Extended-Duration Dosing and Distribution of Dalbavancin into Bone and Articular Tissue

Abstract

Dalbavancin is an intravenous lipoglycopeptide with activity against Gram-positive pathogens and an MIC 90 for Staphylococcus aureus of 0.06 g/ml. With a terminal half-life of >14 days, dosing regimens with infrequent parenteral administration become available to treat infectious diseases such as osteomyelitis and endocarditis that otherwise require daily dosing for many weeks. In order to support a rationale for these novel regimens, the pharmacokinetics over an extended dosing interval and the distribution of dalbavancin into bone and articular tissue were studied in two phase I trials and pharmacokinetic modeling was performed. Intravenous administration of 1,000 mg of dalbavancin on day 1 followed by 500 mg weekly for seven additional weeks was well tolerated and did not demonstrate evidence of drug accumulation. In a separate study, dalbavancin concentrations in cortical bone 12 h after infusion of a single 1,000-mg intravenous infusion were 6.3 g/g and 2 weeks later were 4.1 g/g. A twodose, once-weekly regimen that would provide tissue exposure over the dalbavancin MIC for Staphylococcus aureus for 8 weeks, maximizing the initial exposure to treatment while minimizing the frequency of intravenous therapy, is proposed. Osteomyelitis is an infection of the bone associated with either hematogenous dissemination or direct inoculation as a consequence of trauma or infection from contiguous tissues. Its presentation may be either acute or chronic. The most common pathogen responsible for acute infection in adults is Staphylococcus aureus, with Pseudomonas aeruginosa, Serratia marcescens, and Escherichia coli also involved in traumatic infections and chronic presentations. Infection in children occurs less frequently and is predominantly a result of bacteremia with S. aureus and infection in the growth plate (1). Treatment regimens extend for 4 to 6 weeks, with durations as long as 8 weeks recommended for treatment of infection due to methicillin-resistant S. aureus (MRSA) (2). Commonly used therapies include cefazolin, oxacillin, or vancomycin for coverage of Gram-positive pathogens and cephalosporins, carbapenems, and the ␤-lactamase inhibitor agents for treatment of Gram-negative pathogens (2,3). No other therapies in recent times have received FDA approval.Because the incidence of MRSA in the community in the United States is as high as 40% (4), empirical treatment of osteomyelitis now requires consideration of antimicrobial coverage of this organism, typically with vancomycin. Vancomycin has been demonstrated to be active in animal models of osteomyelitis (5). Concentrations in bone from 2.7 to 9.3 g/ml have been documented (6, 7), exceeding the vancomycin MIC 90 for S. aureus of 1 g/ml (8). Because of the wide variety of underlying etiologies and comorbidities associated with osteomyelitis, it is difficult to generalize the rates of clinical success from clinical trials, but one study documented a clinical response in 10/15 patients after continuous intravenous (i.v.) infusion of vancomycin (9). Long-term d...

Dalbavancin: A Review in Acute Bacterial Skin and Skin Structure Infections

“…Minimum plasma concentrations of dalbavancin on day 22 were similar to those observed on day 8 (i.e. at end of the dosing interval prior to the weekly dose), indicating that steady-state concentrations of the drug were attained by day 8 [32].…”

“…In two phase 1 studies, mean C max values following a single dalbavancin 1000 mg dose were 248.8 and 287.3 mg/L [31]. There was no apparent accumulation of dalbavancin following multiple doses of dalbavancin (1000 mg on day 1 and then 7 weeks of once-weekly 500 mg doses) [32]. Minimum plasma concentrations of dalbavancin on day 22 were similar to those observed on day 8 (i.e.…”

“…After intravenous infusion, dalbavancin shows good tissue penetration, including into skin blister fluid [34], bone [32] and articular cartilage [32]. The mean penetration of dalbavancin into cantharidin-induced skin blisters was 59.6 % after a single 1000 mg dose in healthy adult volunteers [34], with mean blister fluid concentrations ([30.3 mg/L at 7 days post dose) exceeding the MIC 90 values for target bacteria associated with ABSSSI (including for drug-resistant staphylococci and streptococci strains) (Table 1) [34].…”

Lipoglycopeptide Antibacterial Agents in Gram-Positive Infections: A Comparative Review

“…Dalbavancin reaches concentrations of 6.3 and 4.1 lg/g in articular tissues 12 h and 4 weeks, respectively, after the administration of 1000 mg. Subsequent administrations of 500 mg per week for 7 weeks did not cause drug accumulation and was welltolerated, warranting investigation into interest in the use of this drug for the treatment of osteomyelitis [125].…”

New Antibiotics in the Therapy of Osteomyelitis

“…Minimum inhibitory concentrations for S. aureus isolated from diabetic foot ulcers and vancomycin-intermediate and heteroresistant types were measured in vitro, dalbavancin showed excellent activity and was superior to vancomycin [93] . Its distribution to bone and synovial fluid was measured in healthy subjects and shows concentrations superior to the MIC of S. aureus over 50 days [94,95] .…”