Dalbavancin.

Dalbavancin is a long-acting antimicrobial agent with an excellent in vitro activity against Gram-positive pathogens, including staphylococcal biofilms. The unusually long terminal half-life ranging from 149 to 250 hours in human subjects, allows a weekly dose. Currently is indicated in acute bacterial skin and skin structure infections (ABSSSIs), but in real-life clinical practice it has already been used successfully and safely in other infections, especially as consolidation therapy.

INTRODUCTION

Dalbavancin is a semisynthetic lipoglycopeptide with a long lipophilic side chain that confers it two new determining properties: 1) a faster and more potent bactericidal activity than vancomycin or teicoplanin, and 2) a long terminal half-life ranging from 149 to 250 hours in human subjects, allowing for a weekly dose. Dalbavancin also possesses an amidated carboxyl side group that increases the agent’s anti-staphylococcal activity (Figure 1). It was approved by both the FDA in May 2014 and the EMA in February 2015 for the treatment of adult patients with acute bacterial skin and skin structure infections (ABSSSIs). Recently, dalbavancin has also received the FDA approval to treat ABSSSIs in pediatric patient (July 2021) [1].

Figure 1

Structure of dalbavancin

MICROBIOLOGICAL PROFILE

Dalbavancin has a similar microbiological profile to the other available glycopeptides. Against MRSA, dalbavancin has demonstrated to be 16-fold more potent than daptomycin, and 32-fold more potent than vancomycin and linezolid. Dalbavancin is also the most potent agent against coagulase-negative staphylococci (CoNS) (MIC90 0.06 mg/L).

Overall, dalbavancin is 16-fold more potent against -hemolytic streptococci (MICs90 0.03-0.047 mg/L) than vancomycin (MIC90 of 0.75 mg/L). All vancomycin-susceptible Enterococcus faecalis and Enterococcus faecium isolates are inhibited by dalbavancin at ≤ 0.25mg/L, but is not active against enterococci with VanA-mediated glycopeptide resistance and only partially active against VanB isolates [2].

PHARMACODYNAMIC AND PHARMACOKINETIC PROFILE

In staphylococcal animal models the clinical efficacy of dalbavancin has been related to AUC/MIC values > 1000. The main pharmacokinetic properties of dalbavancin are as follows: approximately 93% is binding to serum albumin after an intravenous dose; excretion is through non-microsomal metabolism with inactive metabolites and up to 42% of the dose through the kidneys by glomerular filtration; and a terminal elimination half-life can exceed 200 hours. Dose adjustment is required in patients with severe renal impairment (creatinine clearance <30 mL/min) who do not undergo hemodialysis, and caution is recommended in Child-Pugh class B and/or class C hepatic impairment [3].

CLINICAL EFFICACY

Current indications for the use of dalbavancin in the ABSSSIs come from the pivotal studies DISCOVER 1 and DISCOVER 2 trials (dalbavancin vs vancomycin/linezolid 1:1, double-blind, double dummy, non-inferiority trials), that showed noninferiority of dalbavancin in both DISCOVER 1 and DISCOVER 2. Dalbavancin was better tolerated than vancomycin/ linezolid and significantly fewer patients in the dalbavancin group experienced diarrhea (0.8% vs 2.5%; P=0.02) or pruritis (0.6% vs 2.3%, P=0.01) compared to the vancomycin/linezolid group. A secondary analysis did identify significantly longer duration of therapy in the vancomycin/linezolid treatment group as compared to the dalbavancin arm (38.0% vs 31.0%; P=0.008) [4].

The long terminal half-life of dalbavancin allows its use as consolidation therapy in acute infections that require prolonged treatment, suppressive treatment of chronic infections and prophylaxis of some recurrent processes caused by Gram-positive cocci (Table 1). The use of dalbavancin for bone and joint infections (BJIs), including prosthetic joint infections (PJIs) has also been assessed in several retrospective studies and one randomized clinical trial. In osteomyelitis the cure rates ranged from 65% to 100%. The worst results have been observed in postoperative, chronic and diabetic foot osteomyelitis and when dalbavancin was mainly used as a first or rescue regimen after failure of a previous treatment. The experience of dalbavancin in PJIs is smaller. The cure rate ranged from 33% to 93%. The lack of information in many cases about surgical management and the heterogeneity of PJIs included make it difficult to draw conclusions on the efficacy of dalbavancin in these processes. The use of dalbavancin in BJIs is supported by the activity of dalbavancin against staphylococcal biofilms and its bone and articular tissue penetration that exceeds the MIC90 of S. aureus for extended periods of time after a significantly shortened dosing regimen [4].

Table 1

Potential indications of dalbavancin in real-life clinical practice

Treatment	Prophylaxis
Consolidation therapy in acute infectionsaCatheter-related staphylococcal bacteremiaInfective endocarditisOsteomyelitis SpondylodiscitisAcute septic arthritisDiabetic foot infectionsProsthetic joint infectionsSuppressive treatment of chronic infectionsChronic osteomyelitis Chronic prosthetic joint infections	Recurrent processedRecurrent cellulitis Recurrent enterococcal cholangitisRecurrent enterococcal urinary tract infectionVascular implants at risk of staphylococcal bacteremia

Particularly in infections with prolonged treatment (≥ 14 days)

In catheter-related bloodstream infection (CR-BSIs) caused by gram-positive pathogens (included S. aureus and CoNS), a phase 2, open-label, randomized, controlled, multi-centre study has shown a superior efficacy of dalbavancin compared with vancomycin [5]. In infective endocarditis treated with dalbavancin, clinical cure rates range from 50% to 100%. The best results have been observed when dalbavancin was used as a consolidation therapy after blood culture clearance rather than as a rescue strategy. As in BJIs, the diversity of the therapeutic regimens used and the fact that most patients have previously received other antibiotics, are two important limitations to knowing the efficacy of dalbavancin. In some of the published studies of dalbavancin in BJIs and IE, a reduction in the length of hospital stay (LOS) and economic cost has been observed [6].

SAFETY PROFILE

Dalbavancin, in all published evidence, has been shown to be safe and less nephrotoxic than other glycopeptides. Drug-drug interactions are uncommon with other comedications.

CONCLUSIONS

Dalbavancin, in addition to its indication in ABSSSIs, represents an effective and safe therapeutic alternative in clinically stable patients with other infections requiring prolonged treatment to shorten the LOS.