Abstract

Dalbavancin (Pfizer) is a new lipoglycopeptide antibiotic in phase 3 trials for the treatment of resistant gram-positive pathogens including methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE). This agent exerts its bactericidal activity by binding to the terminal D-alanyl-D-alanine moiety of peptidoglycan precursors, thus blocking enzymes involved in the final stages of peptidoglycan synthesis and cell wall formation. Peak concentrations of dalbavancin occur immediately following infusion and increase in proportion to the dose given. After infusion, there is a rapid decline in plasma concentrations due to distribution of the drug into bodily tissues and fluids (V_ss=0.52 L/kg). This initial rapid decline in plasma concentration is followed by a slower terminal, log-linear elimination phase, in which dalbavancin exhibits an elimination half-life ranging from 149 to 198 hours. Current data suggest that dalbavancin is well-tolerated by patients with most adverse events being described as mild. Dalbavancin may offer advantages over other antibiotics used in the treatment of resistant gram-positive pathogens because of its excellent tolerability and potency. Due to the long elimination half-life of dalbavancin, once-weekly dosing may be an option. (Formulary. 2006;41:59–73.)

Over the past 30 years, methicillin-resistant Staphylococcus aureus (MRSA) has evolved into a significant pathogen among hospitalized and non-hospitalized patients in the United States and around the world. The growing prevalence of MRSA infections not only poses a significant health risk, but also represents a substantial economic burden. Researchers have found that patients infected with MRSA have a longer average hospital stay of 4.5 days and a longer average antibiotic length of stay of 3 days when compared to patients infected with a methicillin-sensitive Staphylococcus aureus (MSSA). This translated into a median cost of $16,575 per patient per hospitalization, or approximately $4,000 more per hospitalization than a patient with a MSSA infection (2004 dollars).¹

It has been estimated that there are approximately 125,969 hospitalizations annually in the United States that carry a diagnosis of infection secondary to MRSA.² Furthermore, MRSA accounts for 12% of all nosocomial bacteremias, 28% of all surgical wound infections, and 21% of all nosocomial skin infections.³ Importantly, surveillance data from the state of Washington have revealed that the prevalence of MRSA from cultures of hospitalized patients and residents of long-term care facilities were 42% and 79%, respectively.⁴

Although MRSA has been found among certain populations in the community, such as dialysis patients and intravenous drug users, for a number of years, this pathogen has recently become more prevalent among the general population.⁵ CDC researchers analyzed MRSA surveillance data from 3 US locations in 2001 and 2002 and found that between 8% and 20% of all MRSA infections were community-acquired.⁶ One study that examined infectious etiologies of diabetic foot ulcers at an outpatient clinic determined that MRSA was responsible for approximately 30% of foot infections in evaluated patients.⁷ In another study, MRSA was isolated from 61 of 137 patients (44.5%) presenting with localized skin or soft-tissue infections in a Los Angeles emergency department.⁸

As a result of the growing incidence of MRSA infections, empiric use of vancomycin has been increasing.⁹ Although vancomycin is commonly regarded as a potent agent against gram-positive microbes, its use is not without shortcomings. First, vancomycin appears to kill less efficiently than other agents such as the beta-lactams.^10,11 This characteristic has led some clinicians to become concerned about slower rates of response to therapy when vancomycin is used. Second, vancomycin is only available as an intravenous agent and is routinely administered multiple times daily. Furthermore, most clinicians continue to monitor vancomycin serum concentrations and adjust therapy based on these levels. Additionally, vancomycin administration has been associated with several adverse events such as phlebitis and Red-man syndrome, which can complicate therapy. Finally, increased use of vancomycin has been associated with the emergence of resistant strains of Enterococcus species (VRE) and, more seriously, Staphylococcus aureus (VISA and VRSA). Vancomycin resistance among staphylococci has long been a concern, owing not only to the prevalence of the bacteria but also to the relatively few options that would be left to clinicians to combat this pathogen.² Despite these problems, vancomycin remains the cornerstone of therapy for MRSA.

Due to the magnitude of the problem of gram-positive resistance, the search for new agents with activity against these pathogens has intensified. Over the past decade, drugs such as quinupristin/dalfopristin, linezolid, and daptomycin have been developed to combat resistant gram-positive pathogens. Another agent currently under development for this purpose is dalbavancin (Pfizer), a semisynthetic glycopeptide antibiotic in phase 3 clinical trials in the United States.

CHEMISTRY AND PHARMACOLOGY

Dalbavancin is a lipoglycopeptide antibiotic that is a semisynthetic derivative of the naturally occuring teicoplanin-like compound A40926. Similar to A40926 and teicoplanin, dalbavancin has a long fatty acyl moiety in an amide linkage to a glucosamine component. This fatty acyl chain is purported to improve activity by anchoring the molecule to the bacterial cell membrane, which prolongs the interaction of the agent with the bacteria.¹²

The glycopeptides are believed to exert their antimicrobial effects by inhibiting cell wall synthesis. This class of antibiotics allows for the synthesis of lipid intermediates, which are required for cell wall synthesis, but prevents their utilization for the synthesis of peptidoglycan through the direct binding to the terminal D-alanyl-D-alanine moiety of pentapeptide peptidoglycan precursors. This prevents the cell wall of bacteria from maturing by blocking the enzymes involved in the final steps of peptidoglycan synthesis.¹³ A mature cell wall is critical for the maintenance of the osmotic gradient between the bacterial cell and its environment. An immature or damaged cell wall cannot maintain this osmotic gradient and therefore ruptures due to osmotic shock.

It has been postulated that dalbavancin exerts its bactericidal effect on bacteria through more than 1 mechanism. In addition to blocking enzymes involved in the final stages of peptidoglycan synthesis, dalbavancin may have a secondary mechanism of action independent of peptide binding. Researchers suggest that dalbavancin may inhibit transglycosylases, such as S aureus penicillin-binding protein 2 (PBP2), by direct interaction with enzymes involved in the final stages of peptidoglycan synthesis.¹⁴

Pharmacokinetics

Table1: Dalbavancin single-dose regimen pharmacokinetics

The pharmacokinetics of dalbavancin have been studied following administration according to 2 distinct dosing regimens. One regimen consisted of a single intravenous dose administered over 30 minutes. The other regimen comprised multiple intravenous infusions. This regimen included a loading dose on Day 1 and lower maintenance doses on the 6 days following the loading dose. Each intravenous infusion in the multiple-dose model was administered over 30 minutes.^15,16 The maximum concentration (C_max) of dalbavancin occurred immediately following the end of the infusion. Following administration at various doses, it was determined that the peak concentrations increased proportionally to the dose given (Tables 1 and 2).^15,16 The area under the curve (AUC) of dalbavancin also increases linearly with dose escalation.¹⁵

Table 2 : Dalbavancin multiple-dose regimen pharmacokinetics

Following the infusion, plasma concentrations of dalbavancin decline rapidly over the first 12 hours. This initial decline represents the distribution phase of the drug. This initial rapid decline is followed by a slower terminal, log-linear elimination phase. Total plasma clearance of dalbavancin is not affected by dose and has been reported to be 0.0379 to 0.535 L/h in trials. The V_ss for dalbavancin ranges from 7.85 to 11.3 L or approximately 0.52 L/kg.^15–16 Dalbavancin exhibits a high degree of protein binding (≥95%), primarily to albumin.¹⁷ Approximately 35% of the dose is excreted unchanged in the urine.¹⁶

Perhaps the most remarkable pharmacokinetic characteristic of dalbavancin is its long terminal half-life. Following single and multiple doses, the terminal half-life of dalbavancin has been reported to be 149 to 188 hours and 184 to 198 hours, respectively. It has been hypothesized that the long half-life of dalbavancin is likely due to the extensive protein-binding of the agent.¹⁷

Table 3 : Dalbavancin versus vancomycin pharmacokinetics

Comparatively, vancomycin is primarily excreted as unchanged drug by the kidneys. Because of this aspect of the agent's kinetics, vancomycin requires a dose adjustment in patients with renal impairment.¹⁸ Vancomycin is approximately 55% bound to serum proteins and has a volume of distribution ranging from 0.5 to 0.9 L/kg.¹⁹ The elimination half-life of vancomycin has been shown to range from 3 to 9 hours in subjects with normal renal function (Table 3).¹⁸

Animal models have demonstrated that dalbavancin penetrates well into a variety of bodily tissues and fluids.^20,21 In a study conducted by Jabes et al,²¹ granuloma pouches were induced in rats and then inoculated with 10⁶ cfu/mL of MSSA and MRSA strains. Following a single dose of dalbavancin, it was noted that the drug demonstrated excellent penetration into the granuloma pouch. The ratio of plasma AUC to exudate AUC was approximately 1:1.²¹ Cavaleri et al²⁰ examined the distribution of dalbavancin in 40 types of tissues. The investigators reported that following a single IV bolus dose, the highest concentrations of dalbavancin were found in the kidney and liver. Other tissues with measurable concentrations of dalbavancin included the heart, lung, spleen, and skin. The researchers observed that almost all tissues reached their maximum observed concentration within 24 hours of dose administration.

Gender. Leighton et al¹⁵ demonstrated that dalbavancin exhibits similar pharmacokinetic properties based on gender when adjusted for weight. The researchers found that males and females exhibit a similar half-life, V_ss, and clearance (Cl) for the drug.

There are no available data on dalbavancin's kinetics in special populations such as the elderly, pediatric patients, and those with renal impairment or hepatic impairment.

SPECTRUM OF ACTIVITY

Table 4 : Dalbavancin activity against resistant gram-positive pathogens

In vitro studies have demonstrated that dalbavancin possesses excellent activity against gram-positive pathogens such as oxacillin-resistant S aureus (ORSA), coagulase-negative staphylococci, and various streptococcal species (Table 4).^15,22–27 One study assessed dalbavancin activity against 6,336 clinical isolates of gram-positive organisms from the Americas and Europe. Isolates included: VRE, penicillin non-susceptible S pneumoniae, coagulase-negative staphylococci, and ORSA. Results from this study demonstrated that more than 99% of strains tested possessed minimum inhibitory concentration (MIC) values of ≤1 mcg/mL. Coagulase-negative staphylococci and ORSA species were extremely sensitive to dalbavancin with MIC₉₀ values of 0.06 mcg/mL.²² Another study assessed the activity of dalbavancin against 1,229 gram-positive isolates from Latin American countries. It was noted that dalbavancin was more active than vancomycin, teicoplanin, quinupristin-dalfopristin, or linezolid against organisms such as MRSA, penicillin-resistant S pneumoniae, viridans streptococci, and various multi-drug-resistant gram-positive organisms.²⁴ Dalbavancin has also demonstrated activity against anaerobic gram-positive species and Corynebacteria, with 91% of isolates inhibited by concentrations ≤1 mcg/mL (Table 5).²⁸ Against clinically important gram-negative bacilli, dalbavancin has not displayed any significant activity.²⁶ Table 5 highlights the activity of dalbavancin against several bacterial species.

Table 5 : Dalbavancin activity against anaerobes and Corynebacterium

Dalbavancin has been shown to exhibit bactericidal activity against gram-positive pathogens.^15,21–27 Also, since teicoplanin activity has been correlated with trough concentrations, structurally related dalbavancin is assumed to possess a similar characteristic.²⁹

Animal Models

Many animal models have been utilized to assess the efficacy of dalbavancin against various gram-positive pathogens. Candiani et al²⁷ conducted a battery of experiments to examine the comparative efficacy of dalbavancin versus other antibiotics for the treatment of select gram-positive infections. In one arm of the study, the researchers compared dalbavancin, vancomycin, and teicoplanin for prophylaxis against septicemia in immunocompetent and neutropenic mice. The immunocompetent mice were infected with either 1.8x10⁶ cfu of MSSA or 2.6x10² cfu of Streptococcus pneumoniae. Neutropenic mice were infected with either 1.1x10⁵ cfu of Staphylococcus epidermidis or 3.2x10⁴ cfu Enterococcus faecalis. Antibiotics were administered subcutaneously within 10 minutes following inoculation. A second dose of vancomycin was administered 5 hours after infection in those mice inoculated with S pneumoniae and S epidermidis. Efficacy was measured in terms of the dose that effectively protected 50% of the mice against septicemia (ED₅₀). Results from this portion of the study indicated that dalbavancin and teicoplanin possess similar protective potency, whereas vancomycin was much less active against MSSA (ED₅₀=0.08, 0.2, and 1.12 mg/kg/dose, respectively). The activities of teicoplanin and dalbavancin against S pneumoniae were slightly better than the double-dose of vancomycin (ED₅₀=0.56, 0.40, and 0.79 mg/kg/dose, respectively). Against E faecalis, teicoplanin was more effective than dalbavancin in preventing septicemia in infected mice (0.51 and 1.53 mg/kg/dose, respectively). Vancomycin was not tested against E faecalis.

Lefort et al³⁰ also examined the efficacy of dalbavancin in an animal model of endocarditis. In this study, researchers inoculated rabbits with 1 of 3 strains of S aureus with reduced susceptibility to vancomycin and teicoplanin. Following inoculation, animals were administered either a single 40 mg/kg IV dose of dalbavancin or a 10 mg/kg daily IV dose for 4 days. Susceptibility testing revealed that dalbavancin was 2 to 4 times more potent than vancomycin and 4 to 8 times more potent than teicoplanin against these isolates. Data of bacterial density in vegetations demonstrated that the multiple-dose dalbavancin regimen decreased bacterial counts by 3.5 to 3.9 log₁₀ cfu/g of vegetation, while the single-dose dalbavancin regimen reduced bacterial counts by 2.1 to 2.5 cfu/g of vegetation (P<.01).

CLINICAL TRIALS

Table 6 : Summary of clinical trials with dalbavancin

To date, there have been a limited number of studies published describing the activity of dalbavancin in human subjects (Table 6). Seltzer et al³¹ conducted a randomized, controlled, open-label trial designed to evaluate the utility of dalbavancin in skin and soft-tissue infections (SSTIs). In this study, patients were eligible if they were aged ≥18 years, not pregnant, and had an SSTI that was known or suspected to be caused by gram-positive bacteria, including MSSA, MRSA, Group B Streptococcus, and Streptococcus pyogenes. Eligibility criteria also required that the SSTI involve deep soft tissue and/or required significant surgical intervention. A total of 62 patients were randomized to receive a single 1,100-mg IV infusion of dalbavancin, a 1,000-mg dose of dalbavancin followed by a 500-mg dose administered 1 week later, or a prospectively defined standard-of-care regimen determined by the investigator before randomization. Results from this study demonstrated that clinical response rate was greatest in patients treated with 2 doses of dalbavancin (94.1%), followed by the standard-of-care regimen and single-dose dalbavancin (76.2% and 61.5%, respectively). The data from this study imply that 2 doses of dalbavancin, administered 1 week apart, are effective for the treatment of SSTIs.

Data from a clinical trial regarding the use of dalbavancin for complicated skin and skin structure infections (cSSSIs) were recently been published in abstract form.³² This was a randomized (2:1, dalbavancin:linezolid), double-blind, comparative trial of dalbavancin (1,000 mg IV on Day 1 and 1,500 mg on Day 8) versus linezolid (600 mg IV every 12 or IV followed by oral therapy in a sequential manner) for the treatment of cSSSIs. Clinical and microbiologic efficacy were each evaluated at the test-of-cure visit. A total of 434 and 226 patients were available for clinical evaluation in the dalbavancin and linezolid groups, respectively. Two hundred seventy-seven dalbavancin-treated and 152 linezolid-treated patients were microbiologically evaluable. The primary skin and skin structure infections (SSSIs) noted among the study population included major abscess (32.3%) and cellulitis (28.2%). Staphylococcus aureus was the most common pathogen identified. Fifty-six percent of the S aureus isolates were resistant to methicillin. Success rates (clinical/microbiologic) of 88.9%/89.5% and 91.2%/ 87.5% were reported for dalbavancin and linezolid, respectively. The investigators noted that <1% of patients in either treatment group experienced a relapse. These findings led the authors to conclude that 2 doses of dalbavancin administered 1 week apart were equally as effective as a twice-daily dosing regimen of linezolid for 14 days.

Data from three phase 3 comparative studies of dalbavancin versus either linezolid, cefazolin, or vancomycin for the treatment of skin and SSSIs were also recently published in abstract form.³³ Dalbavancin was dosed once-weekly and comparators were administered via conventional dosing regimens. Responses were evaluated using clinical and microbiologic end points. Seventy-seven percent of the pathogens recovered were S aureus, and 38% of staphylococcal isolates were methicillin- resistant. Among the 3 studies, the clinical response rate for dalbavancin ranged from 89% to 90% and was similar to the response rates noted for comparator agents. Similarly, microbiologic eradication rates were similar among the study medications. These data led the investigators to conclude that dalbavancin was as equally effective as comparator agents for the treatment of skin and SSSIs caused by S aureus.

The efficacy of dalbavancin for the treatment of catheter-related bloodstream infections caused by gram-positive pathogens has also been studied. In an open-label trial, 75 adult patients with catheter-related bloodstream infections (CR-BSIs) suspected to be caused by coagulase-negative staphylococci or S aureus, including MRSA, were randomized to receive either a multiple-dose dalbavancin regimen consisting of a single 1,000-mg IV dose followed by a single 500-mg IV dose 1 week later, or IV vancomyin administered twice daily for 14 days. Twenty-three patients in the dalbavancin group and 28 patients in the vancomycin group were evaluable for the primary efficacy end point of clinical success at the test-of-cure visit. Overall success rates for the primary efficacy end point revealed that dalbavancin appeared to be superior to vancomycin for the treatment of CR-BSIs (87%; 95% CI, 73.2%–100% vs 50%; 95% CI, 31.5%–68.5%).³²

Adverse Events

Current data demonstrate that dalbavancin is well-tolerated by patients, with most adverse events being described as mild.^15,30–32 In a proof-of-concept study assessing the efficacy and safety of dalbavancin for SSTIs using an intravenous 2-dose scheme of 1,000 mg followed by a 500-mg dose 1 week later or a 1-time 1,100-mg dose, no serious adverse events were reported. Additionally, no discontinuations of therapy were reported that resulted from adverse events due to dalbavancin use. Also, no clinically relevant laboratory value alterations, including serum creatinine elevations, were observed.³¹ Another study using a similar dosing strategy determined that dalbavancin use was not associated with any serious adverse events in study subjects. In this study, the most commonly reported adverse events believed to be related to dalbavancin use included oral candidiasis, diarrhea, constipation, and febrile response. No patients in the dalbavancin group of this study discontinued treatment due to adverse events. Another trial, utilizing intravenously administered multiple-dose and escalating single-dose regimens of dalbavancin, discovered that dalbavancin was well-tolerated and no dose-limiting toxicities were encountered. The most commonly reported adverse events were pyrexia, headache, and nausea.¹⁵ The potential for ototoxicity with dalbavancin use was also determined to be low in phase 1 trials.³³

Safety data from the intent-to-treat (ITT) populations for the phase 2/3 development trials of dalbavancin were recently summarized.³⁶ In these studies a total of 1,126 patients received at least 1 dose of dalbavancin. It was noted that 52% of subjects who had received dalbavancin reported at least 1 adverse event. This is comparable to the 56.9% of subjects enrolled in the comparator arms of these studies. Of these events, 3.5% and 3.8% resulted in discontinuation of the study medication in the dalbavancin and comparator groups, respectively.

Of note, histamine-related adverse events such as flushing, hypotension, and rash reactions that have been described for other glycopeptides have not been reported following dalbavancin administration.

Although dalbavancin may not appear to pose a significant risk for adverse events, consideration should be given to how this agent's pharmacokinetic profile impacts the overall clinical picture. Due to dalbavancin's long half-life, reversal of an adverse event could take an extended period of time.

DOSING AND ADMINISTRATION

Several dosing regimens have been used with dalbavancin in clinical trials. Both one-time doses ranging from 140 mg to 1,120 mg, and multiple-dose regimens with loading doses ranging from 300 mg to 1,000 mg and maintenance doses ranging from 30 mg to 500 mg, have been utilized.^15,31,32 The one-time IV bolus dose of 1,120 mg is the highest dose administered to human subjects, and it was well tolerated.^15,16 Although no dosing regimen for dalbavancin has been approved, it appears that a multiple-dose regimen of 1,000 mg followed by a 500-mg dose 1 week later may be the most likely regimen. This dosing regimen was determined to be safe and effective for the treatment of infections caused by S aureus and coagulase-negative staphylococci-related infections. The administration of dalbavancin was via IV infusion over the course of 30 minutes in clinical trials.^15,31

It does not appear that dalbavancin will require dosage modification in patients with renal dysfunction due to the fact that nonrenal routes play a significant role in the drug's elimination.¹⁵

Drug Interactions

Formulary considerations

One area of concern regarding vancomycin use is its drug interaction profile. Concurrent vancomycin and aminoglycoside use can be problematic due to an increased risk of nephrotoxicity in patients.³⁷ Dalbavancin, however, has not demonstrated any evidence of nephrotoxicity.^15,31,32 This characteristic may allow dalbavancin to be used concurrently with aminoglycosides for polymicrobial infections with a smaller risk of renal damage to patients.

Mr Blostica is a PharmD candidate at Ferris State University, Kalamazoo, Mich. He can be reached at tblostica@yahoo.com
.

Dr Klepser is a pharmacy practice professor at Ferris State University.

In each issue, the "Focus on" feature reviews a newly approved or investigational drug of interest to pharmacy and therapeutics committee members. The column is coordinated by Robert A. Quercia, MS, RPh, director of Drug Information Services at Hartford Hospital in Hartford, Conn, and adjunct associate professor, University of Connecticut School of Pharmacy, Storrs, Conn; and by Craig I. Coleman, PharmD, assistant professor of pharmacy practice, University of Connecticut School of Pharmacy, and director, Pharmacoeconomics and Outcomes Studies Group, Hartford Hospital.

Editors' note: The clinical information provided in "Focus on" articles is as current as possible. Due to regularly emerging data on developmental or newly approved drug therapies, articles include information published or presented and available to the author up until the time of the manuscript submission.

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