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Antimicrob Agents Chemother. 2006 March; 50(3): 862–867.
PMCID: PMC1426424

Telavancin versus Standard Therapy for Treatment of Complicated Skin and Skin Structure Infections Caused by Gram-Positive Bacteria: FAST 2 Study


Telavancin is a bactericidal lipoglycopeptide with a multifunctional mechanism of action. We conducted a randomized, double blind, active-control phase II trial. Patients ≥18 years of age with complicated skin and skin structure infections caused by suspected or confirmed gram-positive organisms were randomized to receive either telavancin at 10 mg/kg intravenously every 24 h (q24h) or standard therapy (antistaphylococcal penicillin at 2 g q6h or vancomycin at 1 g q12h). A total of 195 patients were randomized and received at least one dose of study medication. Clinical success rates were similar in all analysis populations at test of cure. In microbiologically evaluable patients with Staphylococcus aureus at baseline (n = 91), 96% of the telavancin group and 90% of the standard-therapy group were cured. Among patients with methicillin-resistant S. aureus (MRSA) at baseline (n = 45), clinical cure rates were also 96% for telavancin and 90% for standard therapy. Microbiologic eradication in patients with S. aureus infection was better with telavancin compared to standard therapy (92% versus 78%, P = 0.07) and significantly better in patients with MRSA (92% versus 68%; P = 0.04). Therapy was discontinued for an adverse event (AE) in 6% and 3% of the patients receiving telavancin and standard therapy, respectively. Except for two cases of rash in the telavancin group, these AEs were similar in type and severity in the two groups. The overall incidences and severities of AEs and laboratory abnormalities were similar between the two groups. These data support the ongoing studies assessing the efficacy and safety of telavancin in the treatment of serious gram-positive infections, particularly involving MRSA.

Bacterial resistance has risen dramatically during the last few decades (12, 14, 20). In the United States, more than 60% of the Staphylococcus aureus isolates in intensive care units are now resistant to methicillin (MRSA) (14). Growing rates of methicillin resistance among staphylococci have resulted in an increased use of vancomycin, which in turn has been accompanied by the development of vancomycin resistance in clinical strains of enterococci (14, 11) and S. aureus (3, 4). Bacterial resistance has also extended beyond health care facilities, as reflected by recent outbreaks of severe community-acquired infections caused by MRSA (2, 6, 7, 9, 13). Unfortunately, the development of new effective antibacterial agents has not kept pace with these important epidemiologic changes. In fact, antibacterial development has declined while antimicrobial resistance has increased (18).

Telavancin is a novel lipoglycopeptide with rapid, concentration-dependent bactericidal effects. Telavancin exerts these effects through multiple mechanisms of action, including the interaction with d-Ala-d-Ala-containing peptidoglycan intermediates that leads, at submicromolar concentrations, to inhibition of the transglycosylation step of peptidoglycan synthesis during cell wall synthesis (10, 16). Telavancin also affects bacterial plasma membrane functions, such as membrane potential depolarization and increased permeability, which are observed at higher but clinically achievable concentrations (8, 16). Telavancin is primarily eliminated unmodified in the urine, and dose adjustment is needed in patients with renal failure. In vitro studies have shown that telavancin is bactericidal against clinically important gram-positive bacteria, including drug-resistant strains such as MRSA, intermediately vancomycin-susceptible and -resistant S. aureus, and penicillin-resistant pneumococci (8, 10, 16). The MIC of telavancin for 90% of the strains tested (MIC90) was lower for clinical strains of S. aureus compared to that of oxacillin or vancomycin for both methicillin-susceptible S. aureus (MSSA) and MRSA (8, 16). A recent phase II trial using telavancin at 7.5 mg/kg/day provided preliminary evidence of activity in the treatment of complicated skin and skin structure infections (cSSSI), particularly for those patients infected with MRSA (19). In the present study, we explored the safety and efficacy of telavancin at a dose of 10 mg/kg daily for cSSSI.


This study was a randomized, double blind, active-control, parallel-group phase II clinical trial conducted at 11 centers in the United States and 7 centers in South Africa. Centers received approval from their institutional review boards or ethics committees, and informed consent was obtained from all patients prior to participation in the study.

A central interactive voice response system was employed to randomize patients as they were enrolled. The randomization was stratified by choice of standard therapy (antistaphylococcal penicillin or vancomycin) and geographic region (the United States or South Africa).

Patient population.

Patients were eligible for the study if they were males or nonpregnant females ≥18 years of age with a diagnosis of cSSSI caused by a suspected or confirmed gram-positive organism. cSSSI was defined as the presence of the following conditions: a major abscess requiring surgical drainage; deep, extensive cellulitis; an infected wound or ulcer; or an infected burn. In addition, patients were also required to have purulent drainage or collection or at least three of the following: erythema, heat and/or localized warmth, fluctuance, swelling and/or induration, pain and/or tenderness upon palpation, fever (>38°C), a white blood cell count of >10,000/mm3, or >15% bands.

Patients were excluded if they had received prior antibiotic therapy for >24 h within 7 days prior to enrollment (unless the pathogen was resistant or the patient was clinically failing therapy) or had osteomyelitis, necrotizing fasciitis, chronic diabetic foot ulcers, gangrene, burns involving >20% of the body surface, or mediastinitis. Patients were also excluded if they had an un-cSSSI, moderate-to-severe liver disease (Child-Pugh class B or C), an alanine transaminase or aspartate aminotransferase level more than five times the upper normal limit, human immunodeficiency virus infection with a CD4 cell count of <100/mm3, an absolute neutrophil count of <500 cells/mm3, or a QTc interval of >500 ms.

Antimicrobial therapy.

Patients were randomized on a 1:1 basis to receive either intravenous telavancin (10 mg/kg once a day) or intravenous standard therapy (vancomycin at 1 g every 12 h or nafcillin or oxacillin at 2 g or cloxacillin at 0.5 to 1 g every 6 h). The choice of standard therapy was made by the investigator prior to randomization. Dose adjustment was permitted (including adjustment of vancomycin dosing using local serum level monitoring) as dictated by the standard practice of the individual participating site. The dose of telavancin was adjusted in patients with a creatinine clearance of <50 ml/min. Study medications were prepared and doses adjusted in a blinded fashion by an individual (usually a pharmacist) who did not participate in patient evaluation. Site personnel involved in the evaluation of clinical response remained blinded to treatment assignment (including serum vancomycin level reports).

Also, change in the choice of standard therapy was allowed based on baseline culture and susceptibility test results. For example, patients who were randomized to standard therapy and preassigned to vancomycin but with MSSA isolated from baseline cultures could be switched to an antistaphylococcal penicillin. Study medications were administered for a minimum of 4 days and a maximum of 14 days. In order to maintain blinding between the once daily and two or four times daily dosing regimens, dummy infusions were utilized. No switch to oral therapy was permitted. Aztreonam and/or metronidazole were allowed as concomitant antibacterial therapy for those patients with proven or suspected polymicrobial infections.

Clinical and microbiological evaluations.

Clinical assessments were performed at baseline and daily through the end of therapy (EOT). The EOT evaluation was conducted within 3 days following administration of the last dose of the study medication. The test-of-cure visit (TOC) was scheduled 7 to 14 days after administration of the last dose of the study medication. At each evaluation, investigators assessed the extent of the infection, surgical procedures, adverse events (AEs), and concomitant medications. Electrocardiograms (ECGs) and laboratory tests were also performed.

Gram stains and culture specimens were obtained from all patients at baseline. They were repeated at EOT and/or TOC if drainage or significant lesions were present. Needle aspiration was performed in patients with cellulitis. In patients with deeper infections, specimens were collected by needle aspiration or surgical procedures. Culture, organism identification, and susceptibility testing were performed at each site. Confirmatory identification of the pathogens and susceptibility testing against telavancin was conducted in a central laboratory (ICON Laboratories, Farmingdale, NY).

Statistical analysis.

The FAST 2 study was designed to assess safety and to explore the efficacy of telavancin in patients with cSSSI. The sample size was based on clinical judgment as to the number of subjects required to provide clinically meaningful descriptive results. All P values and confidence intervals (CIs) were two sided, and statistical significance was declared at the 0.05 level. For baseline patient characteristics, a two-sample t test for continuous variables, an unadjusted Pearson chi-square test, or Fisher's exact test was used, as appropriate. For clinical and microbiological responses, Barnard's unconditional test of superiority was used, as well as a CI for the difference in proportions to evaluate noninferiority.

Analysis populations.

The following populations were defined for analysis. (i) The all-treated population consisted of patients with a confirmed cSSSI diagnosis who received at least one dose of the study medication. (ii) The clinically evaluable population consisted of patients in the all-treated population who complied with all exclusion and inclusion criteria and had a clinical response of either cure or failure, as assessed at the TOC visit. Patients were excluded from this population if they had only a gram-negative pathogen(s) or a gram-negative pathogen resistant to aztreonam isolated at baseline in patients with polymicrobial infection. (iii) The microbiologically evaluable population consisted of patients in the clinically evaluable population who also had a baseline pathogen recovered from pretreatment cultures.


Patients who received at least one dose of study medication were evaluated for safety. AEs, vital signs, digital ECGs using the same ECG recorders at all sites, and laboratory parameters were evaluated. The relationship between study medications and AEs was determined by the site investigators. A blinded core laboratory (eResearch Technology, Philadelphia, PA) processed and analyzed all ECGs. A central laboratory (ICON Laboratories, Farmingdale, NY) conducted analysis of safety laboratory samples.


Clinical response was classified as cure, failure, or indeterminate at the EOT and TOC visits. Cure was defined as resolution of clinically significant signs and symptoms associated with the skin and skin structure infection present at study admission or improvement to the extent that the infectious process had been controlled and no further antimicrobial therapy was necessary. Failure was defined as inadequate response to study therapy or a need for significant surgical management (e.g., more than routine debridement) of the infection site following antibiotic therapy and prior to the TOC visit. Indeterminate was defined as an inability to determine the outcome. A Clinical Events Committee, blinded as to treatment assignment, reviewed and adjudicated the derived TOC clinical response for all patients in the following categories: (i) indeterminate, (ii) failure, (iii) enrollment under protocol exception, (iv) death or surgical procedure on or before the TOC visit, and (v) a gram-negative pathogen resistant to aztreonam isolated at baseline.

In the microbiologically evaluable population, the baseline pathogen was considered eradicated at EOT or TOC if the pathogen was not detected by culture or if the subject's clinical response was a cure and there was nothing available for culture.


Study population.

A total of 195 patients were randomized and received at least one dose of the study medication (100 patients in the telavancin group and 95 in the standard-therapy group). Among patients in the standard-therapy group, 93% (n = 88) received vancomycin and 7% (n = 7) received antistaphylococcal β-lactams. One patient in the standard-therapy group was switched from a β-lactam to vancomycin after confirmation of MRSA infection.

Baseline patient characteristics were similar for both groups (Table (Table1).1). More than half of the patients were male (60%) and white (65%). The average age was 44 years. The most common diagnoses were major abscess (58%), deep/extensive cellulitis (29%), and wound infection (11%). Infections occurred most frequently in the lower extremities (47%), torso (24%), and upper extremities (21%). Common predisposing factors included recent surgical procedures (33%), trauma (21%), and diabetes (16%). Most patients had received prior antimicrobial therapy (69% in the telavancin group and 65% in the standard-therapy group).

Study population and baseline patient characteristics

Baseline pathogens and in vitro susceptibilities.

Overall, a baseline pathogen was identified in 82% of the all-treated population. A single pathogen was isolated in 64% of the all-treated population, and two or more pathogens (mixed infections) were documented in 18% of the patients (19 and 16 patients in the telavancin and standard-therapy groups, respectively). S. aureus was the most commonly isolated pathogen (52%), followed by gram-negative bacteria (19%) and nonenterococcal streptococci (16%). The MIC90s were determined for 55 strains of MSSA and 54 strains of MRSA. The MIC90 of telavancin was 1.0 μg/ml for MSSA (range, 0.06, 1.0 μg/ml) and 0.25 μg/ml for MRSA (range, 0.06, 1.0 μg/ml). All tested strains of S. aureus recovered from patients in the study were susceptible to ≤1.0 μg/ml of telavancin. Serum levels of telavancin were determined in 47 patients. The mean ± standard deviation (SD) peak and trough concentrations were 82.2 ± 27.3 μg/ml and 8.66 ± 7.28 μg/ml, respectively. Table Table22 displays the in vitro susceptibilities of the most common gram-positive pathogens isolated at baseline.

Most common baseline gram-positive pathogens and MIC90s for different antibacterial agents

Clinical response.

Clinical cure rates at TOC were similar in all populations (Table (Table3).3). For the all-treated population (n = 195), a cure was achieved at TOC in 82 patients (82%) in the telavancin group and 81 patients (85%) in the standard-therapy group (Barnard's test, P = 0.37; 95% CI, −0.04, 0.11). The primary efficacy endpoint was the clinical cure rate in the clinically evaluable population. In this patient population, 74 patients (96%) in the telavancin group and 72 patients (94%) in the standard-therapy group (P = 0.53; 95% CI, −0.05, 0.11) were cured at TOC. In the microbiologically evaluable population at TOC, a cure was obtained in 62 patients (97%) in the telavancin group and 53 patients (93%) in the standard-therapy group (P = 0.37; 95% CI, −0.05, 0.14).

Clinical response at TOCa

Assuming that the cure rates (telavancin, 96.5%; standard therapy, 93.1%) and sample sizes (telavancin, 85; standard therapy, 87) observed in the all-treated population, after excluding patients with a clinical response of indeterminate, were used to evaluate this study's power for a test of noninferiority, then a 95% CI for the difference in proportions would have 95% power to detect a 0.15 difference.

In the all-treated population, S. aureus was isolated at baseline in 59 (59%) and 49 (52%) of the patients in the telavancin and standard-therapy groups, respectively. For these patients, a cure was achieved at TOC in 83% of the telavancin group and 82% of the standard-therapy group. In the all-treated population with MRSA at baseline (n = 53), a cure was achieved in 86% of the cases in the telavancin group and 75% of those in the standard-therapy group. In microbiologically evaluable patients with S. aureus at baseline (n = 91), 96% of those in the telavancin group and 90% of those in the standard-therapy group were cured. The same cure rates (96% and 90% for telavancin and standard therapy, respectively) were observed for those patients who had MRSA (n = 45).

Microbiological response.

One hundred twenty-one patients in the all-treated population (62%) were microbiologically evaluable. Among these patients, baseline pathogens were considered eradicated at EOT in 57 patients (89%) in the telavancin group and 44 patients (77%) in the standard-therapy group (P = 0.09). At TOC, pathogen eradication was again higher in those patients receiving telavancin (94% versus 83%; P = 0.06). In patients with S. aureus isolated at baseline (n = 91), eradication at TOC was obtained in 92% of the patients receiving telavancin and 78% of the patients receiving standard therapy (P = 0.07). In patients infected with MRSA (n = 45), eradication rates were significantly higher in the telavancin group (92% versus 68%; P = 0.04). Table Table44 displays the microbiological responses.

Microbiological response at TOCa

Safety and tolerability.

AEs were documented in 56% and 57% of the patients receiving telavancin and standard therapy, respectively. Among patients with AEs, 73% of the patients in the telavancin group and 59% of the patients in the standard-therapy group had events that were judged to be possibly or probably related to therapy (P = 0.16).

Similar proportions of patients in both groups experienced severe AEs (6% and 4% for the telavancin and standard-therapy groups, respectively) or were removed from the study medication due to an AE (6% in the telavancin group and 3% in the standard-therapy group). Serious AEs (SAEs) were documented in seven patients in the telavancin group and three patients in the standard-therapy group. In the telavancin group, 12 SAEs were reported in seven patients: disseminated intravascular coagulation, atrial fibrillation, gastrointestinal bleeding, lobar pneumonia, subcutaneous abscess, wound infection, myositis, suicidal ideation, renal failure, ileostomy, hypotension, and wound hemorrhage. Although reported as SAEs, the cases involving wound infection and abscess were outcomes related to the primary infection. In the standard-therapy group, eight SAEs were reported in three patients: multiorgan failure, liver failure, bacteremia, sepsis, renal failure, atelectasis, lung infiltration, and respiratory failure.

The most common AEs reported are shown in Table Table5.5. Overall, mild and transient nausea, insomnia, headache, and taste alterations occurred more frequently in patients assigned to the telavancin group. Two patients in the telavancin group had rashes of moderate severity and were removed from the study; no cases of red man syndrome were reported. Vomiting, diarrhea, and constipation occurred with similar frequencies in the two groups, and most cases were judged unrelated to the study medications. All cases of chills in both groups were considered mild and not related to the study medications.

AEs reported in ≥5% of the patients in any group (all-treated population)

Table Table66 displays the incidences of laboratory abnormalities in the two groups. Serum creatinine was increased in five patients in the telavancin group at EOT. Maximum concentrations of serum creatinine were ≤1.8 mg/dl in all but one patient. The patient was a 29-year-old male who had been taking ibuprofen and diclofenac for pain and had a maximum value of 3.5 mg/dl on study day 4. This patient was removed from the study, and his creatinine values returned to the normal range during follow-up. One patient in the standard-therapy group developed multiorgan failure (including renal) and was removed from the study. Hypokalemia was more common in the telavancin group. Hypokalemia was present in seven patients in the telavancin group at EOT; the minimum potassium value was 2.2 meq/liter, and all other values at EOT ranged from 3.4 to 3.5 meq/liter. The occurrences of hypomagnesemia and microalbuminuria were similar in the two groups. Alterations in liver function tests and eosinophilia were less common among those patients receiving telavancin. An analysis of ECG data revealed a mean change from the baseline in QTc (Fridericia corrected) of 12.5 ms longer in the telavancin group compared to the standard-therapy group (P ≤ 0.0001). In addition, more QTcF outliers were noted in the telavancin patients (n = 6) compared to those on standard therapy (n = 1). There were no cardiac AEs reported that were associated with QTc prolongation.

Laboratory abnormalities reported in the all-treated populationa


This is the first study exploring the safety and efficacy of telavancin at 10 mg/kg in patients with complicated skin and skin structure infections. Importantly, S. aureus was the most commonly isolated pathogen and approximately one-half of the patients infected with S. aureus had MRSA, the targeted pathogen. Overall, telavancin was as effective as standard therapy in all of the study populations, including those patients who had MRSA at baseline. In patients infected with MRSA, treatment with telavancin produced significantly higher bacterial eradication rates at TOC (92% versus 68%; P = 0.04). There was also a trend toward higher eradication rates following telavancin treatment in all microbiologically evaluable patients, as well as in those infected with S. aureus. These observations are consistent with both preclinical and previous clinical data (8, 10, 16, 17, 19). Compared with β-lactams or vancomycin in both in vitro and animal models, telavancin exerts more rapid bactericidal effects against gram-positive cocci (8, 16). In the present study, telavancin was fourfold more potent in vitro than vancomycin against the clinical strains of MRSA isolated during the study (MIC90, 0.25 μg/ml for telavancin versus 1.0 μg/ml for vancomycin). Most importantly, telavancin achieved peak concentrations in serum more than 300-fold above the MIC90 for MRSA. A recent phase II study using telavancin at 7.5 mg/kg in patients with cSSSI provided similar findings for patients infected with S. aureus, particularly for those infected with MRSA (19). Comparing the results of the present study with those obtained in the previous study, telavancin at 10 mg/kg achieved higher clinical and microbiological response rates than telavancin at 7.5 mg/kg, which may at least partially be explained by its concentration-dependent bactericidal effects.

The overall frequencies of AEs were similar in the two groups. Telavancin was more frequently associated with nausea, insomnia, headache, and taste alterations (usually described as metallic in nature), though the majority of cases of insomnia and headache were not felt by the study teams to be related to the study medication. In addition, most of these events were mild in severity. Seven patients had mild and easily reversible hypokalemia. Additionally, a clinically significant increase in serum creatinine (creatinine elevation at EOT to ≥1.5 mg/dl with an increase of at least 0.5 mg/dl over the pretreatment level) was documented in three patients in the telavancin group. One patient was removed from the study as a result. All patients who had increases in creatinine experienced a return to baseline values after the drug was stopped. The frequency and clinical characteristics of these renal alterations after longer treatment regimens and in association with concomitant nephrotoxic medications (e.g., aminoglycosides) are unknown and require further studies. In the meantime, regular monitoring of serum creatinine and potassium during therapy seems warranted.

A 12.5-ms QTc prolongation was documented in patients receiving telavancin in this phase II trial. Previously, a definitive QTc study of healthy volunteers demonstrated a QTc prolongation with telavancin of ~5 ms (1). This prolongation was significantly greater than that seen with a placebo but significantly less than the prolongation seen with moxifloxacin, which was included as a positive control. In phase II and III trials, ECGs are used to define immediate patient safety and to determine imbalances in outliers. There were more outliers, defined as a >60-ms change from the baseline QTcF duration on telavancin, confirming that this agent does have an effect, albeit small, on cardiac repolarization. This effect is similar to commonly used antibiotics in the fluoroquinolone group (15). No cardiovascular AEs or arrhythmias associated with QTc prolongation were reported.

In patients infected with MRSA, telavancin achieved higher rates of bacterial eradication. Even though the clinical significance of this eradication is unclear, the finding strongly supports the bactericidal effect of telavancin. Future studies are needed to assess longer-term eradication. The present investigation was designed to explore the safety and efficacy of telavancin at 10 mg/kg in patients with cSSSI and was not powered to provide statistically significant results. Despite this limitation, the study has shown promising results in patients infected with gram-positive cocci, particularly in those infected with MRSA.

Increasing resistance rates, acquisition in the community, and the emergence of more-virulent strains have transformed MRSA into a major global health problem (5, 20). In addition, intermediately vancomycin-susceptible S. aureus and even S. aureus fully resistant to vancomycin have been clinically documented. New therapies against these resistant pathogens are urgently needed. The results of this study support further investigations of telavancin for the treatment of serious infections due to resistant gram-positive pathogens, particularly those caused by MRSA.


This study has been supported by and conducted under the auspices of Theravance, Inc.

This study was coordinated by the Duke Clinical Research Institute, Durham, NC. We give special thanks to Joanne Miller and Beth Spencer at Theravance and Kathleen Trollinger at the Duke Clinical Research Institute for providing invaluable clinical research management support.

Potential conflict of interest are as follows. Steven L. Barriere and Michael M. Kitt are employees of Theravance. Vance G. Fowler, Jr., has received research funding from Theravance, Nabi, Inhibitex, Cubist, and the National Institutes of Health; he is a consultant for Inhibitex, Merck, and Cubist; and he is on the speaker's bureaus for Cubist and Pfizer. Martin E. Stryjewski has received a research grant from Theravance and is a consultant for Theravance. G. Ralph Corey has received research funding from Theravance, Cubist, Merck, and Inhibitex and is a consultant for Cubist, Inhibitex, Pfizer, and Vicuron. Vivian H. Chu received a research grant from Theravance. Joel Morganroth is a consultant for Theravance and is the chief scientist at eResearch Technology, the central laboratory (however, he did not have any involvement in the ECG processing). William D. O'Riordan, Brian L. Warren, Lala M. Dunbar, and David M. Young are investigators for Theravance. Marc Vallée has no potential conflicts of interest.


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