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Drug Profile
Telavancin (VIBATIV) for the treatment of complicated skin and skin structure infections Expert Rev. Anti Infect. Ther. 13(7), 825–833 (2015)
Tamara Nawar and Zeina A Kanafani* Division of Infectious Diseases, Department of Internal Medicine, American University of Beirut Medical Center, Beirut, Lebanon *Author for correspondence: Tel.: +961 1350 000; extn. 4747 Fax: +961 1370 814 [email protected]
Methicillin-resistant Staphylococcus aureus has emerged as a major causative pathogen in complicated skin and skin structure infections (cSSSIs). Unfortunately, treatment failure with vancomycin has been increasingly reported. Over the past decade, several alternative antimicrobial agents have been studied and approved for the treatment of cSSSIs. One such agent is the lipoglycopeptide telavancin, which was approved by the US FDA 2009. Given its dual mechanism of action, telavancin is characterized by a highly bactericidal activity and low potential for resistance selection. In addition, in clinical trials, it was efficacious and safe in the treatment of cSSSI. The purpose of this review is to give a background overview of telavancin, highlighting its microbiological, pharmacokinetic and pharmacodynamics characteristics, to summarize the available evidence for its use in the treatment of cSSSIs, and to provide an updated evaluation of its safety profile. KEYWORDS: complicated skin and skin structure infection . lipoglycopeptide . methicillin-resistant S. aureus . telavancin .
vancomycin
It is estimated that complicated skin and skin structure infections (cSSSIs) occur in approximately 7–10% of hospitalized patients [1]. These common infections may vary from mild cellulitis affecting the dermis and subcutaneous fat to necrotizing fasciitis with spread into the fascial line and necrosis of the subcutaneous tissues. In many US and European centers, methicillin-resistant Staphylococcus aureus (MRSA) is now recognized as a leading pathogen in cSSSIs. In 2004, MRSA was the most commonly identifiable organism in patients with cSSSIs presenting at 11 emergency departments across the USA [2]. In a more recent retrospective study of cSSSIs in hospitalized patients, 66.4% of cultures grew S. aureus, of which 74.8% were MRSA [3]. The management of cSSSIs may vary depending on the severity, risk factors, and epidemiologic background of the patient. In 2014, the Infectious Diseases Society of America updated the guidelines for the management of cSSSIs, describing the various approaches to this complex group of infections [4]. According to current guidelines, when MRSA is a likely informahealthcare.com
10.1586/14787210.2015.1043889
pathogen, empiric therapy in patients with moderate symptoms should consist of oral antibiotics, such as trimethoprim–sulfamethoxazole or doxycycline, whereas in patients with severe symptoms, recommended therapies include vancomycin, daptomycin, linezolid, ceftaroline, or telavancin. The US FDA granted telavancin its approval for the treatment of cSSSIs in September 2009. Telavancin is a once-daily, injectable lipoglycopeptide with a dual mechanism of action: inhibition of bacterial cell wall synthesis, and disruption of the bacterial cell membrane barrier. Overview of the market
In the 1950s, the emergence of S. aureus-resistant isolates prompted researchers to look for new alternatives. Vancomycin was the first of the glycopeptide family of antibiotics to be discovered and used against methicillin-resistant S. aureus [5]. It has been the drug of choice for the treatment of beta-lactam resistant Grampositive organisms, notably MRSA, since the 1980s. Unfortunately, the use of vancomycin
2015 Informa UK Ltd
ISSN 1478-7210
825
Drug Profile
Nawwar & Kanafani
Chemistry
H N
H3C HO
N H HO
CH3 OH
O
H3C
O
OH O
O
CI
O
O Expert Review of Anti-infective Therapy Downloaded from informahealthcare.com by Nyu Medical Center on 07/03/15 For personal use only.
CI HO O
O NH
HO
O N H H
O H H N
Decylaminoethyl hydrophobic side chain
H N
N H H O H2N
OH O N H H O
CH3
Telavancin, formerly known as TD-6424, was derived from vancomycin with the addition of a hydrophobic decylaminoethyl attached to the vancosamine sugar and a hydrophilic phosphonomethylaminomethyl tail (FIGURE 1) [19]. This novel compound with both lipophilic and hydrophilic properties displays good in vitro antibacterial activity against a variety of Gram-positive organisms including MRSA.
NH CH3
Mode of action & pharmacodynamics
Telavancin exhibits a rapid concentration-dependent bactericidal activity against MRSA, vancomycin intermediate S. aureus, hetero-vancomycin intermediOH HO OH ate S. aureus, daptomycin-resistant OH MRSA, and streptococci through a dual N P Phosphonomethyl aminomethyl side chain mechanism of action [20]. First, telavanH OH O cin, like vancomycin, inhibits cell wall synthesis through binding to the D-AlaFigure 1. Chemical structure of telavancin [61]. D-Ala moiety of the bacterial cell wall. According to Higgins et al. [21], telavanhas several restrictions that often make it suboptimal for the cin was 10-times more potent than vancomycin in cell wall eradication of MRSA [6]. For once, current studies have reported synthesis disruption. Second, telavancin disrupts the bacterial a gradual increase in the MICs of vancomycin against S. aureus cell membrane barrier by causing concentration-dependent [7–9]. This MIC increase has been associated with treatment faildepolarization of the plasma membrane, thus leading to leakage ure and the need for higher vancomycin trough serum levels to of ATP and K+ from the cell and induction of bacterial killachieve clinical success [10]. As a matter of fact, treatment fail- ing [21,22]. A recent experiment attempted to study the genome ures with vancomycin reached 60% when MIC values increased transcriptional response of S. aureus to telavancin challenge. above 4 mg/ml [9]. Furthermore, Soriano et al. [11] found that Telavancin induced early and strong expression of the cell wall mortality is higher in patients with strains having high MICs. stress stimulon, as well as various genes involved in the protecThis has prompted the lowering of the susceptibility breakpoints tion of cell membrane against depolarizing agents. These genes to 2 mg/ml by the FDA and European Committee on Antimi- were either not induced or weakly induced by vancomycin [23]. crobial Susceptibility Testing (EUCAST) [12,13]. In addition, Telavancin’s dual mechanism of action permits an early bacvancomycin has been associated with nephrotoxicity at doses tericidal activity with MICs that are lower than those of drugs higher than 4 g/day and when given in conjunction with other commonly used for the treatment of S. aureus, such as vanconephrotoxic agents [14]. In fact, patients receiving more than 4 g mycin, teicoplanin, oxacillin, or linezolid. As a matter of fact, of vancomycin daily had a significantly higher risk of nephro- in MRSA isolates with elevated MIC of vancomycin (4 mg/ml) toxicity compared with patients receiving lower doses. Finally, and daptomycin (2 mg/ml), MIC of telavancin was shown to according to a recent prospective, observational study in 13 pri- be 0.06 mg/ml [24–26]. Moreover, in a study evaluating the mary care clinics, cSSSI treatment failures have been increas- activity of telavancin, vancomycin, and linezolid against 25 hetingly reported with a mean additional cost of US$1933.71 per ero-vancomycin intermediate S. aureus clinical strains [27], telapatient [15]. These reasons raise the need for the development of vancin was found to be superior compared with vancomycin new treatment options for MRSA. and linezolid with lower MIC levels and shorter time to bacteSeveral drugs have been approved for the treatment of cSSSI, ricidal activity (5.6 ± 3.2 h at peak concentration and 12.3 ± each proving their effectiveness while at the same time requir- 5.2 h at trough concentration for telavancin, vs 18.8 ± 2.1 h at ing special considerations with regard to development of resis- peak concentration and 19.1 ± 2.2 h at trough concentration tance (e.g., with daptomycin) [16] or side effects (e.g., with for vancomycin; p < 0.001). linezolid and daptomycin) [17,18]. Telavancin, with its dual Moreover, telavancin exhibits a bactericidal effect against mechanism of action and low resistance potential, offers dis- Enterococcus faecalis isolates, including vancomycin-resistant tinct advantages over currently marketed agents. isolates (VanB phenotype), but weak inhibition of O
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Telavancin (VIBATIV) for the treatment of complicated skin & skin structure infections
vancomycin-resistant isolates displaying a VanA phenotype with higher MIC values. It was also shown that telavancin is at least eightfold more active against vancomycin-susceptible E. faecalis than ampicillin, vancomycin and daptomycin [28]. TABLE 1 shows a summary of the in vitro activity of telavancin and comparator agents against common skin pathogens. In clinical trials, telavancin was dosed at 10 mg/kg every 24 h; however, doses as high as 15 mg/kg were investigated in healthy volunteers with no serious adverse events [29]. Based on the neutropenic murine-thigh infection model, the ratio of the area under the concentration-time curve for 24 h at steady state to MIC (AUC24/MIC ratio) was the pharmacodynamic variable most associated with efficacy [30]. Telavancin is highly protein bound (around 90%) and has a prolonged post-antibiotic effect [31]. There is evidence to suggest that the potential for selection of resistance with telavancin is low. This is illustrated in an in vitro study where multistep and single step resistance experiments failed to yield a significant rise in MIC levels of telavancin against staphylococcal and enterococcal isolates compared with other antiMRSA agents [32]. Pharmacokinetics
Drug Profile
Table 1. In vitro activity of telavancin against various isolates from skin infections compared with other available anti-MRSA agents [62]. Organism (no. of isolates)
Antimicrobial agent
MIC (g/ml)
Staphylococcus aureus (1208)
Telavancin
0.12–1
0.5
Vancomycin
0.5–2
1
Teicoplanin
£0.12–4
1
Daptomycin
£0.03–4
0.5
Linezolid
1–4
4
Telavancin
0.12–1
0.5
Vancomycin
0.5–2
1
Teicoplanin
£0.12–4
1
Daptomycin
£0.03–1
0.5
Linezolid
1–4
4
Telavancin
0.12–1
0.5
Vancomycin
0.5–2
1
Teicoplanin
0.25–4
0.5
Daptomycin
£0.03–4
0.5
Linezolid
1–4
2
Telavancin
0.015–0.12
0.06
Vancomycin
0.25–0.5
0.25
Daptomycin
£0.03–0.25
0.06
Linezolid
0.5–2
2
Telavancin
0.25–1
1
Vancomycin
£0.5–2
2
Range
MSSA (462)
MRSA (746)
S. pyogenes (60)
Enterococcus faecalis (78)
90%
Telavancin follows linear pharmacokinetTeicoplanin 0.12–0.5 0.25 ics with single-dose administration of Daptomycin 0.25–2 2 1–12.5 mg/kg doses, based on Cmax and Linezolid 1–2 2 AUC values [29]. With multiple doses over 7 days, steady state is achieved by MIC: Minimal inhibitory concentration; MSSA: Methicillin-sensitive Staphylococcus aureus; days 3 and 4, with no further increases MRSA: Methicillin-resistant Staphylococcus aureus. in serum concentrations with continued dosing. At the end of a 7-day course of 7.5, 12.5 and concentration (free and protein bound) of telavancin was 15 mg/kg/day, Cmax values were 96.7, 151.3 and 202.5 mg/ml, almost parallel to that of blister fluid. Telavancin is eliminated by the kidney largely unchanged respectively, and steady-state AUC values were 700, 1033 and (>80%), whereas 20% is hydroxylated and eliminated in the 1165 mg h/ml, respectively [29]. To assess the penetration of telavancin in skin tissue, urine 48 h after infusion [35]. The clearance of telavancin in Sun et al. [33] performed a study comparing the plasma Cmax, patients with cSSSIs was 0.93 l/h similar to what was demonAUC and t1/2 with those of skin tissue. Nine volunteers were strated in healthy subjects [36]. In patients with cSSSI, telavanrecruited and given telavancin at a dose of 7.5 mg/kg/day for cin clearance was shown to be slightly higher in males but this 3 days. A skin blister was created using cantharidin ointment, difference is thought to be minimal and of slight clinical and fluid from the blister was analyzed [34]. A comparison of relevance. As telavancin clearance decreases in parallel with creatinine plasma levels and blister fluid level showed that AUC in the blister fluid was >40% that of the plasma, (604 ± 83 mg h/ml clearance, dose adjustment is required in patients with kidney in the plasma compared with 241 ± 33 mg h/ml in the blis- disease, to 7.5 mg/kg/day for moderate renal impairment, and ter fluid). Also, 12 h after infusion, the total plasma 10 mg/kg every 48 h for severe renal impairment [36]. It is informahealthcare.com
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Nawwar & Kanafani
Table 2. Summary of response rates of telavancin compared with standard therapy in the FAST (Phase II) trials [41,42]. Response by population
FAST I Telavancin 7.5 mg/kg/day n/N (%)
FAST II
ST n/N (%)
p-value
Telavancin 10 mg/kg/day n/N (%)
ST n/N (%)
p-value
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Cure rates at TOC All treated
66/84 (79)
66/83 (80)
0.53
82/100 (82)
81/95 (85)
0.37
CE
66/72 (92)
66/69 (96)
0.53
74/77 (96)
72/77 (94)
0.53
ME
52/56 (93)
53/56 (95)
0.79
62/64 (97)
53/77 (93)
0.37
S. aureus
40/50 (80)
40/52 (77)
0.80
48/50 (96)
37/41 (90)
0.36
MRSA
18/22 (82)
18/26 (69)
1.00
25/26 (96)
17/19 (90)
0.42
Eradication rates at TOC Total
44/56 (80)
46/56 (82)
0.53
60/64 (94)
45/57 (83)
0.06
MRSA
16/19 (84)
14/19 (74)
0.83
24/26 (92)
13/19 (68)
0.04
CE: Clinically evaluable; ME: Microbiologically evaluable; MRSA: Methicillin-resistant Staphylococcus aureus; ST: Standard therapy; TOC: Test-of-cure.
worth noting that telavancin’s biological activity (serum inhibitory and bactericidal concentrations) is unchanged in patients with renal impairment [37]. The pharmacokinetics of telavancin are constant in patients with mild hepatic impairment [38], and in elderly men and women [39]. On the other hand, body weight significantly affects the volume of distribution of telavancin because of the drug’s diffusion into the extracellular fluid [36]. Obese patients with larger extracellular fluid volume would have a higher volume of distribution, and this supports the mg/kg dosing used in Phase II and III trials. Finally, telavancin does not affect the pharmacokinetics of drugs metabolized by cytochrome P450 and thus is expected to have few drug interactions [40]. Clinical efficacy
The efficacy of telavancin has been established in Phase II and III clinical trials, which led to its approval by the FDA for use in cSSSIs. Phase II clinical trials
The FAST-1 and -2 trials were blinded multi-centered randomized controlled trials conducted in the USA and South Africa [41,42]. In each of the trials, adult patients with cSSSIs were randomized to receive either telavancin (at a dose of 7.5 mg/kg/day in FAST-1 and 10 mg/kg/day in FAST-2) or standard therapy (nafcillin or oxacillin at 2 g every 6 h; cloxacillin at 0.5–1 g every 6 h; or vancomycin at 1 g every 12 h). All antimicrobial agents were administered intravenously with no possibility for switching to oral therapy. A total of 362 patients were recruited in both trials (n = 167 in FAST-1 and n = 195 in FAST-2). Treatment was continued for a minimum of 4 days but did not exceed 14 days. The end of therapy evaluation was performed within 3 days of the last 828
dose of study medication, and the test-of-cure visit occurred at 7–14 days after the last dose of study medication. In both studies, ‘cure’ was defined as resolution of clinically significant signs and symptoms associated with the cSSSI, or improvement so that no further antimicrobial therapy was required. On the other hand, ‘failure’ was defined as inadequate response to study therapy or the need for significant surgical management of the infection site after antibiotic therapy and before test-ofcure evaluation. ‘Indeterminate’ was defined as an outcome that could not be determined. In both FAST studies, telavancin was not inferior to standard therapy in all treatment population (TABLE 2) [41,42]. In addition, in the FAST-2 study, telavancin was superior to standard therapy in the microbiological eradication rates for MRSA at test-of-cure (92 vs 68%; p = 0.04). Phase III clinical trials
After establishing the efficacy and safety of telavancin in the FAST trials, two parallel Phase III randomized double-blind studies were initiated (ATLAS-1 and -2), comparing telavancin at 10 mg/kg/day to vancomycin at 1 g every 12 h [43]. The studies enrolled patients from 129 centers in 21 different countries. Inclusion criteria included men or non-pregnant women ‡18 years of age with a diagnosis of cSSSI caused by a suspected or confirmed Gram-positive organism, and requiring 7 days of parenteral antibacterial therapy. Vancomycin dosing was adjusted based on serum level monitoring, while telavancin dosing was adjusted based on estimated creatinine clearance. Treatment duration ranged from 7 to 14 days, and additional antibiotic coverage with aztreonam and/or metronidazole was allowed for suspected or confirmed polymicrobial infections. The clinical and microbiological evaluations, analysis populations, and responses were similar to those of the FAST trials. Expert Rev. Anti Infect. Ther. 13(7), (2015)
Drug Profile
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Telavancin (VIBATIV) for the treatment of complicated skin & skin structure infections
The clinically evaluable (CE) population for both studies consisted of 1489 patients, of whom 745 received telavancin and 744 patients received vancomycin (TABLE 3). Cure rates were 88.3% in the telavancin arm and 87.1% in the vancomycin arm (difference 1.2; 95% CI: 2.1–4.6). The most commonly isolated pathogen was S. aureus in 83% of patients, and 63% of all S. aureus isolates were methicillin resistant. The cure rates in the MRSA subgroup were 90.6% with telavancin and 86.4% with vancomycin (difference 4.1; 95% CI: 1.1–9.3), whereas microbiological eradication rates were 89.9% with telavancin and 85.4% with vancomycin. None of the differences in response rates were statistically significant. The study concluded that telavancin was non-inferior to vancomycin in the treatment of cSSSIs.
Table 3. Summary of response rates of telavancin compared with vancomycin in the ATLAS (Phase III) trials [43]. Response by population
Telavancin n/N(%)
Vancomycin n/N(%)
Difference in response rate (95% CI)
All treated
710/928 (76.5)
697/939 (74.2)
2.3 ( 1.6,6.2)
CE
658/745 (88.3)
648/744 (87.1)
1.2 ( 2.1,4.6)
ME
467/527 (88.6)
462/536 (86.2)
2.4 ( 1.6, 6.4)
S. aureus
160/181 (88.4)
154/176 (87.5)
NA
MRSA
252/278 (90.6)
260/301 (86.4)
4.1 ( 1.1,9.3)
Cure rates at TOC
Eradication rates at TOC Total
473/527 (89.8)
468/536 (87.3)
( 1.4,6.2)
MRSA
250/278 (89.9)
257/301 (85.4)
( 0.9,9.8)
CE: Clinically evaluable; ME: Microbiologically evaluable; MRSA: Methicillin-resistant Staphylococcus aureus; NA: Not available; TOC: Test-of-cure.
Safety & tolerability
Overall, telavancin was shown to have a satisfactory safety and tolerability profile compared with commonly used therapeutic agents. In the FAST-2 study, patients receiving telavancin at 10 mg/kg/day had similar adverse events as those receiving standard therapy (56% in telavancin group vs 57% in standard therapy group; p = 1.00) [42]. Adverse events were deemed to be related to study drug in 73% of patients on telavancin and 59% of patients on standard therapy (p = 0.16). Apart from taste disturbance, nausea and insomnia, which were more common in the telavancin arm, the frequency of adverse events was similar between both study groups. Taste disturbance was transient in patients on telavancin and was described as a bitter metallic taste. During the trial, 6% of patients who received telavancin and 4% of patients who received standard therapy experienced serious adverse events (SAEs). SAEs reported in patients receiving telavancin included disseminated intravascular coagulopathy, atrial fibrillation, gastrointestinal bleeding, lobar pneumonia, myositis, suicidal ideation, and renal failure. On the other hand, SAEs with standard therapy included multiorgan failure, bacteremia, atelectasis, sepsis, lung infiltration, and respiratory failure. The incidence of laboratory abnormalities was mostly similar between two therapies, except for the disturbed liver function tests, which were seen more frequently in patients on standard therapy (33 vs 10%; p < 0.01), and hypokalemia, which was more common in the telavancin population (7 vs 0%; p = 0.01). The analysis of ECGs from patients receiving telavancin revealed a mean increase in QTc of 12.5 milliseconds compared with those on standard therapy (p < 0.0001), although no cardiac adverse events were associated with the QTc prolongation. In contrast to the results seen in the FAST trials, there was no statistically significant difference in QTc informahealthcare.com
prolongation in both treatment groups; one patient in the telavancin group and two patients in the vancomycin group had a QTc interval > 500 milliseconds during the trial but no cardiac events were associated with this finding. In the Phase III trials, 79% of patients receiving telavancin report adverse events compared with 72% of those receiving vancomycin as presented in TABLE 4 [43]. SAEs were slightly higher in patients receiving telavancin compared with those treated with vancomycin (7 vs 4%), with study drug discontinuation occurring in 8 and 6%, respectively. As seen in the FAST trials, the frequency of adverse events was similar in both groups except for taste disturbance, mild nausea, and foamy urine. There has been growing concern about the use of telavancin in the setting of renal insufficiency. In the ATLAS trials, 3% of patients treated with telavancin developed renal dysfunction compared with 1% of patients treated with vancomycin. Renal adverse events (termed by investigators collectively as renal failure, renal impairment, renal insufficiency, and elevated creatinine) were attributed to patients’ own risk factors, such as cardiovascular disease or preexisting renal dysfunction and creatinine clearance had returned to baseline or was improving 14 days after stopping therapy. However, later in the ATTAIN trials, increases in serum creatinine levels were more frequently observed in the telavancin arm compared with the vancomycin arm (16 vs 10%). In addition, there was excess mortality among telavancin-treated patients with poor kidney function compared with vancomycin-treated patients [44,45]. In a recent retrospective cohort, seven of 21 patients who received telavancin (33%) developed acute renal insufficiency during therapy. This adverse event was seen mostly in patients with high body mass index (p = 0.025), those who were given an intravenous contrast dye (p = 0.017), and those who had high vancomycin trough levels (p = 0.017) [46]. More recently, a meta-analysis looking at pooled data from the FAST, ATLAS and ATTAIN 829
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Nawwar & Kanafani
Table 4. Most common adverse events reported in the FAST (Phase II) and ATLAS (Phase III) trials in the all-treated population.
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Adverse event
FAST-1 n (%) Telavancin (n = 84)
FAST-2 n (%)
ATLAS n (%)
ST (n = 83)
Telavancin (n = 100)
ST (n = 95)
Telavancin (n = 929)
Vancomycin (n = 938)
Total
47 (56)
50 (60)
56 (56)
54 (57)
735 (79)
676 (72)
Taste disturbance
–
–
–
–
311 (33)
62 (7)
Nausea
13 (15)
11 (13)
16 (16)
6 (6)
249 (27)
142 (15)
Headache
9 (11)
8 (10)
8 (8)
4 (4)
130 (14)
120 (13)
Foamy urine
–
–
–
–
122 (13)
27 (3)
Vomiting
8 (10)
3 (4)
8 (8)
6 (6)
127 (14)
69 (7)
Constipation
3 (4)
5 (6)
5 (5)
7 (7)
96 (10)
61 (7)
ST: Standard therapy.
trials showed similar mortality rates with telavancin and vancomycin (8.9 vs 8.3%; OR: 1.08 [0.84–1.38]) [47]. As for renal side effects, they were more common in the telavancin group compared with the vancomycin group (10 vs 5%; OR: 2.22 [1.38–3.57]). Data for the use of telavancin during pregnancy are not available but studies have shown teratogenicity when used in animal models [48,49]. Therefore, the use of telavancin is not recommended during pregnancy and a pregnancy test must be ordered before its use in women of childbearing age. Due to its renal side effects and potential for fetal teratogenicity, a black box warning was issued for the use of telavancin in June 2013. The warning states that telavancin use in patients with preexisting renal impairment and pregnant women should be restricted to situations where the benefits of the drug outweigh the associated risks [50]. Regulatory affairs
In 2008, the application for the use of telavancin in the treatment of cSSSI in Europe was withdrawn due to insufficient data analyzing the risk/benefit of the drug for the treatment of skin infections [51]. However, in 2009, after the completion of the ATLAS trials with data showing a satisfactory safety and efficacy profile, the FDA and Health Canada approved the use of telavancin for the treatment of cSSSI in the US and Canada, respectively. In addition, in 2012, telavancin was approved for the treatment of nosocomial pneumonia including ventilator-associated pneumonia in the European Union, Norway, and Iceland based on the ATTAIN studies comparing telavancin to vancomycin [48,49,52]. Investigators showed that the overall cure rates were similar in both groups and telavancin was superior to vancomycin in patients infected with S. aureus. Telavancin also had a similar safety profile compared with vancomycin, except in patients with moderate to severe renal impairment where mortality was slightly higher in the telavancin group. Currently, telavancin is approved in the EU for the treatment of MRSA 830
nosocomial pneumonia, including ventilator-associated pneumonia, only when other alternatives are not suitable therapies [51]. Telavancin was studied for the treatment of S. aureus bacteremia in a randomized Phase II trial (ASSURE) showing similar cure rates compared with vancomycin [45,53]. Although results from the ASSURE trial are promising, telavancin has not so far received a clinical indication for its use in bacteremia. Currently, a Phase III trial is ongoing for the use of telavancin in S. aureus bacteremia and endocarditis [54]. Conclusion
Randomized active controlled data from clinical trials have shown that telavancin at a dose of 10 mg/kg/day has similar efficacy to vancomycin in the treatment of cSSSIs. Telavancin is also effective in the treatment of respiratory infections. Given its satisfactory safety profile, this drug is a useful addition to the arsenal of agents for the treatment of Gram-positive infections. The therapeutic value of the drug in S. aureus bacteremia remains to be determined but preliminary data seem promising. Expert commentary
The Infectious Diseases Society of America guidelines recommend the use of anti-MRSA agents in the empiric treatment of severe purulent skin and soft tissue infections. These include vancomycin, daptomycin, linezolid, telavancin, and ceftaroline [4].Other potentially useful agents include tedizolid, oritavancin, and dalbavancin, all of which have recently obtained FDA approval for use in complicated skin infections. The available clinical data regarding the efficacy of telavancin in the treatment of cSSSIs are quite promising. The rapid bactericidal activity and prolonged post-antibiotic effect distinguish telavancin from vancomycin, which had been for a long time the drug of choice for the treatment of MRSA infections. Other available antimicrobial agents have also been effective, and each offers distinct advantages, such as once-daily dosing Expert Rev. Anti Infect. Ther. 13(7), (2015)
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Telavancin (VIBATIV) for the treatment of complicated skin & skin structure infections
(daptomycin) [55], high oral bioavailability (linezolid and tedizolid) [56–58], single dosing (oritavancin and dalbavancin) [59], and added Gram-negative coverage (ceftaroline) [60]. However, each agent is associated with its own adverse event profile, which needs to be balanced against the drug’s efficacy. The renal side effects observed with telavancin warrant caution, as described above. Ultimately, the choice of treatment in serious MRSA infections will have to be individualized based on the patient’s risk profile, underlying comorbidities, and previous exposure to antimicrobial agents. In an era where antibiotic resistance has been an increasing challenge, and where high MRSA rates and reduced susceptibility to vancomycin remain serious concerns, telavancin may be an appropriate first-line treatment option in cSSSIs, particularly if post-marketing studies continue to demonstrate favorable efficacy endpoints, and if the safety profile becomes more elucidated.
Drug Profile
Five-year view
In the next 5 years, we expect that the uses of telavancin in Gram-positive infections to be fully demonstrated. Specifically, our experience with using telavancin as a first-line treatment over standard therapies in suspected or confirmed resistant Gram-positive infections will have grown. Future studies will also elucidate the role of telavancin in treatment of other infections such as infective endocarditis, urinary tract, abdominal, or bone and joint infections. Financial & competing interests disclosure
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.
Key issues .
Telavancin is a rapidly bactericidal lipoglycopeptide.
.
Telavancin has a dual mechanism of action through inhibition of cell-wall synthesis and disruption of bacterial cell membrane barrier.
.
Telavancin is bactericidal against Staphylococcus aureus regardless of methicillin resistance, streptococci, enterococci (vancomycinresistant and sensitive) and retains activity against vancomycin-resistant Staphylococcus aureus.
.
Telavancin has a long serum half-life allowing once daily intravenous dosing and exhibits prolonged post-antibiotic effect.
.
Phase II and III trials have demonstrated that telavancin is non-inferior to standard therapy in the treatment of complicated skin and skin structure infections.
.
Collective data from clinical trials suggest that telavancin is well tolerated and has a favorable safety profile in most patient populations.
.
In patients with renal impairment and in pregnant women, telavancin should only be used when benefits outweigh the risks.
References 1.
Ki V, Rotstein C. Bacterial skin and soft tissue infections in adults: A review of their epidemiology, pathogenesis, diagnosis, treatment and site of care. Can J Infect Dis Med Microbiol 2008;19(2):173-84
2.
Moran GJ, Krishnadasan A, Gorwitz RJ, et al. Methicillin-resistant S. aureus infections among patients in the emergency department. N Engl J Med 2006;355(7): 666-74
3.
Zervos MJ, Freeman K, Vo L, et al. Epidemiology and outcomes of complicated skin and soft tissue infections in hospitalized patients. J Clin Microbiol 2012;50(2): 238-45
4.
Stevens DL, Bisno AL, Chambers HF, et al. Practice guidelines for the diagnosis and management of skin and soft tissue infections: 2014 update by the infectious diseases society of America. Clin Infect Dis 2014;59(2):147-59
5.
Griffith RS. Introduction to vancomycin. Rev Infect Dis 1981;3 suppl:S200-4
informahealthcare.com
6.
Rybak MJ. The pharmacokinetic and pharmacodynamic properties of vancomycin. Clin Infect Dis 2006;42(Suppl 1):S35-9
7.
Steinkraus G, White R, Friedrich L. Vancomycin MIC creep in non-vancomycin-intermediate Staphylococcus aureus (VISA), vancomycin-susceptible clinical methicillin-resistant S. aureus (MRSA) blood isolates from 2001-05. J Antimicrob Chemother 2007;60(4):788-94
8.
Wang G, Hindler JF, Ward KW, Bruckner DA. Increased vancomycin MICs for Staphylococcus aureus clinical isolates from a university hospital during a 5-year period. J Clin Microbiol 2006;44(11): 3883-6
9.
Rubinstein E, Keynan Y. Vancomycin revisited - 60 years later. Front Public Health 2014;2:217
10.
Hidayat LK, Hsu DI, Quist R, et al. High-dose vancomycin therapy for methicillin-resistant Staphylococcus aureus infections: efficacy and toxicity. Arch Intern Med 2006;166(19):2138-44
11.
Soriano A, Marco F, Martinez JA, et al. Influence of vancomycin minimum inhibitory concentration on the treatment of methicillin-resistant Staphylococcus aureus bacteremia. Clin Infect Dis 2008;46(2): 193-200
12.
Clinical breakpoints (Bacterial v3.1 and Fungal v6.1). The European Committee on Antimicrobial Susceptibility Testing. Available from: www.eucast.org/ clinical_breakpoints Published February 11, 2013 [Accessed 4 October 2013]
13.
CLSI. Performance standards for antimicrobial susceptibility testing. CLSI approved stan- dard M100-S16. Wayne, PA: CLSI, 2006
14.
Lodise TP, Lomaestro B, Graves J, Drusano GL. Larger vancomycin doses (at least four grams per day) are associated with an increased incidence of nephrotoxicity. Antimicrob Agents Chemother 2008;52(4): 1330-6
15.
Labreche MJ, Lee GC, Attridge RT, et al. Treatment failure and costs in patients with methicillin-resistant Staphylococcus aureus
831
Drug Profile
Nawwar & Kanafani
(MRSA) skin and soft tissue infections: a South Texas Ambulatory Research Network (STARNet) study. J Am Board Fam Med 2013;26(5):508-17 16.
Expert Review of Anti-infective Therapy Downloaded from informahealthcare.com by Nyu Medical Center on 07/03/15 For personal use only.
17.
18.
19.
20.
21.
22.
23.
24.
25.
Mishra NN, Bayer AS, Weidenmaier C, et al. Phenotypic and genotypic characterization of daptomycin-resistant methicillin-resistant Staphylococcus aureus strains: relative roles of mprF and dlt operons. PLoS One 2014;9(9):e107426 Natsumoto B, Yokota K, Omata F, Furukawa K. Risk factors for linezolid-associated thrombocytopenia in adult patients. Infection 2014;42(6): 1007-12 Bhavnani SM, Rubino CM, Ambrose PG, Drusano GL. Daptomycin exposure and the probability of elevations in the creatine phosphokinase level: data from a randomized trial of patients with bacteremia and endocarditis. Clin Infect Dis 2010; 50(12):1568-74 Leadbetter MR, Adams SM, Bazzini B, et al. Hydrophobic vancomycin derivatives with improved ADME properties: discovery of telavancin (TD-6424). J Antibiot (Tokyo) 2004;57(5):326-36 Saravolatz LD, Pawlak J, Johnson LB. In vitro susceptibilities and molecular analysis of vancomycin-intermediate and vancomycin-resistant Staphylococcus aureus isolates. Clin Infect Dis 2012;55(4):582-6 Higgins DL, Chang R, Debabov DV, et al. Telavancin, a multifunctional lipoglycopeptide, disrupts both cell wall synthesis and cell membrane integrity in methicillin-resistant Staphylococcus aureus. Antimicrob Agents Chemother 2005;49(3): 1127-34 Nannini EC, Stryjewski ME, Corey GR. Telavancin’s interactions with the bacterial cell membrane. Future Microbiol 2010;5(3): 355-8 Song Y, Lunde CS, Benton BM, Wilkinson BJ. Further insights into the mode of action of the lipoglycopeptide telavancin through global gene expression studies. Antimicrob Agents Chemother 2012;56(6):3157-64 Pace JL, Krause K, Johnston D, et al. In vitro activity of TD-6424 against Staphylococcus aureus. Antimicrob Agents Chemother 2003;47(11):3602-4 Mendes RE, Sader HS, Flamm RK, et al. Telavancin in vitro activity against a USA collection of methicillin-resistant Staphylococcus aureus, including resistant subsets. Antimicrob Agents Chemother 2015;59(3):1811-14
832
26.
Mendes RE, Sader HS, Farrell DJ, Jones RN. Update on the telavancin activity tested against European staphylococcal clinical isolates (2009-2010). Diagn Microbiol Infect Dis 2011;71(1):93-7
36.
Samara E, Shaw JP, Barriere SL, et al. Population pharmacokinetics of telavancin in healthy subjects and patients with infections. Antimicrob Agents Chemother 2012;56(4):2067-73
27.
Leonard SN, Szeto YG, Zolotarev M, Grigoryan IV. Comparative in vitro activity of telavancin, vancomycin and linezolid against heterogeneously vancomycin-intermediate Staphylococcus aureus (hVISA). Int J Antimicrob Agents 2011;37(6):558-61
37.
Barriere SL, Farrell DJ, Rhomberg PR, Jones RN. Serum inhibitory and bactericidal activity of telavancin in non-infected subjects with severe renal impairment or end-stage renal disease. Diagn Microbiol Infect Dis 2014;80(4):327-9
38.
28.
Mendes RE, Farrell DJ, Sader HS, et al. Baseline activity of telavancin against Gram-positive clinical isolates responsible for documented infections in U.S. Hospitals (2011-2012) as determined by the revised susceptibility testing method. Antimicrob Agents Chemother 2015;59(1):702-6
Goldberg MR, Wong SL, Shaw JP, et al. Lack of effect of moderate hepatic impairment on the pharmacokinetics of telavancin. Pharmacotherapy 2010;30(1): 35-42
39.
Goldberg MR, Wong SL, Shaw JP, et al. Single-dose pharmacokinetics and tolerability of telavancin in elderly men and women. Pharmacotherapy 2010;30(8): 806-11
40.
Wong SL, Goldberg MR, Ballow CH, et al. Effect of Telavancin on the pharmacokinetics of the cytochrome P450 3A probe substrate midazolam: a randomized, double-blind, crossover study in healthy subjects. Pharmacotherapy 2010; 30(2):136-43
41.
Stryjewski ME, O’Riordan WD, Lau WK, et al. Telavancin versus standard therapy for treatment of complicated skin and soft-tissue infections due to gram-positive bacteria. Clin Infect Dis 2005;40(11): 1601-7
29.
30.
Shaw JP, Seroogy J, Kaniga K, et al. Pharmacokinetics, serum inhibitory and bactericidal activity, and safety of telavancin in healthy subjects. Antimicrob Agents Chemother 2005;49(1):195-201 Reyes N, Skinner R, Kaniga K, et al. Efficacy of telavancin (TD-6424), a rapidly bactericidal lipoglycopeptide with multiple mechanisms of action, in a murine model of pneumonia induced by methicillin-resistant Staphylococcus aureus. Antimicrob Agents Chemother 2005;49(10):4344-6
31.
Nannini EC, Stryjewski ME. A new lipoglycopeptide: telavancin. Expert Opin Pharmacother 2008;9(12):2197-207
32.
Kosowska-Shick K, Clark C, Pankuch GA, et al. Activity of telavancin against staphylococci and enterococci determined by MIC and resistance selection studies. Antimicrob Agents Chemother 2009;53(10): 4217-24
42.
Stryjewski ME, Chu VH, O’Riordan WD, et al. Telavancin versus standard therapy for treatment of complicated skin and skin structure infections caused by gram-positive bacteria: FAST 2 study. Antimicrob Agents Chemother 2006;50(3):862-7
33.
Sun HK, Duchin K, Nightingale CH, et al. Tissue penetration of telavancin after intravenous administration in healthy subjects. Antimicrob Agents Chemother 2006;50(2):788-90
43.
34.
Lodise TP, Butterfield JM, Hegde SS, et al. Telavancin pharmacokinetics and pharmacodynamics in patients with complicated skin and skin structure infections and various degrees of renal function. Antimicrob Agents Chemother 2012;56(4):2062-6
Stryjewski ME, Graham DR, Wilson SE, et al. Telavancin versus vancomycin for the treatment of complicated skin and skin-structure infections caused by gram-positive organisms. Clin Infect Dis 2008;46(11):1683-93
44.
Rubinstein E, Lalani T, Corey GR, et al. Telavancin versus vancomycin for hospital-acquired pneumonia due to gram-positive pathogens. Clin Infect Dis 2011;52(1):31-40
45.
Corey GR RE, Stryjewski ME, Bassetti M, Barriere SL. Potential Role for Telavancin in Bacteremic Infections Due to Gram-Positive Pathogens: Focus on Staphylococcus aureus. Clin Infect Dis 2014;60(5):787-96
46.
Marcos LA, Camins BC, Ritchie DJ, et al. Acute renal insufficiency during telavancin
35.
Shaw JP, Cheong J, Goldberg MR, Kitt MM. Mass balance and pharmacokinetics of [14C]telavancin following intravenous administration to healthy male volunteers. Antimicrob Agents Chemother 2010;54(8):3365-71
Expert Rev. Anti Infect. Ther. 13(7), (2015)
Telavancin (VIBATIV) for the treatment of complicated skin & skin structure infections
Expert Review of Anti-infective Therapy Downloaded from informahealthcare.com by Nyu Medical Center on 07/03/15 For personal use only.
therapy in clinical practice. J Antimicrob Chemother 2012;67(3):723-6 47.
Polyzos KA, Mavros MN, Vardakas KZ, et al. Efficacy and safety of telavancin in clinical trials: a systematic review and meta-analysis. PLoS ONE 2012;7(8):e41870
48.
Briefing Document for the Anti-Infective Drugs Advisory Committee. Telavancin for the Treatment of Nosocomial Pneumonia. South San Francisco, CA: Theravance, Inc
49.
Rubinstein E, Corey GR, Stryjewski ME, Kanafani ZA. Telavancin for the treatment of serious gram-positive infections, including hospital acquired pneumonia. Expert Opin Pharmacother 2011;12(17):2737-50
50.
51.
52.
53.
Barriere SL. The ATTAIN trials: efficacy and safety of telavancin compared with vancomycin for the treatment of hospital-acquired and ventilator-associated bacterial pneumonia. Future Microbiol 2014;9(3):281-9 Stryjewski ME, Lentnek A, O’Riordan W, et al. A randomized Phase 2 trial of telavancin versus standard therapy in patients with uncomplicated Staphylococcus aureus bacteremia: the ASSURE study. BMC Infect Dis 2014;14:289
54.
A phase 2 telavancin Staphylococcus aureus bacteremia trial. Available from: https:// clinicaltrials.gov/ct2/show/NCT02208063
Steven Barriere P, FIDSA, FCCP. Increased risk of mortality in patients with pre-existing renal impairment, risk of nephrotoxicity and risk of fetal development toxicity with VIBATIV (telavancin). June 2013
55.
Dvorchik BH, Brazier D, DeBruin MF, Arbeit RD. Daptomycin pharmacokinetics and safety following administration of escalating doses once daily to healthy subjects. Antimicrob Agents Chemother 2003;47(4):1318-23
Vibativ Summary of product characteristics. Clinigen Healthcare Ltd Pitcairn House, Crown Square, First Avenue, Burton-on-Trent United Kingdom; 2011
56.
Rybak JM, Roberts K. Tedizolid Phosphate: a Next-Generation Oxazolidinone. Infect Dis Ther 2015. [Epub ahead of print]
57.
Kanafani ZA, Corey GR. Tedizolid (TR701): a new oxazolidinone with enhanced
informahealthcare.com
Drug Profile
potency. Expert Opin Investig Drugs 2012; 21(4):515-22 58.
Batts DH. Linezolid–a new option for treating gram-positive infections. Oncology (Williston Park) 2000;14(8 Suppl 6):23-9
59.
Kmeid J, Kanafani ZA. Oritavancin for the treatment of acute bacterial skin and skin structure infections: an evidence-based review. Core Evid 2015;10:39-47
60.
Kanafani ZA. Ceftaroline fosamil: drug profile and clinical data. Future Microbiol 2011;6(1):9-18
61.
Kanafani ZA. Telavancin: a new lipoglycopeptide with multiple mechanisms of action. Expert Rev Anti Infect Ther 2006;4(5):743-9
62.
Krause KM, Barriere SL, Kitt MM, Benton BM. In vitro activity of telavancin against Gram-positive isolates from complicated skin and skin structure infections: results from 2 phase 3 (ATLAS) clinical studies. Diagn Microbiol Infect Dis 2010;68(2):181-5
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Telavancin (VIBATIV) for the treatment of complicated skin and skin structure infections Expert Rev. Anti Infect. Ther. 13(7), 825–833 (2015)
Tamara Nawar and Zeina A Kanafani* Division of Infectious Diseases, Department of Internal Medicine, American University of Beirut Medical Center, Beirut, Lebanon *Author for correspondence: Tel.: +961 1350 000; extn. 4747 Fax: +961 1370 814 [email protected]
Methicillin-resistant Staphylococcus aureus has emerged as a major causative pathogen in complicated skin and skin structure infections (cSSSIs). Unfortunately, treatment failure with vancomycin has been increasingly reported. Over the past decade, several alternative antimicrobial agents have been studied and approved for the treatment of cSSSIs. One such agent is the lipoglycopeptide telavancin, which was approved by the US FDA 2009. Given its dual mechanism of action, telavancin is characterized by a highly bactericidal activity and low potential for resistance selection. In addition, in clinical trials, it was efficacious and safe in the treatment of cSSSI. The purpose of this review is to give a background overview of telavancin, highlighting its microbiological, pharmacokinetic and pharmacodynamics characteristics, to summarize the available evidence for its use in the treatment of cSSSIs, and to provide an updated evaluation of its safety profile. KEYWORDS: complicated skin and skin structure infection . lipoglycopeptide . methicillin-resistant S. aureus . telavancin .
vancomycin
It is estimated that complicated skin and skin structure infections (cSSSIs) occur in approximately 7–10% of hospitalized patients [1]. These common infections may vary from mild cellulitis affecting the dermis and subcutaneous fat to necrotizing fasciitis with spread into the fascial line and necrosis of the subcutaneous tissues. In many US and European centers, methicillin-resistant Staphylococcus aureus (MRSA) is now recognized as a leading pathogen in cSSSIs. In 2004, MRSA was the most commonly identifiable organism in patients with cSSSIs presenting at 11 emergency departments across the USA [2]. In a more recent retrospective study of cSSSIs in hospitalized patients, 66.4% of cultures grew S. aureus, of which 74.8% were MRSA [3]. The management of cSSSIs may vary depending on the severity, risk factors, and epidemiologic background of the patient. In 2014, the Infectious Diseases Society of America updated the guidelines for the management of cSSSIs, describing the various approaches to this complex group of infections [4]. According to current guidelines, when MRSA is a likely informahealthcare.com
10.1586/14787210.2015.1043889
pathogen, empiric therapy in patients with moderate symptoms should consist of oral antibiotics, such as trimethoprim–sulfamethoxazole or doxycycline, whereas in patients with severe symptoms, recommended therapies include vancomycin, daptomycin, linezolid, ceftaroline, or telavancin. The US FDA granted telavancin its approval for the treatment of cSSSIs in September 2009. Telavancin is a once-daily, injectable lipoglycopeptide with a dual mechanism of action: inhibition of bacterial cell wall synthesis, and disruption of the bacterial cell membrane barrier. Overview of the market
In the 1950s, the emergence of S. aureus-resistant isolates prompted researchers to look for new alternatives. Vancomycin was the first of the glycopeptide family of antibiotics to be discovered and used against methicillin-resistant S. aureus [5]. It has been the drug of choice for the treatment of beta-lactam resistant Grampositive organisms, notably MRSA, since the 1980s. Unfortunately, the use of vancomycin
2015 Informa UK Ltd
ISSN 1478-7210
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Chemistry
H N
H3C HO
N H HO
CH3 OH
O
H3C
O
OH O
O
CI
O
O Expert Review of Anti-infective Therapy Downloaded from informahealthcare.com by Nyu Medical Center on 07/03/15 For personal use only.
CI HO O
O NH
HO
O N H H
O H H N
Decylaminoethyl hydrophobic side chain
H N
N H H O H2N
OH O N H H O
CH3
Telavancin, formerly known as TD-6424, was derived from vancomycin with the addition of a hydrophobic decylaminoethyl attached to the vancosamine sugar and a hydrophilic phosphonomethylaminomethyl tail (FIGURE 1) [19]. This novel compound with both lipophilic and hydrophilic properties displays good in vitro antibacterial activity against a variety of Gram-positive organisms including MRSA.
NH CH3
Mode of action & pharmacodynamics
Telavancin exhibits a rapid concentration-dependent bactericidal activity against MRSA, vancomycin intermediate S. aureus, hetero-vancomycin intermediOH HO OH ate S. aureus, daptomycin-resistant OH MRSA, and streptococci through a dual N P Phosphonomethyl aminomethyl side chain mechanism of action [20]. First, telavanH OH O cin, like vancomycin, inhibits cell wall synthesis through binding to the D-AlaFigure 1. Chemical structure of telavancin [61]. D-Ala moiety of the bacterial cell wall. According to Higgins et al. [21], telavanhas several restrictions that often make it suboptimal for the cin was 10-times more potent than vancomycin in cell wall eradication of MRSA [6]. For once, current studies have reported synthesis disruption. Second, telavancin disrupts the bacterial a gradual increase in the MICs of vancomycin against S. aureus cell membrane barrier by causing concentration-dependent [7–9]. This MIC increase has been associated with treatment faildepolarization of the plasma membrane, thus leading to leakage ure and the need for higher vancomycin trough serum levels to of ATP and K+ from the cell and induction of bacterial killachieve clinical success [10]. As a matter of fact, treatment fail- ing [21,22]. A recent experiment attempted to study the genome ures with vancomycin reached 60% when MIC values increased transcriptional response of S. aureus to telavancin challenge. above 4 mg/ml [9]. Furthermore, Soriano et al. [11] found that Telavancin induced early and strong expression of the cell wall mortality is higher in patients with strains having high MICs. stress stimulon, as well as various genes involved in the protecThis has prompted the lowering of the susceptibility breakpoints tion of cell membrane against depolarizing agents. These genes to 2 mg/ml by the FDA and European Committee on Antimi- were either not induced or weakly induced by vancomycin [23]. crobial Susceptibility Testing (EUCAST) [12,13]. In addition, Telavancin’s dual mechanism of action permits an early bacvancomycin has been associated with nephrotoxicity at doses tericidal activity with MICs that are lower than those of drugs higher than 4 g/day and when given in conjunction with other commonly used for the treatment of S. aureus, such as vanconephrotoxic agents [14]. In fact, patients receiving more than 4 g mycin, teicoplanin, oxacillin, or linezolid. As a matter of fact, of vancomycin daily had a significantly higher risk of nephro- in MRSA isolates with elevated MIC of vancomycin (4 mg/ml) toxicity compared with patients receiving lower doses. Finally, and daptomycin (2 mg/ml), MIC of telavancin was shown to according to a recent prospective, observational study in 13 pri- be 0.06 mg/ml [24–26]. Moreover, in a study evaluating the mary care clinics, cSSSI treatment failures have been increas- activity of telavancin, vancomycin, and linezolid against 25 hetingly reported with a mean additional cost of US$1933.71 per ero-vancomycin intermediate S. aureus clinical strains [27], telapatient [15]. These reasons raise the need for the development of vancin was found to be superior compared with vancomycin new treatment options for MRSA. and linezolid with lower MIC levels and shorter time to bacteSeveral drugs have been approved for the treatment of cSSSI, ricidal activity (5.6 ± 3.2 h at peak concentration and 12.3 ± each proving their effectiveness while at the same time requir- 5.2 h at trough concentration for telavancin, vs 18.8 ± 2.1 h at ing special considerations with regard to development of resis- peak concentration and 19.1 ± 2.2 h at trough concentration tance (e.g., with daptomycin) [16] or side effects (e.g., with for vancomycin; p < 0.001). linezolid and daptomycin) [17,18]. Telavancin, with its dual Moreover, telavancin exhibits a bactericidal effect against mechanism of action and low resistance potential, offers dis- Enterococcus faecalis isolates, including vancomycin-resistant tinct advantages over currently marketed agents. isolates (VanB phenotype), but weak inhibition of O
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Telavancin (VIBATIV) for the treatment of complicated skin & skin structure infections
vancomycin-resistant isolates displaying a VanA phenotype with higher MIC values. It was also shown that telavancin is at least eightfold more active against vancomycin-susceptible E. faecalis than ampicillin, vancomycin and daptomycin [28]. TABLE 1 shows a summary of the in vitro activity of telavancin and comparator agents against common skin pathogens. In clinical trials, telavancin was dosed at 10 mg/kg every 24 h; however, doses as high as 15 mg/kg were investigated in healthy volunteers with no serious adverse events [29]. Based on the neutropenic murine-thigh infection model, the ratio of the area under the concentration-time curve for 24 h at steady state to MIC (AUC24/MIC ratio) was the pharmacodynamic variable most associated with efficacy [30]. Telavancin is highly protein bound (around 90%) and has a prolonged post-antibiotic effect [31]. There is evidence to suggest that the potential for selection of resistance with telavancin is low. This is illustrated in an in vitro study where multistep and single step resistance experiments failed to yield a significant rise in MIC levels of telavancin against staphylococcal and enterococcal isolates compared with other antiMRSA agents [32]. Pharmacokinetics
Drug Profile
Table 1. In vitro activity of telavancin against various isolates from skin infections compared with other available anti-MRSA agents [62]. Organism (no. of isolates)
Antimicrobial agent
MIC (g/ml)
Staphylococcus aureus (1208)
Telavancin
0.12–1
0.5
Vancomycin
0.5–2
1
Teicoplanin
£0.12–4
1
Daptomycin
£0.03–4
0.5
Linezolid
1–4
4
Telavancin
0.12–1
0.5
Vancomycin
0.5–2
1
Teicoplanin
£0.12–4
1
Daptomycin
£0.03–1
0.5
Linezolid
1–4
4
Telavancin
0.12–1
0.5
Vancomycin
0.5–2
1
Teicoplanin
0.25–4
0.5
Daptomycin
£0.03–4
0.5
Linezolid
1–4
2
Telavancin
0.015–0.12
0.06
Vancomycin
0.25–0.5
0.25
Daptomycin
£0.03–0.25
0.06
Linezolid
0.5–2
2
Telavancin
0.25–1
1
Vancomycin
£0.5–2
2
Range
MSSA (462)
MRSA (746)
S. pyogenes (60)
Enterococcus faecalis (78)
90%
Telavancin follows linear pharmacokinetTeicoplanin 0.12–0.5 0.25 ics with single-dose administration of Daptomycin 0.25–2 2 1–12.5 mg/kg doses, based on Cmax and Linezolid 1–2 2 AUC values [29]. With multiple doses over 7 days, steady state is achieved by MIC: Minimal inhibitory concentration; MSSA: Methicillin-sensitive Staphylococcus aureus; days 3 and 4, with no further increases MRSA: Methicillin-resistant Staphylococcus aureus. in serum concentrations with continued dosing. At the end of a 7-day course of 7.5, 12.5 and concentration (free and protein bound) of telavancin was 15 mg/kg/day, Cmax values were 96.7, 151.3 and 202.5 mg/ml, almost parallel to that of blister fluid. Telavancin is eliminated by the kidney largely unchanged respectively, and steady-state AUC values were 700, 1033 and (>80%), whereas 20% is hydroxylated and eliminated in the 1165 mg h/ml, respectively [29]. To assess the penetration of telavancin in skin tissue, urine 48 h after infusion [35]. The clearance of telavancin in Sun et al. [33] performed a study comparing the plasma Cmax, patients with cSSSIs was 0.93 l/h similar to what was demonAUC and t1/2 with those of skin tissue. Nine volunteers were strated in healthy subjects [36]. In patients with cSSSI, telavanrecruited and given telavancin at a dose of 7.5 mg/kg/day for cin clearance was shown to be slightly higher in males but this 3 days. A skin blister was created using cantharidin ointment, difference is thought to be minimal and of slight clinical and fluid from the blister was analyzed [34]. A comparison of relevance. As telavancin clearance decreases in parallel with creatinine plasma levels and blister fluid level showed that AUC in the blister fluid was >40% that of the plasma, (604 ± 83 mg h/ml clearance, dose adjustment is required in patients with kidney in the plasma compared with 241 ± 33 mg h/ml in the blis- disease, to 7.5 mg/kg/day for moderate renal impairment, and ter fluid). Also, 12 h after infusion, the total plasma 10 mg/kg every 48 h for severe renal impairment [36]. It is informahealthcare.com
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Table 2. Summary of response rates of telavancin compared with standard therapy in the FAST (Phase II) trials [41,42]. Response by population
FAST I Telavancin 7.5 mg/kg/day n/N (%)
FAST II
ST n/N (%)
p-value
Telavancin 10 mg/kg/day n/N (%)
ST n/N (%)
p-value
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Cure rates at TOC All treated
66/84 (79)
66/83 (80)
0.53
82/100 (82)
81/95 (85)
0.37
CE
66/72 (92)
66/69 (96)
0.53
74/77 (96)
72/77 (94)
0.53
ME
52/56 (93)
53/56 (95)
0.79
62/64 (97)
53/77 (93)
0.37
S. aureus
40/50 (80)
40/52 (77)
0.80
48/50 (96)
37/41 (90)
0.36
MRSA
18/22 (82)
18/26 (69)
1.00
25/26 (96)
17/19 (90)
0.42
Eradication rates at TOC Total
44/56 (80)
46/56 (82)
0.53
60/64 (94)
45/57 (83)
0.06
MRSA
16/19 (84)
14/19 (74)
0.83
24/26 (92)
13/19 (68)
0.04
CE: Clinically evaluable; ME: Microbiologically evaluable; MRSA: Methicillin-resistant Staphylococcus aureus; ST: Standard therapy; TOC: Test-of-cure.
worth noting that telavancin’s biological activity (serum inhibitory and bactericidal concentrations) is unchanged in patients with renal impairment [37]. The pharmacokinetics of telavancin are constant in patients with mild hepatic impairment [38], and in elderly men and women [39]. On the other hand, body weight significantly affects the volume of distribution of telavancin because of the drug’s diffusion into the extracellular fluid [36]. Obese patients with larger extracellular fluid volume would have a higher volume of distribution, and this supports the mg/kg dosing used in Phase II and III trials. Finally, telavancin does not affect the pharmacokinetics of drugs metabolized by cytochrome P450 and thus is expected to have few drug interactions [40]. Clinical efficacy
The efficacy of telavancin has been established in Phase II and III clinical trials, which led to its approval by the FDA for use in cSSSIs. Phase II clinical trials
The FAST-1 and -2 trials were blinded multi-centered randomized controlled trials conducted in the USA and South Africa [41,42]. In each of the trials, adult patients with cSSSIs were randomized to receive either telavancin (at a dose of 7.5 mg/kg/day in FAST-1 and 10 mg/kg/day in FAST-2) or standard therapy (nafcillin or oxacillin at 2 g every 6 h; cloxacillin at 0.5–1 g every 6 h; or vancomycin at 1 g every 12 h). All antimicrobial agents were administered intravenously with no possibility for switching to oral therapy. A total of 362 patients were recruited in both trials (n = 167 in FAST-1 and n = 195 in FAST-2). Treatment was continued for a minimum of 4 days but did not exceed 14 days. The end of therapy evaluation was performed within 3 days of the last 828
dose of study medication, and the test-of-cure visit occurred at 7–14 days after the last dose of study medication. In both studies, ‘cure’ was defined as resolution of clinically significant signs and symptoms associated with the cSSSI, or improvement so that no further antimicrobial therapy was required. On the other hand, ‘failure’ was defined as inadequate response to study therapy or the need for significant surgical management of the infection site after antibiotic therapy and before test-ofcure evaluation. ‘Indeterminate’ was defined as an outcome that could not be determined. In both FAST studies, telavancin was not inferior to standard therapy in all treatment population (TABLE 2) [41,42]. In addition, in the FAST-2 study, telavancin was superior to standard therapy in the microbiological eradication rates for MRSA at test-of-cure (92 vs 68%; p = 0.04). Phase III clinical trials
After establishing the efficacy and safety of telavancin in the FAST trials, two parallel Phase III randomized double-blind studies were initiated (ATLAS-1 and -2), comparing telavancin at 10 mg/kg/day to vancomycin at 1 g every 12 h [43]. The studies enrolled patients from 129 centers in 21 different countries. Inclusion criteria included men or non-pregnant women ‡18 years of age with a diagnosis of cSSSI caused by a suspected or confirmed Gram-positive organism, and requiring 7 days of parenteral antibacterial therapy. Vancomycin dosing was adjusted based on serum level monitoring, while telavancin dosing was adjusted based on estimated creatinine clearance. Treatment duration ranged from 7 to 14 days, and additional antibiotic coverage with aztreonam and/or metronidazole was allowed for suspected or confirmed polymicrobial infections. The clinical and microbiological evaluations, analysis populations, and responses were similar to those of the FAST trials. Expert Rev. Anti Infect. Ther. 13(7), (2015)
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Telavancin (VIBATIV) for the treatment of complicated skin & skin structure infections
The clinically evaluable (CE) population for both studies consisted of 1489 patients, of whom 745 received telavancin and 744 patients received vancomycin (TABLE 3). Cure rates were 88.3% in the telavancin arm and 87.1% in the vancomycin arm (difference 1.2; 95% CI: 2.1–4.6). The most commonly isolated pathogen was S. aureus in 83% of patients, and 63% of all S. aureus isolates were methicillin resistant. The cure rates in the MRSA subgroup were 90.6% with telavancin and 86.4% with vancomycin (difference 4.1; 95% CI: 1.1–9.3), whereas microbiological eradication rates were 89.9% with telavancin and 85.4% with vancomycin. None of the differences in response rates were statistically significant. The study concluded that telavancin was non-inferior to vancomycin in the treatment of cSSSIs.
Table 3. Summary of response rates of telavancin compared with vancomycin in the ATLAS (Phase III) trials [43]. Response by population
Telavancin n/N(%)
Vancomycin n/N(%)
Difference in response rate (95% CI)
All treated
710/928 (76.5)
697/939 (74.2)
2.3 ( 1.6,6.2)
CE
658/745 (88.3)
648/744 (87.1)
1.2 ( 2.1,4.6)
ME
467/527 (88.6)
462/536 (86.2)
2.4 ( 1.6, 6.4)
S. aureus
160/181 (88.4)
154/176 (87.5)
NA
MRSA
252/278 (90.6)
260/301 (86.4)
4.1 ( 1.1,9.3)
Cure rates at TOC
Eradication rates at TOC Total
473/527 (89.8)
468/536 (87.3)
( 1.4,6.2)
MRSA
250/278 (89.9)
257/301 (85.4)
( 0.9,9.8)
CE: Clinically evaluable; ME: Microbiologically evaluable; MRSA: Methicillin-resistant Staphylococcus aureus; NA: Not available; TOC: Test-of-cure.
Safety & tolerability
Overall, telavancin was shown to have a satisfactory safety and tolerability profile compared with commonly used therapeutic agents. In the FAST-2 study, patients receiving telavancin at 10 mg/kg/day had similar adverse events as those receiving standard therapy (56% in telavancin group vs 57% in standard therapy group; p = 1.00) [42]. Adverse events were deemed to be related to study drug in 73% of patients on telavancin and 59% of patients on standard therapy (p = 0.16). Apart from taste disturbance, nausea and insomnia, which were more common in the telavancin arm, the frequency of adverse events was similar between both study groups. Taste disturbance was transient in patients on telavancin and was described as a bitter metallic taste. During the trial, 6% of patients who received telavancin and 4% of patients who received standard therapy experienced serious adverse events (SAEs). SAEs reported in patients receiving telavancin included disseminated intravascular coagulopathy, atrial fibrillation, gastrointestinal bleeding, lobar pneumonia, myositis, suicidal ideation, and renal failure. On the other hand, SAEs with standard therapy included multiorgan failure, bacteremia, atelectasis, sepsis, lung infiltration, and respiratory failure. The incidence of laboratory abnormalities was mostly similar between two therapies, except for the disturbed liver function tests, which were seen more frequently in patients on standard therapy (33 vs 10%; p < 0.01), and hypokalemia, which was more common in the telavancin population (7 vs 0%; p = 0.01). The analysis of ECGs from patients receiving telavancin revealed a mean increase in QTc of 12.5 milliseconds compared with those on standard therapy (p < 0.0001), although no cardiac adverse events were associated with the QTc prolongation. In contrast to the results seen in the FAST trials, there was no statistically significant difference in QTc informahealthcare.com
prolongation in both treatment groups; one patient in the telavancin group and two patients in the vancomycin group had a QTc interval > 500 milliseconds during the trial but no cardiac events were associated with this finding. In the Phase III trials, 79% of patients receiving telavancin report adverse events compared with 72% of those receiving vancomycin as presented in TABLE 4 [43]. SAEs were slightly higher in patients receiving telavancin compared with those treated with vancomycin (7 vs 4%), with study drug discontinuation occurring in 8 and 6%, respectively. As seen in the FAST trials, the frequency of adverse events was similar in both groups except for taste disturbance, mild nausea, and foamy urine. There has been growing concern about the use of telavancin in the setting of renal insufficiency. In the ATLAS trials, 3% of patients treated with telavancin developed renal dysfunction compared with 1% of patients treated with vancomycin. Renal adverse events (termed by investigators collectively as renal failure, renal impairment, renal insufficiency, and elevated creatinine) were attributed to patients’ own risk factors, such as cardiovascular disease or preexisting renal dysfunction and creatinine clearance had returned to baseline or was improving 14 days after stopping therapy. However, later in the ATTAIN trials, increases in serum creatinine levels were more frequently observed in the telavancin arm compared with the vancomycin arm (16 vs 10%). In addition, there was excess mortality among telavancin-treated patients with poor kidney function compared with vancomycin-treated patients [44,45]. In a recent retrospective cohort, seven of 21 patients who received telavancin (33%) developed acute renal insufficiency during therapy. This adverse event was seen mostly in patients with high body mass index (p = 0.025), those who were given an intravenous contrast dye (p = 0.017), and those who had high vancomycin trough levels (p = 0.017) [46]. More recently, a meta-analysis looking at pooled data from the FAST, ATLAS and ATTAIN 829
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Nawwar & Kanafani
Table 4. Most common adverse events reported in the FAST (Phase II) and ATLAS (Phase III) trials in the all-treated population.
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Adverse event
FAST-1 n (%) Telavancin (n = 84)
FAST-2 n (%)
ATLAS n (%)
ST (n = 83)
Telavancin (n = 100)
ST (n = 95)
Telavancin (n = 929)
Vancomycin (n = 938)
Total
47 (56)
50 (60)
56 (56)
54 (57)
735 (79)
676 (72)
Taste disturbance
–
–
–
–
311 (33)
62 (7)
Nausea
13 (15)
11 (13)
16 (16)
6 (6)
249 (27)
142 (15)
Headache
9 (11)
8 (10)
8 (8)
4 (4)
130 (14)
120 (13)
Foamy urine
–
–
–
–
122 (13)
27 (3)
Vomiting
8 (10)
3 (4)
8 (8)
6 (6)
127 (14)
69 (7)
Constipation
3 (4)
5 (6)
5 (5)
7 (7)
96 (10)
61 (7)
ST: Standard therapy.
trials showed similar mortality rates with telavancin and vancomycin (8.9 vs 8.3%; OR: 1.08 [0.84–1.38]) [47]. As for renal side effects, they were more common in the telavancin group compared with the vancomycin group (10 vs 5%; OR: 2.22 [1.38–3.57]). Data for the use of telavancin during pregnancy are not available but studies have shown teratogenicity when used in animal models [48,49]. Therefore, the use of telavancin is not recommended during pregnancy and a pregnancy test must be ordered before its use in women of childbearing age. Due to its renal side effects and potential for fetal teratogenicity, a black box warning was issued for the use of telavancin in June 2013. The warning states that telavancin use in patients with preexisting renal impairment and pregnant women should be restricted to situations where the benefits of the drug outweigh the associated risks [50]. Regulatory affairs
In 2008, the application for the use of telavancin in the treatment of cSSSI in Europe was withdrawn due to insufficient data analyzing the risk/benefit of the drug for the treatment of skin infections [51]. However, in 2009, after the completion of the ATLAS trials with data showing a satisfactory safety and efficacy profile, the FDA and Health Canada approved the use of telavancin for the treatment of cSSSI in the US and Canada, respectively. In addition, in 2012, telavancin was approved for the treatment of nosocomial pneumonia including ventilator-associated pneumonia in the European Union, Norway, and Iceland based on the ATTAIN studies comparing telavancin to vancomycin [48,49,52]. Investigators showed that the overall cure rates were similar in both groups and telavancin was superior to vancomycin in patients infected with S. aureus. Telavancin also had a similar safety profile compared with vancomycin, except in patients with moderate to severe renal impairment where mortality was slightly higher in the telavancin group. Currently, telavancin is approved in the EU for the treatment of MRSA 830
nosocomial pneumonia, including ventilator-associated pneumonia, only when other alternatives are not suitable therapies [51]. Telavancin was studied for the treatment of S. aureus bacteremia in a randomized Phase II trial (ASSURE) showing similar cure rates compared with vancomycin [45,53]. Although results from the ASSURE trial are promising, telavancin has not so far received a clinical indication for its use in bacteremia. Currently, a Phase III trial is ongoing for the use of telavancin in S. aureus bacteremia and endocarditis [54]. Conclusion
Randomized active controlled data from clinical trials have shown that telavancin at a dose of 10 mg/kg/day has similar efficacy to vancomycin in the treatment of cSSSIs. Telavancin is also effective in the treatment of respiratory infections. Given its satisfactory safety profile, this drug is a useful addition to the arsenal of agents for the treatment of Gram-positive infections. The therapeutic value of the drug in S. aureus bacteremia remains to be determined but preliminary data seem promising. Expert commentary
The Infectious Diseases Society of America guidelines recommend the use of anti-MRSA agents in the empiric treatment of severe purulent skin and soft tissue infections. These include vancomycin, daptomycin, linezolid, telavancin, and ceftaroline [4].Other potentially useful agents include tedizolid, oritavancin, and dalbavancin, all of which have recently obtained FDA approval for use in complicated skin infections. The available clinical data regarding the efficacy of telavancin in the treatment of cSSSIs are quite promising. The rapid bactericidal activity and prolonged post-antibiotic effect distinguish telavancin from vancomycin, which had been for a long time the drug of choice for the treatment of MRSA infections. Other available antimicrobial agents have also been effective, and each offers distinct advantages, such as once-daily dosing Expert Rev. Anti Infect. Ther. 13(7), (2015)
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Telavancin (VIBATIV) for the treatment of complicated skin & skin structure infections
(daptomycin) [55], high oral bioavailability (linezolid and tedizolid) [56–58], single dosing (oritavancin and dalbavancin) [59], and added Gram-negative coverage (ceftaroline) [60]. However, each agent is associated with its own adverse event profile, which needs to be balanced against the drug’s efficacy. The renal side effects observed with telavancin warrant caution, as described above. Ultimately, the choice of treatment in serious MRSA infections will have to be individualized based on the patient’s risk profile, underlying comorbidities, and previous exposure to antimicrobial agents. In an era where antibiotic resistance has been an increasing challenge, and where high MRSA rates and reduced susceptibility to vancomycin remain serious concerns, telavancin may be an appropriate first-line treatment option in cSSSIs, particularly if post-marketing studies continue to demonstrate favorable efficacy endpoints, and if the safety profile becomes more elucidated.
Drug Profile
Five-year view
In the next 5 years, we expect that the uses of telavancin in Gram-positive infections to be fully demonstrated. Specifically, our experience with using telavancin as a first-line treatment over standard therapies in suspected or confirmed resistant Gram-positive infections will have grown. Future studies will also elucidate the role of telavancin in treatment of other infections such as infective endocarditis, urinary tract, abdominal, or bone and joint infections. Financial & competing interests disclosure
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.
Key issues .
Telavancin is a rapidly bactericidal lipoglycopeptide.
.
Telavancin has a dual mechanism of action through inhibition of cell-wall synthesis and disruption of bacterial cell membrane barrier.
.
Telavancin is bactericidal against Staphylococcus aureus regardless of methicillin resistance, streptococci, enterococci (vancomycinresistant and sensitive) and retains activity against vancomycin-resistant Staphylococcus aureus.
.
Telavancin has a long serum half-life allowing once daily intravenous dosing and exhibits prolonged post-antibiotic effect.
.
Phase II and III trials have demonstrated that telavancin is non-inferior to standard therapy in the treatment of complicated skin and skin structure infections.
.
Collective data from clinical trials suggest that telavancin is well tolerated and has a favorable safety profile in most patient populations.
.
In patients with renal impairment and in pregnant women, telavancin should only be used when benefits outweigh the risks.
References 1.
Ki V, Rotstein C. Bacterial skin and soft tissue infections in adults: A review of their epidemiology, pathogenesis, diagnosis, treatment and site of care. Can J Infect Dis Med Microbiol 2008;19(2):173-84
2.
Moran GJ, Krishnadasan A, Gorwitz RJ, et al. Methicillin-resistant S. aureus infections among patients in the emergency department. N Engl J Med 2006;355(7): 666-74
3.
Zervos MJ, Freeman K, Vo L, et al. Epidemiology and outcomes of complicated skin and soft tissue infections in hospitalized patients. J Clin Microbiol 2012;50(2): 238-45
4.
Stevens DL, Bisno AL, Chambers HF, et al. Practice guidelines for the diagnosis and management of skin and soft tissue infections: 2014 update by the infectious diseases society of America. Clin Infect Dis 2014;59(2):147-59
5.
Griffith RS. Introduction to vancomycin. Rev Infect Dis 1981;3 suppl:S200-4
informahealthcare.com
6.
Rybak MJ. The pharmacokinetic and pharmacodynamic properties of vancomycin. Clin Infect Dis 2006;42(Suppl 1):S35-9
7.
Steinkraus G, White R, Friedrich L. Vancomycin MIC creep in non-vancomycin-intermediate Staphylococcus aureus (VISA), vancomycin-susceptible clinical methicillin-resistant S. aureus (MRSA) blood isolates from 2001-05. J Antimicrob Chemother 2007;60(4):788-94
8.
Wang G, Hindler JF, Ward KW, Bruckner DA. Increased vancomycin MICs for Staphylococcus aureus clinical isolates from a university hospital during a 5-year period. J Clin Microbiol 2006;44(11): 3883-6
9.
Rubinstein E, Keynan Y. Vancomycin revisited - 60 years later. Front Public Health 2014;2:217
10.
Hidayat LK, Hsu DI, Quist R, et al. High-dose vancomycin therapy for methicillin-resistant Staphylococcus aureus infections: efficacy and toxicity. Arch Intern Med 2006;166(19):2138-44
11.
Soriano A, Marco F, Martinez JA, et al. Influence of vancomycin minimum inhibitory concentration on the treatment of methicillin-resistant Staphylococcus aureus bacteremia. Clin Infect Dis 2008;46(2): 193-200
12.
Clinical breakpoints (Bacterial v3.1 and Fungal v6.1). The European Committee on Antimicrobial Susceptibility Testing. Available from: www.eucast.org/ clinical_breakpoints Published February 11, 2013 [Accessed 4 October 2013]
13.
CLSI. Performance standards for antimicrobial susceptibility testing. CLSI approved stan- dard M100-S16. Wayne, PA: CLSI, 2006
14.
Lodise TP, Lomaestro B, Graves J, Drusano GL. Larger vancomycin doses (at least four grams per day) are associated with an increased incidence of nephrotoxicity. Antimicrob Agents Chemother 2008;52(4): 1330-6
15.
Labreche MJ, Lee GC, Attridge RT, et al. Treatment failure and costs in patients with methicillin-resistant Staphylococcus aureus
831
Drug Profile
Nawwar & Kanafani
(MRSA) skin and soft tissue infections: a South Texas Ambulatory Research Network (STARNet) study. J Am Board Fam Med 2013;26(5):508-17 16.
Expert Review of Anti-infective Therapy Downloaded from informahealthcare.com by Nyu Medical Center on 07/03/15 For personal use only.
17.
18.
19.
20.
21.
22.
23.
24.
25.
Mishra NN, Bayer AS, Weidenmaier C, et al. Phenotypic and genotypic characterization of daptomycin-resistant methicillin-resistant Staphylococcus aureus strains: relative roles of mprF and dlt operons. PLoS One 2014;9(9):e107426 Natsumoto B, Yokota K, Omata F, Furukawa K. Risk factors for linezolid-associated thrombocytopenia in adult patients. Infection 2014;42(6): 1007-12 Bhavnani SM, Rubino CM, Ambrose PG, Drusano GL. Daptomycin exposure and the probability of elevations in the creatine phosphokinase level: data from a randomized trial of patients with bacteremia and endocarditis. Clin Infect Dis 2010; 50(12):1568-74 Leadbetter MR, Adams SM, Bazzini B, et al. Hydrophobic vancomycin derivatives with improved ADME properties: discovery of telavancin (TD-6424). J Antibiot (Tokyo) 2004;57(5):326-36 Saravolatz LD, Pawlak J, Johnson LB. In vitro susceptibilities and molecular analysis of vancomycin-intermediate and vancomycin-resistant Staphylococcus aureus isolates. Clin Infect Dis 2012;55(4):582-6 Higgins DL, Chang R, Debabov DV, et al. Telavancin, a multifunctional lipoglycopeptide, disrupts both cell wall synthesis and cell membrane integrity in methicillin-resistant Staphylococcus aureus. Antimicrob Agents Chemother 2005;49(3): 1127-34 Nannini EC, Stryjewski ME, Corey GR. Telavancin’s interactions with the bacterial cell membrane. Future Microbiol 2010;5(3): 355-8 Song Y, Lunde CS, Benton BM, Wilkinson BJ. Further insights into the mode of action of the lipoglycopeptide telavancin through global gene expression studies. Antimicrob Agents Chemother 2012;56(6):3157-64 Pace JL, Krause K, Johnston D, et al. In vitro activity of TD-6424 against Staphylococcus aureus. Antimicrob Agents Chemother 2003;47(11):3602-4 Mendes RE, Sader HS, Flamm RK, et al. Telavancin in vitro activity against a USA collection of methicillin-resistant Staphylococcus aureus, including resistant subsets. Antimicrob Agents Chemother 2015;59(3):1811-14
832
26.
Mendes RE, Sader HS, Farrell DJ, Jones RN. Update on the telavancin activity tested against European staphylococcal clinical isolates (2009-2010). Diagn Microbiol Infect Dis 2011;71(1):93-7
36.
Samara E, Shaw JP, Barriere SL, et al. Population pharmacokinetics of telavancin in healthy subjects and patients with infections. Antimicrob Agents Chemother 2012;56(4):2067-73
27.
Leonard SN, Szeto YG, Zolotarev M, Grigoryan IV. Comparative in vitro activity of telavancin, vancomycin and linezolid against heterogeneously vancomycin-intermediate Staphylococcus aureus (hVISA). Int J Antimicrob Agents 2011;37(6):558-61
37.
Barriere SL, Farrell DJ, Rhomberg PR, Jones RN. Serum inhibitory and bactericidal activity of telavancin in non-infected subjects with severe renal impairment or end-stage renal disease. Diagn Microbiol Infect Dis 2014;80(4):327-9
38.
28.
Mendes RE, Farrell DJ, Sader HS, et al. Baseline activity of telavancin against Gram-positive clinical isolates responsible for documented infections in U.S. Hospitals (2011-2012) as determined by the revised susceptibility testing method. Antimicrob Agents Chemother 2015;59(1):702-6
Goldberg MR, Wong SL, Shaw JP, et al. Lack of effect of moderate hepatic impairment on the pharmacokinetics of telavancin. Pharmacotherapy 2010;30(1): 35-42
39.
Goldberg MR, Wong SL, Shaw JP, et al. Single-dose pharmacokinetics and tolerability of telavancin in elderly men and women. Pharmacotherapy 2010;30(8): 806-11
40.
Wong SL, Goldberg MR, Ballow CH, et al. Effect of Telavancin on the pharmacokinetics of the cytochrome P450 3A probe substrate midazolam: a randomized, double-blind, crossover study in healthy subjects. Pharmacotherapy 2010; 30(2):136-43
41.
Stryjewski ME, O’Riordan WD, Lau WK, et al. Telavancin versus standard therapy for treatment of complicated skin and soft-tissue infections due to gram-positive bacteria. Clin Infect Dis 2005;40(11): 1601-7
29.
30.
Shaw JP, Seroogy J, Kaniga K, et al. Pharmacokinetics, serum inhibitory and bactericidal activity, and safety of telavancin in healthy subjects. Antimicrob Agents Chemother 2005;49(1):195-201 Reyes N, Skinner R, Kaniga K, et al. Efficacy of telavancin (TD-6424), a rapidly bactericidal lipoglycopeptide with multiple mechanisms of action, in a murine model of pneumonia induced by methicillin-resistant Staphylococcus aureus. Antimicrob Agents Chemother 2005;49(10):4344-6
31.
Nannini EC, Stryjewski ME. A new lipoglycopeptide: telavancin. Expert Opin Pharmacother 2008;9(12):2197-207
32.
Kosowska-Shick K, Clark C, Pankuch GA, et al. Activity of telavancin against staphylococci and enterococci determined by MIC and resistance selection studies. Antimicrob Agents Chemother 2009;53(10): 4217-24
42.
Stryjewski ME, Chu VH, O’Riordan WD, et al. Telavancin versus standard therapy for treatment of complicated skin and skin structure infections caused by gram-positive bacteria: FAST 2 study. Antimicrob Agents Chemother 2006;50(3):862-7
33.
Sun HK, Duchin K, Nightingale CH, et al. Tissue penetration of telavancin after intravenous administration in healthy subjects. Antimicrob Agents Chemother 2006;50(2):788-90
43.
34.
Lodise TP, Butterfield JM, Hegde SS, et al. Telavancin pharmacokinetics and pharmacodynamics in patients with complicated skin and skin structure infections and various degrees of renal function. Antimicrob Agents Chemother 2012;56(4):2062-6
Stryjewski ME, Graham DR, Wilson SE, et al. Telavancin versus vancomycin for the treatment of complicated skin and skin-structure infections caused by gram-positive organisms. Clin Infect Dis 2008;46(11):1683-93
44.
Rubinstein E, Lalani T, Corey GR, et al. Telavancin versus vancomycin for hospital-acquired pneumonia due to gram-positive pathogens. Clin Infect Dis 2011;52(1):31-40
45.
Corey GR RE, Stryjewski ME, Bassetti M, Barriere SL. Potential Role for Telavancin in Bacteremic Infections Due to Gram-Positive Pathogens: Focus on Staphylococcus aureus. Clin Infect Dis 2014;60(5):787-96
46.
Marcos LA, Camins BC, Ritchie DJ, et al. Acute renal insufficiency during telavancin
35.
Shaw JP, Cheong J, Goldberg MR, Kitt MM. Mass balance and pharmacokinetics of [14C]telavancin following intravenous administration to healthy male volunteers. Antimicrob Agents Chemother 2010;54(8):3365-71
Expert Rev. Anti Infect. Ther. 13(7), (2015)
Telavancin (VIBATIV) for the treatment of complicated skin & skin structure infections
Expert Review of Anti-infective Therapy Downloaded from informahealthcare.com by Nyu Medical Center on 07/03/15 For personal use only.
therapy in clinical practice. J Antimicrob Chemother 2012;67(3):723-6 47.
Polyzos KA, Mavros MN, Vardakas KZ, et al. Efficacy and safety of telavancin in clinical trials: a systematic review and meta-analysis. PLoS ONE 2012;7(8):e41870
48.
Briefing Document for the Anti-Infective Drugs Advisory Committee. Telavancin for the Treatment of Nosocomial Pneumonia. South San Francisco, CA: Theravance, Inc
49.
Rubinstein E, Corey GR, Stryjewski ME, Kanafani ZA. Telavancin for the treatment of serious gram-positive infections, including hospital acquired pneumonia. Expert Opin Pharmacother 2011;12(17):2737-50
50.
51.
52.
53.
Barriere SL. The ATTAIN trials: efficacy and safety of telavancin compared with vancomycin for the treatment of hospital-acquired and ventilator-associated bacterial pneumonia. Future Microbiol 2014;9(3):281-9 Stryjewski ME, Lentnek A, O’Riordan W, et al. A randomized Phase 2 trial of telavancin versus standard therapy in patients with uncomplicated Staphylococcus aureus bacteremia: the ASSURE study. BMC Infect Dis 2014;14:289
54.
A phase 2 telavancin Staphylococcus aureus bacteremia trial. Available from: https:// clinicaltrials.gov/ct2/show/NCT02208063
Steven Barriere P, FIDSA, FCCP. Increased risk of mortality in patients with pre-existing renal impairment, risk of nephrotoxicity and risk of fetal development toxicity with VIBATIV (telavancin). June 2013
55.
Dvorchik BH, Brazier D, DeBruin MF, Arbeit RD. Daptomycin pharmacokinetics and safety following administration of escalating doses once daily to healthy subjects. Antimicrob Agents Chemother 2003;47(4):1318-23
Vibativ Summary of product characteristics. Clinigen Healthcare Ltd Pitcairn House, Crown Square, First Avenue, Burton-on-Trent United Kingdom; 2011
56.
Rybak JM, Roberts K. Tedizolid Phosphate: a Next-Generation Oxazolidinone. Infect Dis Ther 2015. [Epub ahead of print]
57.
Kanafani ZA, Corey GR. Tedizolid (TR701): a new oxazolidinone with enhanced
informahealthcare.com
Drug Profile
potency. Expert Opin Investig Drugs 2012; 21(4):515-22 58.
Batts DH. Linezolid–a new option for treating gram-positive infections. Oncology (Williston Park) 2000;14(8 Suppl 6):23-9
59.
Kmeid J, Kanafani ZA. Oritavancin for the treatment of acute bacterial skin and skin structure infections: an evidence-based review. Core Evid 2015;10:39-47
60.
Kanafani ZA. Ceftaroline fosamil: drug profile and clinical data. Future Microbiol 2011;6(1):9-18
61.
Kanafani ZA. Telavancin: a new lipoglycopeptide with multiple mechanisms of action. Expert Rev Anti Infect Ther 2006;4(5):743-9
62.
Krause KM, Barriere SL, Kitt MM, Benton BM. In vitro activity of telavancin against Gram-positive isolates from complicated skin and skin structure infections: results from 2 phase 3 (ATLAS) clinical studies. Diagn Microbiol Infect Dis 2010;68(2):181-5
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