Introduction

Records from the National Hospital Ambulatory Medicare Survey from 2010 show that skin and soft-tissue infections (SSTI) were the 7th most common ED discharge diagnosis and accounted for approximately 3.5 million ED visits [1]. Antibiotic resistance continues to be on the rise and in a healthcare environment with an aging population with an increasing number of co-morbidities, the ability to treat SSTIs with outpatient antibiotics has become increasing difficult. These factors have led to an increase in the number of hospitalizations for SSTIs, adding to the rising cost of health care, the dangers associated with hospitalization, and overcrowding of our already stressed healthcare delivery system.

Gram-positive multidrug-resistance pathogens became a significant problem in the 1980s. The prevalence of MRSA has drastically increased over the last 2 decades and in recent studies has been estimated to account for up to 59 % of SSTI identified in the emergency department [2]. Even more concerning is the more recent rise in glycopeptide-resistant enterococci (GRE), vancomycin-intermediate S. aureus, and the isolation of vancomycin-resistant S. aureus. The increasing rise of multi-drug resistant organisms (MDROs) has pushed the pharmaceutical world to try to create novel antibiotics against these difficult-to-treat bacteria and inspired the infectious disease world to promote the ideal of antimicrobial stewardship to “achieve optimal clinical outcomes… and limit the selection for antimicrobial resistant strains” [3].

A new lipoglycopeptide, dalbavancin (Durata Therapeutics, INC), has recently been approved by the FDA for patients with SSTIs caused by gram-positive microorganisms, including MRSA. Dalbavancin show promise due to its high efficacy against gram-positive SSTI, its favorable pharmacokinetics allowing for once-weekly dosing, and its lack of significant adverse effects or drug interactions. The purpose of this paper is to summarize the clinical data on Dalbavancin and discuss its potential role in the treatment of SSTI and the role of antimicrobial stewardship in our every changing world of multi-drug resistance organisms.

Chemistry

Dalbavancin is a semisynthetic lipoglycopeptide, with a similar structure and activity to teicoplanin. Glycopeptide antibiotics all work in similar fashion by inhibiting bacterial cell-wall synthesis. They bind to the d-alanyl-d-alanine subgroup of the bacterial cell wall and mechanically prevent cross-linking of the peptidoglycan backbone chains leading to lysis of the bacterial cell. Dalbavancin is classified as a lipoglycopeptide, a second-generation glycopeptide, due to a long lipophilic side chain which helps anchor it to the membrane for increased antibacterial efficacy.

Suceptibility/Clinical Efficacy

Dalbavancin has been studied extensively in vitro. The first large in vitro study was performed in 2002 by Streit et al. [4]. More than 6,000 gram-positive isolates from 70 different medical centers spanning 3 different continents and minimum inhibitory concentrations (MIC) were determined. Results from this study showed that 98 % of isolates had MIC ≤ 0.12 microgram/ml to dalbavancin, well below easily obtainable non-toxic concentrations in humans. More recently, the SENTRY trial, a surveillance study performed in 2011, took >1,500 isolates from across the US and determined MICs [5∙∙]. Results from this study showed a stable MIC ≤ 0.12 microgram/ml for 99.7 % of isolates, showing no evidence of emerging resistance or increasing MICs. These results have been seen in multiple in vitro studies in a variety of geographic and clinical settings, and resistance patterns have not significantly changed since its creation [6–30]

Both the earlier Streit study and SENTRY trial show that dalbavancin has excellent in vitro activity against gram-positive organisms. This encompasses streptococcal species, including S. pyogenes, S. viridans, and S. agalactiae, and staphylococcal species including MRSA, MSSA, and coagulase-negative staphylococci. These studies have also shown that dalbavancin has good activity against vancomycin-resistant enterococci (VRE) including both E. faecalis and E. faecium compared to teicoplanin, including activity against VRE expressing vanB and vanC genes. There does appear to be significant resistance to dalbavancin for VRE expressing the vanA gene [31] the VanY gene [32, 33] and emerging resistance in vancomycin-resistant staph aureus (VRSA). [34–36]

A phase 2, proof of concept trial looked at the efficacy of a single-dose dalbavancin regimen compared to a two dose, once-weekly dalbavancin regimen versus a standard of care antimicrobial regimen selected by the investigator prior to randomization. This study showed the biweekly dalbavancin regimen to have higher eradication rates then the other two arms [37∙∙]. While this study was not powered to determine statistical significance, the results showed that the two dose dalbavancin arm had a 94 % clinical success rate versus 76 % in the standard of care group.

In a dalbavancin phase 3, non-inferiority double blind study, dalbavancin was compared with twice-daily linezolid [38∙∙]. In this study greater than 600 patients from 65 centers from 7 countries received either two doses of once-weekly dalbavancin or linezolid every 12 h for 14 days. Over half of the isolates obtained in this study were found to be MRSA. The cure rate for the dalbavancin arm was 89 % and for the linezolid arm was 91 % that statistically demonstrated non-inferiority. Dalbavancin was well tolerated in the study with the most common side effect being nausea (occurring in 3 %) and the only serious adverse effect being a single episode of mild leukopenia which resolved after discontinuation of the antibiotic.

The results of Discover 1 and Discover 2 a combination of two large randomized non-inferiority trials of dalbavancin versus vancomycin-linezolid were recently published. This study one again showed once-weekly dalbavancin to be non-inferior for clinically important outcomes of skin and soft-tissue infections [39∙∙].

Like all glycopeptides and lipoglycopeptides, dalbavancin does not have activity against gram-negative bacteria and should not be used for confirmed or suspected gram-negative infections.

Pharmokinetics

Some of the most exciting and useful features of dalbavancin are its extended half-life, its dual elimination, and that it is well tolerated in a wide variety of patients.

The pharmacokinetics of dalbavancin were studied by Cavaleri et al. in a rat model in which the rats were given a single IV dose of dalbavancin and had serial levels measured in blood, plasma, tissue, bile, urine and feces levels over time. Results showed that the half-life in rats was approximately 8 days, that elimination was both renal (2/3) and fecal (1/3). Post-mortem studies 70 days after initial dose showed no significant accumulation in any tissues [40∙].

Dalbavancin was further studied in healthy patients. In a double-blind study looking at the tolerability, pharmacokinetics, and serum bactericidal activity of dalbavancin, subjects were given multiple small doses or one time large loading doses. Dalbavancin was found to be well tolerated with no episodes of toxicity, even with a single dose of 1,120 mg. This study also confirmed the half-life to be 181 h (8 days) in human subjects, and showed bactericidal activity for all subjects given a dose of 500 mg or greater [41∙∙]. The extended half-life has been further verified in multiple additional studies [42–46]

Another benefit of dalbavancin is that dose adjustment appears to be rarely needed in the vast majority of patients. In multiple studies dalbavancin has shown a linear, dose-proportional pharmacokinetics in single or multiple-dosing regimens. The individual characteristics which may affect dalbavancin dosing were studied by Buckwalter et al. In a subset of greater than 500 healthy patients, dalbavancin clearance was found to be influenced by body surface area and creatinine clearance [47∙] but there was significantly overlap within this population suggesting that changing of dosage regimen were not needed for the majority of patients. This study also found that concomitant medications, which were both inhibitors and inducers of cytochrome p450, had no significant effect on dalbavancin levels. Commonly used antibiotics do not appear to have any antagonistic effect on dalbavancin whereas oxacillin shows significant synergy with Dalbavancin for treatment of MRSA and VISA [48].

A study to find whether dalbavancin would have significant penetration into vesicles, a common complication of SSTIs, was performed by Nicolau et al. [49] The study took healthy patients and chemically induced blisters and then measured dalbavancin concentrations in serum and within the blister. The study found the mean penetration to be 60 % of plasma concentration that is well above the MIC with the standard dosing regimen.

Renal Impairment

Dalbavancin appears to have significantly decreased renal excretion. In human studies in appears only 1/3 of dalbavancin exertion was renally mediated. Marbury et al. have demonstrated that dalbavancin is well tolerated in patients with mild to severe renal dysfunction as measured by creatinine clearance (CrCl) [50∙]. The study showed that dalbavancin concentration in patients with mild (CrCl > 60) to moderate renal function (CrCl 30–60) were similar and suggested no need for dose modification. There was a separate study, however, that suggested that smaller doses (750 loading dose and 375 maintenance dose) should be used in patients with severe renal disease (CrCl < 30). However, these doses show bactericidal concentrations in serum and are well tolerated, with no patients in this study showing signs of toxicity. This study found that: (1) dialysis has little to no effect on serum concentrations, (2) that no further dose adjustment is needed, and (3) the relationship to timing of dialysis is unimportant.

One in vitro study evaluated dalbavancin concentration during renal replacement therapy (RRT) and showed that rates of filtration vary depending on RRT modality, filtration type and effluent flow [51]. While this suggests that patients on RRT may need dose adjustment, no dosing recommendations were provided.

Hepatic Impairment

Dalbavancin is not metabolized by cytochrome p450 and does not appear to have any significant pharmacokinetic changes in patients with mild to severe hepatic impairment. Dose adjustment does not appear necessary even in patients with Childs-Pugh class C disease.

Safety

Dalbavancin safety profile was studied in a group of 52 healthy volunteers and showed no evidence of toxicity or serious adverse effects. This study was performed by taking serial clinical assessments, blood work, EKGs, and audiology assessments throughout dalbavancin therapy [52]. The dalbavancin side effect profile was similar to placebo with the most common side effect being pyrexia and headache which were not correlated with serum concentrations. No significant EKG changes or changes in audiology assessment were noted and laboratory analysis showed only 1 episode of asymptomatic mild transaminitis and 1 episode of asymptomatic mild hyperglycemia.

A study examining the effect of dalbavancin on healthy patient’s normal GI flora showed that dalbavancin did have a small impact on the number of Escherichia coli and enterococci, but no change in the number of lactobacilli, clostridia, or bacteroides. Furthermore, no Clostridium difficile strains were isolated [53]. The study concluded “Dalbavancin has no major ecologic effect on the human normal intestinal microflora”.

Future Uses

Dalbavancin has only recently been approved by the FDA for treatment of SSTI, however, there have been multiple in vivo studies on its possible use for a wide variety of diseases, including anthrax prophylaxis treatment, surgical prophylaxis, catheter-related infections, and bacterial endocarditis.

Dalbavancin as a therapeutic agent for anthrax inhalation was tested in a murine population and was found to have 80–100 % efficacy and shows promise as a possible alternative to ciprofloxacin with an easier dosing regimen [54]. A separate murine study was preformed showing high survival rates when the anthrax vaccine and dalbavancin were given in conjunction within 3 days of exposure to inhaled anthrax [55].

Dalbavancin appears to have good osseous penetration well above the MIC needed for typical infections [56]. It has also been study as a possible alternative to vancomycin for surgical prophylaxis of implanted devices in a rabbit model. The study showed a lower rate of device colonization compared to vancomycin, with a p = 0.07 and recommended further evaluation to determine the role of dalbavancin for prevention and treatment of device-related infections [57].

A randomized control study of 75 adult patients with catheter-related bloodstream infection due to by S. aureus (including MRSA) and coagulase-negative staphylococci were given vancomycin twice daily for 14 days, versus dalbavancin once weekly for two doses [58]. This study showed that dalbavancin had a statistically significant overall success rate with a confidence interval of 73–100 % versus vancomycin 31.5–68.5 %.

The activity of dalbavancin in vitro was study in rabbits with S. aureus endocarditis and showed strong activity in all specimens including S. aureus with decreased susceptibility to glycopeptides [59].

Discussion

There is increased emphasis in today’s healthcare environment on outpatient treatments and avoiding or minimizing hospitalization. With the proliferation of MDRO, treatment often requires intravenous infusion. Frequently, these are initiated during inpatient hospitalization and, if complicated or deep space infections, followed by prolonged intravenous outpatient therapy. These new lipoglycopeptide once-weekly antibiotics show potential for reducing the need for prolonged hospitalizations and the use of long-term indwelling intravenous lines. The convenience of once-weekly dosing and the excellent safety profile, while warranting additional studies, suggest that outpatient therapy without daily infusion may be an option. These treatments may even be considered in the ambulatory or emergency department setting for selected cases, limiting need for hospitalization or observation care.

Like all new options, concerns exist for duration of action in the setting of undetected and unforeseen adverse reactions. While currently unclear, the prolonged excretion may pose some risk for prolonged or complicated adverse reactions.

Early studies suggest that new lipoglycopeptide once-weekly antibiotics have the potential to combat multidrug resistant gram-positive skin and soft tissue infections without requiring prolonged hospitalization or outpatient infusion services.