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Efficacy and Safety of Weekly Dalbavancin Therapy for Catheter-Related Bloodstream Infection Caused by Gram-Positive Pathogens

  1. Issam Raad1,
  2. Rabih Darouiche2,
  3. Jose Vazquez3,
  4. Arnold Lentnek4,
  5. Ray Hachem1,
  6. Hend Hanna1,
  7. Beth Goldstein5,
  8. Tim Henkel5, and
  9. Elyse Seltzer5
  1. 1The M. D. Anderson Cancer Center, Houston, Texas
  2. 2Veterans Affairs Medical Center, Houston, Texas
  3. 3Harper University Hospital, Detroit, Michigan
  4. 4Wellstar/Kennestone Hospital, Marietta, Georgia
  5. 5Vicuron Pharmaceuticals, King of Prussia, Pennsylvania
  1. Reprints or correspondence: Dr. Elyse Seltzer, 455 South Gulph Rd., Ste. 310, King of Prussia, PA 19406 (eseltzer{at}vicuron.com).
 
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Abstract

Background. Catheter-related bloodstream infections (CR-BSIs) are associated with substantial mortality, prolongation of hospital stay, and increased cost of care. Dalbavancin, a new glycopeptide antibiotic with unique pharmacokinetic properties that have allowed clinical development of a weekly dosing regimen, possesses excellent activity against clinically important gram-positive bacteria, suggesting utility in the treatment of patients with CR-BSIs.

Methods. A phase 2, open-label, randomized, controlled, multicenter study of 75 adult patients with CR-BSIs compared treatment with intravenous dalbavancin, administered as a single 1000-mg dose followed by a 500-mg dose 1 week later, with intravenous vancomycin, administered twice daily for 14 days. Gram-positive bacteria isolated in this study included coagulase-negative staphylococci (CoNS) and Staphylococcus aureus, including methicillin-resistant S. aureus (MRSA).

Results. Infected patients who received weekly dalbavancin (n = 33) had an overall success rate (87.0%; 95% confidence interval [CI], 73.2%–100.0%) that was significantly higher than that of those who received vancomycin (n = 34) (50.0%; 95% CI, 31.5%–68.5%). Adverse events and laboratory abnormalities were generally mild and were comparable for the 2 drugs.

Conclusions. Dalbavancin thus appears to be an effective and well-tolerated treatment option for adult patients with CR-BSIs caused by CoNS and S. aureus, including MRSA.

Intravascular access devices are essential components of medical care. Although invaluable, these devices introduce a persistent risk of infection. Catheter-related bloodstream infections (CR-BSIs) are the most commonly reported nosocomial bloodstream infections, particularly among patients in intensive care units (ICUs) [1]. They are most often caused by gram-positive bacteria, especially coagulase-negative staphylococci (CoNS), Staphylococcus aureus (including methicillin-resistant S. aureus [MRSA]), and enterococci [2], and they have a substantial impact on morbidity, mortality, duration of hospital stay, and cost of care. Current estimates of infection rates associated with central venous catheters (the devices most commonly associated with CR-BSIs) range from 8.5 to 19.8 cases of infection per 1000 catheter-days [1, 3, 4]. The number of intravascular devices purchased annually by hospitals is estimated to be in the hundreds of millions, including ⩾5 million central venous or pulmonary artery catheters. Even a modest rate of infection can generate costs in the billions of dollars [5–7].

Antibiotic therapy for CR-BSIs is frequently initiated empirically. Vancomycin is the standard of care for empirical use and for infections due to methicillin-resistant organisms. The only glycopeptide choice other than vancomycin is teicoplanin, which is not available in the United States; thus, the search for other effective agents is warranted [8]. Dalbavancin is a new, semisynthetic, glycopeptide antibiotic with excellent activity against gram-positive bacteria. It is active against major skin flora associated with catheter-related infection, demonstrating potent inhibition of S. aureus (including MRSA), CoNS, streptococci, and enterococci [9, 10]. In a recent in vitro assessment, dalbavancin activity against >6000 gram-positive clinical isolates was equal or superior to the activity of linezolid, quinupristin/dalfopristin, teicoplanin, and vancomycin, with >98% of bacteria inhibited at ≤0.12 µg/mL [10].

Pharmacokinetic properties support the administration of dalbavancin at a substantially reduced frequency, compared with vancomycin and teicoplanin. Dalbavancin has a long half-life (t1/2) (∼9–12 days), which is longer than that of any currently available glycopeptide. In phase 1 dose-ranging studies involving healthy subjects, blood samples obtained from patients at ⩾7 days after administration of a single dose of dalbavancin demonstrated persistence of bactericidal activity against isolates of MRSA [11]. In a phase 2 clinical trial involving patients with skin and skin-structure infections, a single infusion of 1000 mg of dalbavancin resulted in mean plasma concentrations of >35 mg/L for a 7-day period [12]. Serum levels remained greater than MICs and typically above concentrations that are bactericidal for target organisms throughout the proposed dosing interval of 1 week.

This prospective trial was undertaken to evaluate the safety and efficacy of dalbavancin given in 2 doses administered 1 week apart, compared with a 14-day course of twice-daily vancomycin, in the treatment of adult patients with CR-BSIs.

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Methods

Patient Selection

Adult patients >18 years old with signs of bacteremia (e.g., fever or chills) possibly or definitely associated with CR-BSI were screened for enrollment. Eligibility requirements included ⩾1 of the following characteristics: intravascular access catheter (i.e., tunneled or nontunneled catheter, single-lumen or multilumen catheter, peripherally inserted central catheter, or implanted port) present at the time of initial signs of infection; absence of any other likely source of infection; and either microbiologically documented, gram-positive bacteremia or ⩾2 signs of bacteremia (core temperature of >38.0°C or <36.0°C, WBC count of >12,000 cells/mm3 or <4000 cells/mm3, tachycardia, tachypnea, or transient hypotension).

Exclusion criteria included significant renal or hepatic impairment, receipt of immunosuppressive therapy, prolonged neutropenia, prior treatment with an antibiotic active against gram-positive bacteria for >24 h within 48 h of study medication initiation, S. aureus bacteremia within the previous 3 months from a source other than a central venous catheter, alternative focus of infection (e.g., endocarditis, osteomyelitis, infected prosthesis, presence of prosthetic endovascular material, deep abscess, or septic thrombophlebitis), and use of pulmonary artery catheter.

Study Design

This was a phase 2, randomized, controlled, open-label trial conducted at 13 centers in the United States from 21 April 2002 to 11 September 2003. Approximately 80 patients were to be enrolled. With an observed success rate of 85% for overall response, this sample size would ensure that the bounds of the 2-sided 95% CI for the success rate would not exceed 13% (i.e., the 95% CI would not exceed 73%–97%). Point estimates of overall success rates with 95% CIs were prospectively specified. Patients were randomly assigned to receive either 2 doses of intravenous dalbavancin (a 1000-mg loading dose on day 1 and a 500-mg dose on day 8) or intravenous vancomycin (1000 mg b.i.d.), with the dose to be adjusted on the basis of serum levels, per investigator routine. The study was initially designed with a daily treatment arm of dalbavancin (650 mg iv on day 1, followed by 65 mg iv q.d.). During the trial, the protocol was amended, and this arm was dropped. The primary outcome measure was overall efficacy at the follow-up visit (i.e., test-of-cure [TOC]), which was determined on the basis of combined clinically and microbiologically documented responses among patients with a bacterial pathogen identified at study entry. Secondary outcomes included clinical and microbiological responses at end of therapy (EOT) and TOC. Because of dalbavancin's long t, a single dose was considered equivalent to 7 days of therapy.

Safety evaluations included assessment of adverse events and laboratory parameters over time. Patients were assessed clinically and blood culture results were obtained at baseline (day 1), during treatment (day 4), at EOT, and at the TOC visit. Clinical responses were assessed at the EOT (i.e., within 2 days after the treatment period) and at the TOC visit (21 ± 3 days after the treatment period). The TOC visit was the last assessment time in the study design. A microbiological outcome for each causative organism identified at baseline was assessed programmatically, with success (eradication or presumed eradication of the organism) and failure (persistence, presumed persistence, recurrence, or presumed recurrence of the organism, or indeterminate outcome) prospectively defined to determine by-pathogen and by-patient microbiological response at EOT and TOC.

Antimicrobials with no activity against gram-positive bacteria, such as metronidazole for anaerobes and aztreonam or ceftazidime for gram-negative bacterial infections, were permitted at the investigator's discretion. Ceftazidime was allowed as an acceptable method to treat infections with gram-negative organisms if aztreonam was unavailable at a particular institution.

Microbiological Evaluation

S. aureus was considered a causative pathogen on the basis of documentation of ⩾1 peripheral venous blood culture positive for S. aureus. CoNS and other gram-positive bacteria were considered causative pathogens if they demonstrated concordant growth from paired samples. Duplicate CoNS isolates were first matched on the basis of colony morphology, physiological reactions (≤2 differences according to the Vitek system), and MICs of a panel of antibiotics (≤2 antibiotics with differences of >2 dilutions), as determined by the broth microdilution method. Any paired isolates that were neither obviously distinct nor clearly identical according to all of these criteria were analyzed by PFGE.

In instances in which a sample was drawn directly from a suspected catheter, either a difference in bacterial titers when compared with concurrent peripheral blood samples or a difference in time-to-positivity between centrally and peripherally drawn blood samples was acceptable evidence supporting the catheter as the definitive source of infection. All gram-positive isolates were tested for susceptibility to vancomycin and methicillin. Strains were sent to a central reference laboratory for confirmation of identity and determination of MICs of dalbavancin and other antimicrobial agents.

Catheter Management

Catheter removal was required in all instances of confirmed S. aureus infection. For CoNS, management was at the discretion of the investigator, although removal of the catheter was recommended. Use of antibiotic-lock treatment was not permitted. Antibiotic-impregnated catheters were allowed. If the catheter was removed in cases of CR-BSI due to CoNS, the investigator had the option to treat with a single dose of dalbavancin (or 7 days of vancomycin therapy). Whenever possible, catheter tips were sent for culture. Timing of catheter removal was not captured.

Categories of Catheter Infection

Infections were classified as either definite CR-BSI, probable CR-BSI, possible CR-BSI, secondary bacteremia, or catheter-related infection. These categories were differentiated by rigor of clinical specimen collection; method of culture and subsequent results, including concordance and time-to-positivity; and whether a secondary source for bacteremia (e.g., pneumonia or skin and skin-structure infection) was identified.

A diagnosis of definite CR-BSI required identification of an identical bacterial species (or, in the case of CoNS, a clonally unique isolate) from both catheter and percutaneous blood samples obtained within 24 h of one another, as well as either a 2-h difference for time-to-positivity for samples of centrally drawn blood relative to samples of peripheral blood; a ⩾5-fold concentration of the bacteria from the central blood sample, compared with the peripheral blood sample; or ⩾1 positive catheter or hub culture [13, 14]. Probable CR-BSI was diagnosed if the catheter was not cultured but ⩾1 peripheral blood culture was positive for S. aureus or ⩾2 blood cultures yielded identical species, with ⩾1 sample obtained from a peripheral site and with no other apparent source for the bacteremia. Possible CR-BSI was the presumed diagnosis when the culture media did not yield identical CoNS bacteria or if there were <2 cultures positive for a nonstaphylococcal pathogen. Patients were classified with secondary bacteremia if bacteremia was identified as being associated with a source other than the central catheter. Catheter-related infection (CR-I) was the diagnosis reserved for all patients enrolled empirically with negative culture results. Patients with a diagnosis of CR-I, possible CR-BSI, or secondary bacteremia were excluded from the microbiologically confirmed intent-to-treat (microITT) population but were included in the safety analysis.

Statistical Analysis

Study populations. All patients who received ⩾1 dose of the study drug constituted the intent-to-treat population and were evaluated for safety. The microITT population included patients infected with a protocol-defined, gram-positive pathogen at baseline who received ⩾1 dose of the study medication. The evaluable population was the subset of the microITT population who adhered to the treatment protocol and did not have either a medical condition that precluded accurate clinical assessment or a clinical outcome of indeterminate bacteremia.

Responses. The primary outcome parameter was overall response (i.e., combined clinical and microbiological response) in the microITT population as assessed at the TOC visit, within 18–24 days after EOT. Secondary outcome evaluations of both the evaluable and microITT populations were performed at the EOT and TOC visits. Clinical success was defined as resolution of signs and symptoms of CR-BSI such that no additional antibacterial treatment was warranted. Clinical failure was defined as persistence of local or systemic signs and symptoms of catheter-related infection such that continuing antibiotic therapy was indicated, death that was considered related to CR-BSI, or situations in which a definitive clinical assessment could not be made due to other factors, such as absence of follow-up data.

Microbiological responses of eradication or presumed eradication of the organism were considered successful outcomes in the primary analysis. All patients, regardless of whether they were evaluable, had a clinical response (success or failure) assessed by the investigator. Whether the patient was evaluable was determined centrally by the sponsor with use of prospectively defined criteria.

Safety evaluation. All safety analyses were conducted in the ITT population. Adverse event reporting was standardized, and adverse events were classified as mild, moderate, severe, or life-threatening. Criteria used were those defined in the study protocol for clinical assessment and identification of changes in vital signs and pertinent changes in serum chemistry or hematologic values, as well as changes since baseline noted by electrocardiography.

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Results

Study population. Seventy-five patients were randomized to receive treatment. There were 8 patients randomized to the daily treatment arm who are not included in the efficacy analysis. Pertinent demographic characteristics of enrolled patients are shown in table 1. Although slightly fewer female patients than male patients were enrolled in the vancomycin group, subjects were otherwise well matched in both treatment groups. The numerical differences between the microITT and evaluable populations in both treatment arms were largely due to receipt of prohibited concomitant antibacterial therapy during the course of the study, rendering patients unevaluable. Approximately one-quarter of patients from each group required ICU-level care at some point during the study period. Antibiotic- or antiseptic-coated catheters were more common in the vancomycin group than in the dalbavancin group (56% vs. 30%, respectively). The most common type of catheter in each group was a nontunneled device. Comparable numbers of catheters were removed or replaced in both treatment groups. Three catheters, all in the dalbavancin group, were changed over a guidewire.

Table 1
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Table 1

Study populations and demographic characteristics of study subjects receiving either dalbavancin or vancomycin for treatment of catheter-related bloodstream infection (CR-BSI).

Baseline microbiology. Baseline pathogens, presented in table 2, were evenly distributed across study arms. The most common pathogens identified were CoNS, followed by S. aureus. MRSA was encountered more frequently among patients in the vancomycin group (15 isolates, compared with 9 in the dalbavancin group). The distribution of baseline pathogens was similar in the evaluable populations.

Table 2
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Table 2

Isolates at baseline for the microbiologically confirmed intent-to-treat population.

Efficacy. The overall success rate for the primary efficacy population (i.e., the microITT population) for patients treated with dalbavancin was 87%, compared with 50% for the patients treated with vancomycin (table 3). Dalbavancin therapy was statistically superior to vancomycin therapy (P < .05) by virtue of the nonoverlapping 95% CIs around the response rates. Dalbavancin treatment was associated with greater success at the TOC visit, regardless of category of catheter-related infection or catheter status at baseline. Both treatment arms were more successful if the catheter was removed than if it was retained at baseline. At EOT, most patients in both treatment arms demonstrated resolution of local signs and symptoms of catheter-site infection.

Table 3
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Table 3

Clinical and microbiological response rates of study subjects receiving either dalbavancin or vancomycin for treatment of catheter-related bloodstream infection.

The rate of microbiological success at the TOC visit was higher in the dalbavancin group. Results of the secondary outcomes analysis for clinically evaluable patients at EOT and TOC assessments were consistent with those documented for the microITT population, favoring dalbavancin in terms of overall clinical and microbiological success.

Prognostic factor analyses with the primary efficacy assessment as the dependent variable was performed with use of logistic regression. Logistic regression analysis was used to explore possible associations between the primary efficacy parameter, overall response for the microITT population at the TOC visit, and selected covariates. Exploratory variables analyzed included treatment group, type of central venous catheter, baseline pathogen, baseline MIC, and catheter status at baseline. The best subset selection method was used in building the model. Multivariate analysis suggested that the best model was the one in which treatment group was the only exploratory variable. There was a significant association between treatment group and overall success rate (P = .0355). None of the other exploratory variables evaluated were found to have a significant association with overall success at TOC.

Safety. Overall, both treatments were well tolerated. Adverse events were reported by 71 patients; the number of patients in each arm who reported ⩾1 adverse event was similar. Most adverse events were mild or moderate in intensity. The most commonly reported adverse events in the dalbavancin group that were considered to be related to treatment were oral candidiasis, diarrhea, constipation, and febrile response; in the vancomycin group, the most commonly reported treatment-related adverse events were oral candidiasis, loose stools, fungal infections of the skin, vaginal fungal infections, acute renal failure, and renal impairment. No adverse events led to discontinuation of dalbavancin therapy or withdrawal from the study. The most common adverse events are presented in table 4.

Table 4
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Table 4

Adverse events reported by >3 study subjects in the intent-to-treat population receiving either dalbavancin or vancomycin for treatment of catheter-related bloodstream infection.

Three patients who were treated with vancomycin experienced adverse events that led to discontinuation of treatment, with 2 adverse events resulting in withdrawal from the study. One patient experienced a serious adverse event (acute renal failure) that was considered to be possibly related to vancomycin therapy; there were no serious adverse events in the dalbavancin treatment arm that were considered to be related to study medication. Five patients died in the course of the study; no deaths were related to use of the study medications. The number of patients with clinically significant changes from baseline in hematologic values and serum chemistry was low and similar between treatment arms, and few laboratory abnormalities were reported as adverse events.

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Discussion

In this phase 2, open-label, randomized, multicenter study, a 2-dose regimen of parenteral dalbavancin provided highly efficacious treatment of CR-BSIs caused by gram-positive bacteria. Compared with vancomycin—a standard antibiotic used for this indication—dalbavancin, administered as an initial 1000-mg dose followed 1 week later by a second infusion of 500 mg, achieved a significantly higher overall success rate. Dalbavancin also demonstrated higher response rates than vancomycin when stratified according to the strategy of catheter management (removal or replacement).

Less frequent dosing and lower total dosages in the treatment of serious bacterial infections are important potential benefits of dalbavancin. The current trial enrolled a representative cohort of patients who had a clinical course complicated by signs suggestive of nosocomial CR-BSI. The epidemiology of gram-positive pathogens (S. aureus and CoNS) in this study was consistent with that typically seen for CR-BSI [2]. In this study, the clinical efficacy is consistent with the pharmacokinetic properties of dalbavancin that support the maintenance of therapeutic drug concentrations over the course of a week. Use of an extended interval to the TOC visit is appropriate to survey for late metastatic sequelae of S. aureus bacteremia [15], such as abscesses, septic emboli, endocarditis, and osteomyelitis [16]. The TOC assessments uniformly favored dalbavancin over vancomycin in all efficacy populations.

The inferior efficacy of vancomycin, compared with dalbavancin, in this current study could be attributed to several factors. First, several studies have suggested that the antistaphylococcal clinical activity of vancomycin is inferior to that of semisynthetic antistaphylococcal penicillins, particularly in the treatment of deep-seated S. aureus infections, such as endocarditis [17–20]. Second, vancomycin has been shown to have limited activity against staphylococcal organisms embedded in biofilm on a catheter surface [21–23]. This limited activity of vancomycin in biofilm could be relevant, particularly in those patients whose catheters have not been removed. Activity in biofilm has not been studied in relation to dalbavancin, although peak plasma concentrations of dalbavancin are significantly higher than those of vancomycin [11], which could contribute to better penetration into a biofilm. Additionally, dalbavancin is a lipoglycopeptide, and the lipophilic side chain could contribute to better penetration; further studies are warranted to demonstrate this.

This study has several potential limitations. The open-label study design may lead to bias in subjective assessments by the investigator, although the micro assessments, made of the basis of culture results, were objective. Although CR-BSI is a commonly encountered clinical entity, identification of patients with CR-BSI who were eligible for study (i.e., those with no confounding conditions or treatments) was extremely difficult. The t of dalbavancin, compared with that of vancomycin, might affect the efficacy evaluation. Future studies of bacteremia should take this into account in planning the timing of efficacy assessments. Finally, because of the small size of the study, statistical inferences about the results are limited.

Dalbavancin was well tolerated, and there were no adverse events that led to its discontinuation. This is consistent with what has been reported for dalbavancin in the treatment of skin and skin-structure infections. The safety profile of dalbavancin should be further evaluated through large prospective phase 3 trials.

Nosocomial infections result in prolonged hospitalization and significant increases in cost [24, 25]. Total costs of intravenous antibiotic treatment include acquisition expenses, costs associated with disposable materials, and overhead costs. Indirect costs associated with the administration of each dose of daily intravenous antibiotic therapy represent >50% of the total daily costs of antibiotic therapy and may therefore exceed the entire cost of drug acquisition [26]. Other expenses include the costs of nursing and physician intervention, as well as the indirect costs associated with skilled personnel who supervise or implement medication delivery [26].

The extended half-life of dalbavancin may facilitate reduction of resource-intensive therapeutics in hospital settings and promote outpatient or skilled nursing facility treatment of S. aureus bacteremia and its consequences, which currently require a prolonged course of parenteral therapy [5]. Furthermore, weekly dosing with dalbavancin may reduce the need for indwelling devices in patients with catheter-related bacteremia, for whom treatment generally involves daily parenteral antibiotic administration.

Dalbavancin is a new glycopeptide antibiotic with a unique dosing regimen and demonstrated efficacy in the treatment of infections caused by gram-positive pathogens, including resistant strains. In this study, 2 doses of dalbavancin administered 1 week apart demonstrated superior efficacy rates, compared with a 14-day course of twice-daily parenteral vancomycin. This suggests advantages in cost of therapy and may offer invaluable flexibility in implementing innovative approaches to antibiotic treatment of adult patients with bacteremia.

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Acknowledgments

Financial support. Vicuron Pharmaceuticals.

Potential conflicts of interest. B.G., T.H., and E.S. are employees of Vicuron Pharmaceuticals. R.D. has received a research grant and consultant fees from Vicuron Pharmaceuticals. I.R. has received a research grant and consultant fees from Vicuron Pharmaceuticals. All other authors: no conflicts.

  • Received June 22, 2004.
  • Accepted September 22, 2004.
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  1. Clin Infect Dis. (2005) 40 (3): 374-380. doi: 10.1086/427283
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