at least three mechanisms [8]. First, the glycopeptide moiety causes steric hinderance of transglycosylation of the cell wall. Second, lipoglycopeptides inhibit transpeptidation in a manner similar to vancomycin. Third, the lipid moiety alters the cell membrane causing membrane permeability and rapid cell death. Because these antibiotic agents work through multiple mechanisms, they have the potential to maintain activity against many bacteria that are resistant to antimicrobial agents that work by only one mechanism of action.

The long-acting lipoglycopeptides have excellent in vitro activity against both antibiotic susceptible and multi-drug–resistant bacteria such as MRSA, methicillin-resistant coagulase-negative staphylococcus, streptococcal species, and some vancomycin-resistant Enterococcus (VRE). In vitro testing of gram-positive clinical isolates from bone and joint infections found that dalbavancin inhibited 90% of Staphlococcus aureus isolates at a concentration (MIC₉₀) of ≤0.06 mg/L [9]. This MIC₉₀ is substantially lower than reported for vancomycin and daptomycin. Coagulase-negative staphylococci and β-hemolytic streptococci strains were also found to have a MIC₉₀ of ≤0.06 mg/L. Oritavancin demonstrated similar MIC₉₀ against gram-positive clinical isolates in Europe and United States hospitals along with good activity against VRE [10]. Van A positive Enterococcus faecium exhibited a MIC₉₀ of ≤0.12 mg/L and the Van B phenotype had a MIC₉₀ ≤0.06 mg/L. In contrast, these VRE isolates have a MIC₉₀ >2 mg/L to dalbavancin [11]. Oritavancin is also active against vancomycin-resistant Staphylococcus aureus [12].

Oritavancin has been shown to have activity against intracellular as well as small-colony variants of Staphylococcus aureus that have been incriminated in persistent infections such as chronic osteomyelitis [13,14]. The long-acting lipoglycopeptides also exhibit antimicrobial activity against MRSA biofilm-related infections both in vitro and in vivo [15,16]. Additionally, oritavancin has been shown to exhibit in vitro synergy with linezolid and rifampin against of isolates of MRSA [17].

The prolonged low-level exposure of these long-acting lipoglycopeptides carries a theoretical risk of increased antimicrobial resistance. Additional clinical research is ongoing to determine the risk of these antibiotic agents to select for resistance to themselves and cross-resistance to other glycopeptides.

Pharmacokinetics/Pharmacodynamics

Oritavancin and dalbavancin have similar pharmacokinetic profiles [7]. They are large molecules and both drugs are highly protein bound (85%–95%). These agents are eliminated slowly with a terminal half-life of more than 200 hours.

After multiple infusions of dalbavancin (1,000 mg on day one, followed by 500 mg weekly) in healthy subjects, peak concentrations (Cmax) were between 160 and 187 mg/L and minimum concentrations (Cmin) were between 33 and 43 mg/L [18]. Weekly dosing did not result in appreciable drug accumulation. In a follow-up bone and synovial tissue penetration study patients received 1,000 mg of dalbavancin prior to knee or hip surgery. Mean cortical bone concentrations 12 hours after the infusion were 6.3 mcg/g and 4.1 mcg/g two weeks later. Mean levels at 12 hours post-infusion and two weeks post-dose in synovial tissue were 25 mcg/g and 15.9 mcg/g, respectively. It was concluded that these concentrations would provide tissue exposure over a dalbavancin MIC for Staphylococcus aureus for an extended period of time (≥6 weeks).

Oritavancin has been shown to accumulate in cell lysosomes through endocytosis and these cellular concentrations may improve drug delivery to infected areas [19]. When exposed to therapeutic oritavancin concentrations macrophages exhibited no changes in phagocytosis, killing capacity, or oxygen radical production. Intracellular concentrations reversed after drug removal.

The pharmacodynamic activity of the long-acting lipoglycopeptides in murine infection models is correlated with the ratio of area under the free-drug 24-hour concentration-time curve (AUC) to MIC calculation (AUC/MIC) as well as the Cmax/MIC ratio [20,21]. Furthermore, microbiologic responses in patients with Staphlococcus aureus bacteremia were correlated with free-drug percentage time > MIC [22]. These findings suggest that maximum exposure of these antimicrobial agents over an extended period of time optimizes both microbiologic and clinical responses. Therefore, dosing strategies should attempt to maximize the free-drug serum concentrations of these long-acting agents with each dose.

Clinical Studies

Bone and joint infections

Several studies have evaluated the role of long-acting lipoglycopeptides for the treatment of osteomyelitis [23 –35]. Most of the data are from retrospective reviews and case reports, although, one randomized trial has been published. A few studies have also included native joint septic arthritis (Table 1).

Table 1.

Summary of Studies with Outcomes Reported for Treatment of Bone and Joint Infections with Long-Acting Lipoglycopeptides

Study	Design	Infection Site	Medication	Dose	Sample Size	Adverse Events	Outcome
Rappo et al., 2019 [23]	Randomized open label	Osteomyelitis	Dalbavancin	1,500 mg on day 1 and day 8	70 patients in the treatment arm. Ten patients in standard of care.	Ten (14.3%) patients. No serious treatment related events.	Clinical response at day 42 was 97% with dalbavancin and 88% with the standard of care. The response was maintained in 94% of dalbavancin patients at 1 y.
Almangour et al., 2019 [24]	Retrospective	Osteomyelitis	Dalbavancin	1,000 mg followed by 500 mg weekly (range, 1–13 wks) in 15 patients 1,500 mg weekly × 2 in 7 patients 1,500 mg × 1 in 6 patients Other regimens in 3 patients	Thirty-one osteomyelitis patients.	None	Twenty-eight of 31 (90%) patients with clinical cure at 3 mo post-treatment
Van Hise et al., 2020 [25]	Retrospective	Osteomyelitis	Oritavancin	1,200 mg followed by 800 mg × 4 doses (118 cases) 1200 mg followed by 800 mg × 5 doses (16 cases)	One undred thirty-four patients with osteomyelitis	Five patients with mild reactions, including 3 patients with hypoglycemia	Clinical success was achieved in 104/130 (80%) of patients who were evaluated at 6 mo post-treatment
Wunsch et al., 2019 [26]	Retrospective	All infections	Dalbavancin	Bone and joint-specific regimens not reported	One hundred one patients, including PJI in 32 (31%) and osteomyelitis in 30 (30%).	Six of 101 patients, including 1 mandibular osteomyelitis patient who developed permanent vertigo. Three patients had reversible creatinine elevation.	Infection resolution in 84/94 (89%) of total evaluable patients after 90 d. Treatment failure was noted in 2 cases of PJI.
Bouza et al., 2018 [27]	Retrospective	All infections	Dalbavancin	Bone and joint-specific regimens not reported	Sixty-nine patients overall. There were 20 PJI (29%), 12 (17/4%) osteomyelitis, and 1 (1.4%) septic arthritis.	Nine (13%) patients. Reported as mild in 7 (10.1%) patients. Two (2.9 %) patients had severe reactions, which consisted of rectal bleeding and tachycardia.	Clinical success, at 1-mo post-treatment, was 91.7% for patients with osteomyelitis and 80% for PJI.
Morata et al., 2019 [28]	Retrospective	Bone and joint infections	Dalbavancin	Variable First dose: 1,000 mg in 50 cases, 1,500 mg in 12 d. other dose in 2 cases Followed by 500 mg weekly in 54 cases [median 4 doses] in 54 cases Single dose in 9 cases 1,500 mg every 2 wks × 4 doses in 1 case	Sixty-four patients overall. There were 45 patients with implant-related infections and 19 patients without implants (12 osteomyelitis and 7 septic arthritis).	There were 7 adverse events. However, no patient had to discontinue treatment.	Clinical success was 14/19 (73.6%) among patients without implants. Clinical success was 15/23 (65.2%) with a retained prosthesis. Clinical success was 16/21 (76.2%) with the prosthesis removed.
Tobudic et al., 2019 [29]	Retrospective	All infections	Dalbavancin	[Only bone and joint dosing] 1,000 mg on first day and 500 mg every 7 d, in 8 (17%) patients 1,500 mg on first day and 1,000 mg every 14 d, in 35 (76%) patents 1,500 mg on first day, and on day 8 in 4 (9%) patients	Seventy-two patients overall with 34 cases of osteomyelitis, 8 PJI, and 4 septic arthritis.		Clinical success at 6 mo was achieved in 20/24 (59%) of osteomyelitis, 6/8 (75%) of PJI, and 4/4 (100%) of septic arthritis.
Bryson-Cahn et al., 2019 [30]	Retrospective	PWUD with “serious” S aureus infections	Dalbavancin	Variable	Thirty-two patients with osteomyelitis in 7 patients and septic arthritis in 3 patients.	No adverse events requiring re-admission	Clinical response in 18/32 (56%) of patients, including 5/7 (71%) of cases. Ten of 32 (31%) patients were lost to follow-up.
Bork et al., 2019 [31]	Retrospective	Non-ABSSSI	Dalbavancin	Dosing regimens not reported. A median of 3 doses was received	Twenty-eight patients total with 13 cases of osteomyelitis, 1 PJI, and 1 septic arthritis. Sixteen of 28 (56%) were PWID	Three adverse events, including 1 case of renal failure requiring treatment discontinuation	Osteomyelitis clinical success was 6/13 (46%) at 30 d.
Chastain et al., 2019 [32]	Retrospective	Chronic osteomyelitis	Oritavancin	Variable	9 patients	None	100% clinical success at 6 mo
Dinh et al., 2019 [33]	Retrospective	All infections	Dalbavancin	[Only bone and joint dosing]1,500 mg weekly × 2 in 29 patients1,500 mg × 1 in 4 patients1,500 mg every 2 wks × 2 doses in 2 patients1,000 mg followed by 500 mg every 2 wks × 3 doses in 2 patientsOther regimens in 11 patients	Seventy-five patients overall. Forty-eight patients with bone and joint infections.	Five patients with adverse events. No events required treatment to be stopped	Thirty-five of 46 (76.1%) for bone and joint infections. Follow-up timeframe not reported.
Morrisette et al., 2019 [34]	Retrospective	All infections	Dalbavancin and oritavancin	Dosing regimens not reported	Fifty-six patients overall with osteomyelitis in 15 patients (27%).	Mild adverse events occurred in 6 patients (11%).	Clinical success was 11/12 cases (92%) of evaluable cases of osteomyelitis, at 60 d post-treatment
Schulz et al., 2018 [35]	Retrospective	All infections	Oritavancin	1,200 mg weekly × 2 in 1 case1,200 mg followed by 800 mg weekly × 2 doses in 2 cases1,200 mg followed by 800 mg weekly × 4 doses in 1 case	Seventeen patients. Four patients with orthopedic infections	Four patients with mild reactions.	100% clinical improvement. Follow-up timeframe not reported.

PJI = prosthetic joint infection; PWUD = people who use drugs; PWID = people who inject drugs; ABSSSI = acute bacterial skin and skin structure infections.

The strongest evidence for treatment with long-acting lipoglycopeptides in orthopedic infections is a single-center, randomized (7:1), open-label clinical trial, conducted in the Ukraine for first-time osteomyelitis patients [23]. A two-dose regimen of intravenous dalbavancin (1,500 mg on day one, followed by 1,500 mg on day eight) was compared with the standard of care, with the standard of care determined by the treating clinician. Clinical cure on day 42 was observed in 65 of 67 (97%) participants in the dalbavancin cohort versus seven of eight (88%) in the standard of care cohort. Ninety-four percent of these subjects maintained a good clinical response at their one-year follow-up evaluation. It should be noted that all patients had baseline debridement with a bone culture obtained. Sixty percent had Staphlococcus aureus isolated in the bone culture and 61% of patients had evidence of chronic osteomyelitis on bone histology. Forty-seven percent of the infections were caused by fracture complications. Interestingly, two patients with concurrent MRSA bacteremia cleared their blood stream infection by day three of dalbavancin. Among the four patients who were considered clinical failure at one year, two participants were lost to follow-up, one died of an unrelated illness, and one developed a surgical site infection at the biopsy site. None of the clinical failures were related to a relapse of osteomyelitis. No serious drug-related adverse events occurred and none of the patients discontinued dalbavancin because of side effects.

A few limitations should be noted for the Ukraine study. The sample size in the standard of care group was small, with only 10 patients randomized to this arm and only eight subjects completing the protocol. In addition, only five patients with diabetic foot infections were included in the study population. Because individuals with poorly controlled diabetes mellitus may have poor blood flow to the affected area, these results may not be applicable to this population.

Multiple retrospective reviews have analyzed the clinical characteristics and outcomes of individuals treated with dalbavancin for bone and joint infections (Table 1). A variety of dosing regimens have been utilized with low rates of adverse events. The reported rates of clinical cure, which included intravenous drug users, ranged from 46%–92%, which is similar to the rates reported with the current standard of care. In one retrospective analysis, 28 of 31 (90%) patients with osteomyelitis were treated successfully with dalbavancin [24]. The subjects included 14 cases of vertebral osteomyelitis and nine cases of foot infections. All three clinical failures were foot infections including two patients without source control.

The development of osteomyelitis with oritavancin was noted in the early acute bacterial skin trial data. In the pooled SOLO data, the percentage of participants who were discovered to have osteomyelitis was greater when receiving oritavancin (0.6%; 6/976) compared to subjects administered vancomycin (0.1%; 1/983) [36,37]. Because of the discrepancy in osteomyelitis rates, the FDA requires a warning in the package insert related to osteomyelitis. However, all the cases of osteomyelitis were diagnosed within nine days of oritavancin initiation. Overall, the median time to diagnosis of osteomyelitis was 4.6 days for oritavancin versus 2.6 days for vancomycin. The short time frame to osteomyelitis discovery suggests that the osteomyelitis was likely a pre-existing condition in both groups.

Despite the early concerns, oritavancin has been used successfully for treatment of bone infections including chronic osteomyelitis [32]. The largest study to date of long-acting lipoglycopeptides was a retrospective analysis of oritavancin for the treatment of osteomyelitis [25]. It was conducted in 20 infusion centers across the United States. Oritavancin was administered to 134 patients with acute osteomyelitis with Staphylococcus aureus identified as the pathogen in 89.5% of cases. Patients received an initial intravenous dose of 1,200 mg followed by 800 mg intravenous weekly. Clinical success was attained in 80% (104/130) of the patients who were evaluated six months post-treatment. Although nine subjects required re-admission, none of the re-admissions were related to treatment failure or drug-related adverse events.

Overall, both of these antibiotic agents appear to be effective for the treatment of bone and joint infections. Clinical outcomes were similar to current treatment standards without an increased risk of untoward events. Furthermore, these long-acting agents allow for a simplified OPAT regimen.

Implant-associated infections

Infections involving orthopedic implants are particularly difficult to treat. Management usually involves a combination of surgical intervention combined with several months of antibiotic therapy, frequently with concomitant rifampin administration. A few retrospective reviews and case reports have evaluated the role of long-acting lipoglycopeptides in the treatment of orthopedic implant infections (Table 1) [26 –29].

In a retrospective study, Wunsch et al. [26] reported on their clinical experience with dalbavancin in 101 gram-positive infections including 32 patients with prosthetic joint infections (PJI). Treatment was unsuccessful in only two patients with PJI, both of whom refused surgery. Ninety-three percent of patients treated for PJI had no evidence of infection at day 90.

Another retrospective analysis reported on the use of dalbavancin for treatment of 69 gram-positive infections [27]. The cases included 20 PJIs. Clinical success was 80% for patients with PJI. However, none of the four PJI treatment failures underwent removal of the infected prosthesis.

A retrospective case analysis of 64 patients with bone and joint infections reviewed the efficacy of dalbavancin [28]. This study included 45 individuals with orthopedic implant-associated infections. The implants included prosthetic joints in 26 (58%) cases and other orthopedic implants, such as vertebral or long-bone implants, in 19 (42%) cases. Patients with an orthopedic implant-associated infection had received other antibiotic agents for a median of 41 days before starting dalbavancin. The explanations for changing to dalbavancin included treatment simplification (51%), adverse events (22%), or failure of the previous regimen (27%). Concomitant antibiotic agents were administered in 33% of cases including rifampin in 18% of cases. Most patients received dalbavancin 1,000 mg initially and 500 mg doses at weekly intervals thereafter. A median of five doses were administered to patients. Patients who underwent implant removal had a treatment success rate of 76% (16/21) compared to 65% (15/23) for patients who had implant retention. No patients discontinued dalbavancin because of adverse events.

Oritavancin plus ampicillin has been utilized successfully for treatment in a case of vancomycin-resistant Enterococcus faecium vertebral osteomyelitis associated with orthopedic hardware [38]. In addition, weekly oritavancin was reported to treat a case of daptomycin-resistant VRE osteomyelitis secondary to a prosthetic hip replacement successfully [39].

Overall, the long-acting lipoglycopeptides appear to be effective in these difficult-to-treat orthopedic implant-associated infections. Outcomes appear similar to current treatment standards and good patient tolerability was observed. The activity of lipoglycopeptides in biofilm may contribute to these outcomes. The use of combination antibiotic therapy requires further study.

People Who Use Drugs

A particularly challenging patient population are people who inject drugs (PWID). Numerous concerns exist when injection drug users are discharged with long-term outpatient intravenous access. Clinicians are apprehensive about misuse of the vascular access device, treatment adherence, vascular complications, poor outpatient follow-up, and risk for drug overdose. People who inject drugs who received OPAT have been shown to have vascular complication rates 3.3 times greater than non-PWID [40]. The long-acting lipoglycopeptides offer the possibility for line-sparing therapy, which can help facilitate hospital discharge among patients who are not considered candidates for long-term intravenous access as well as prevent line-related complications.

Bryson-Cahn et al. [30] analyzed retrospectively outcome data from 32 people who use drugs (PWUD) and were treated with dalbavancin for serious Staphlococcus aureus infections. The infections included seven patients with osteomyelitis and three individuals with septic arthritis. Most patients (88%) were injection drug users and 47% were homeless. After standard inpatient antibiotic therapy for an average of 12 days, including a first dose of dalbavancin, patients were discharged with plans for one to five weekly doses of dalbavancin. Seventeen (53%) patients completed therapy. A clinical response was seen in 18 patients (56%), clinical failure in four (13%), and 10 (31%) were lost to follow-up. No patients reported adverse effects related to dalbavancin.

Another retrospective review included 28 patients who were treated with dalbavancin for non-ABSSSI [31]. The reason cited for choosing dalbavancin was PWID in 16 (57%) cases and homelessness/lack of home support in six (21%) cases. There were 13 cases of osteomyelitis, one case of septic arthritis, and one PJI. Patients received a median of three dalbavancin doses with 22 (79%) individuals receiving their first dose prior to discharge. Seven (25%) patients were lost to follow-up, including the PJI case. Clinical success among all the clinically evaluable patients was 15 of 21 (71%). Clinical success among the osteomyelitis cases was only six of 13 (46%). Four of the five clinical failures were attributed to a lack of source control.

Additionally, a retrospective chart review compared outcomes between PWUD and non-PWUD who were treated with long-acting lipoglycopeptides [41]. There were 17 patients in the PWUD group (six with osteomyelitis) and 39 patients in the non-PWUD group (nine with osteomyelitis). Overall, 10 patients were lost to follow-up. Among the clinical evaluable patients, therapy was successful in 13 of 14 (93%) of PWUD cases and 27 of 33 (82%) of non-PWUD cases.

Safety and Financial Impact

The utilization of OPAT for bone and joint infections requires adequate home support or the ability of the patient to return to an infusion center one or more times per day for several weeks. Additionally, long-term intravenous access is often necessary to infuse standard antibiotic agents over a prolonged course of therapy. The long-acting lipoglycopeptides could impact the patient burden of OPAT of bone and joint infections. These agents require infrequent intravenous infusions in the outpatient setting and do not require therapeutic drug monitoring. Moreover, they are well tolerated and have similar rates of adverse events to comparative antibiotics (Table 1). Common (>2%) side effects associated with dalbavancin and oritavancin include nausea, vomiting, headache, diarrhea, rash, and pruritis. The monitoring for resolution of these infections and management of antibiotic side effects should be similar to standard treatment protocols.

The estimated cost per hospital day among Staphylococcus aureus ABSSSI is $2,090 [42]. The use of long-acting lipoglycopeptides have the potential for cost savings for healthcare systems primarily through a reduction in hospital length of stay (LOS). However, current pharmacoeconomic analyses are limited regarding the financial savings specific to bone and joint infections. The economic impact of these antibiotics may even be underestimated by these studies because the cost of vascular access complications and the fiscal impact of missed days of work were not included.

One retrospective study analyzed the economic impact of dalbavancin on 26 patients hospitalized with osteomyelitis [24]. It was estimated that total LOS could be reduced by 735 days with a hospital cost savings of $649,954. However, it should be noted that this study did not account for potential OPAT discharges and used a standard LOS of 42 days for osteomyelitis. In another retrospective chart review of 37 patients with complicated and uncomplicated infections, including 11 (30%) with osteomyelitis, dalbavancin was found to decrease hospital LOS by 617 days [43]. This resulted in an estimated savings of $1.5 million and a mean cost avoidance of $40,414 per patient. In a similar retrospective analysis of 24 patients, who were determined not to be OPAT candidates and received at least one dose of a long-acting lipoglycopeptide, projected reduction in hospital LOS and health system costs were 514 days (9 days per person) and $963,456 ($17,204 per person), respectively [34].

Conclusion

There has been rising interest in “lineless” treatment regimens for orthopedic infections. The long-acting lipoglycopeptides have excellent microbiologic potency against gram-positive cocci, good penetration at sites of infection, and provide prolonged tissue exposure. Some dosing regimens have used as few as one dose to treat serious invasive gram-positive infections while others have used weekly dosing. Clinical data suggest that response rates are comparable to standard antibiotic agents used for the treatment of bone and joint infectious. The long-acting lipoglycopeptides are also well tolerated. This simplified regimen with these long-acting agents could also lead to substantial cost savings to the healthcare system.

Several limitations should be noted in the current research. Most of the clinical data is retrospective and many of the studies had small sample sizes with short durations of follow-up. Furthermore, data in PWID remain scarce and large-scale pharmacoeconomic studies have not been conducted. Additional prospective randomized research is required to validate past results and clarify the optional dosing regimens of these long-acting lipoglycopeptides. Based on present data, we recommend a minimum of two doses of either agent given one to two weeks apart for the treatment of bone and joint infections. Additional doses may be warranted based on the clinical response of the patient.

Footnotes

Funding Information

No funding was received for this article.

Author Disclosure Statement

None of the authors have a conflict of interest nor were they compensated for their involvement with this article.

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