TY - JOUR
AU - LaPlante, Kerry, L.
AB - Abstract Purpose. The pharmacology, activity, pharmacokinetics, pharmacodynamics, clinical efficacy, safety, dosage, and place in therapy of telavancin are reviewed. Summary. Telavancin is a lipoglycopeptide antimicrobial agent under development for use in the treatment of multidrug-resistant gram-positive infections. Telavancin, like vancomycin, inhibits cell-wall biosynthesis by binding to late-stage cell-wall precursors. However, unlike vancomycin, telavancin also depolarizes the bacterial cell membrane and disrupts its functional integrity. Telavancin has concentration-dependent bactericidal activity and is active against gram-positive aerobic and anaerobic organisms. It is highly protein bound (93%) and has a volume of distribution of 115 mL/kg and a half-life of approximately eight hours. Telavancin is eliminated renally, and a dosage reduction is required in renally impaired patients. Animal models suggest that telavancin may be effective in the treatment of soft-tissue infections, bacteremia, endocarditis, meningitis, and pneumonia caused by gram-positive pathogens. Telavancin was not inferior to standard treatment for complicated skin and soft-tissue infections in two Phase II clinical trials and two Phase III clinical trials. A new drug application has been submitted for this indication, and Phase III trials to evaluate use in hospital-acquired-pneumonia, including infections caused by methicillin-resistant Staphylococcus aureus (MRSA), are planned. Adverse effects include metallic taste, nausea, vomiting, headache, foamy urine, Q-Tc-interval prolongation, hypokalemia, and serum creatinine increases. In trials evaluating telavancin for skin and soft-tissue infections, the dosage was 10 mg/kg i.v. once daily. Conclusion. Telavancin is a promising new agent for gram-positive infections and may offer an alternative to vancomycin for MRSA-associated infections. Antibiotics, Bacterial infections, Binding, Dosage, Drugs, body distribution, Excretion, Half-life, Kidney failure, Mechanism of action, Pharmacokinetics, Telavancin, Toxicity Staphylococcus aureus, a gram-positive bacterium, is a leading cause of community- and hospital-acquired infections.1 These infections are often complicated and difficult to treat, and they cause significant morbidity and mortality worldwide. New agents effective against these bacteria are needed. S. aureus is commonly resistant to several classes of antimicrobials, including β-lactams, and has recently shown intermediate resistance or heteroresistance to vancomycin, a glycopeptide. Infections by methicillin-resistant S. aureus (MRSA) have steadily increased in the United States since 1998. In 2005, MRSA was identified in 47.9% of isolates obtained in outpatient settings, 59.2% of isolates obtained in inpatient settings, and 55% of isolates from intensive care units.1 Although vancomycin-resistant S. aureus (VRSA) is still rare, six cases have been documented since 2002.2,–5,S. aureus strains with intermediate resistance to vancomycin (VISA) are more common. Current data suggest that fully intermediate strains of S. aureus can be preceded by heteroresistant VISA (hVISA), isolates with small subpopulations with intermediate susceptibility to vancomycin, which are difficult to detect using standard clinical laboratory methods. Infections involving VISA and hVISA may be associated with vancomycin treatment failure, increased bacterial load, longer time to resolution of fever, and greater number of positive blood cultures.6 Few treatment options exist for patients with drug-resistant S. aureus infections.7 Although vancomycin is currently the mainstay of therapy for MRSA infections, this drug has slower bactericidal activity than β-lactams in vitro.8 Increasing resistance to currently available antimicrobials has led to the development of new agents. Currently available agents for drug-resistant, gram-positive organisms include daptomycin, linezolid, quinupristin–dalfopristin, tigecycline, and vancomycin. All these agents except linezolid and tigecycline have bactericidal activity against S. aureus.9,10 Telavancin (TD-6424, Theravance, San Francisco, CA) is an investigational lipoglycopeptide antimicrobial agent under development for use in the treatment of multidrug-resistant gram-positive infections. In contrast to vancomycin and other glycopeptides, telavancin is of interest because of its rapid bactericidal activity against gram-positive bacteria and its favorable spectrum of activity against drug-resistant strains of streptococci, enterococci, and staphylococci, including MRSA. Recent clinical trials suggest that telavancin is not inferior to standard therapies (vancomycin or antistaphylococcal penicillins) for complicated skin and soft-tissue infections.11,–13 This article reviews the chemistry, pharmacology, activity, pharmacokinetics, pharmacodynamics, clinical efficacy, safety, dosage and administration, and place in therapy of telavancin. Chemistry and pharmacology Telavancin, a semisynthetic derivative of the glycopeptide vancomycin, is structurally similar to the glycopeptides but has an additional hydrophobic and hydrophilic moiety (Figure 11). Specifically, telavancin contains a lipophilic (decylaminoethyl) side chain attached to the vancosamine sugar, as well as a hydrophilic ([phosphonomethyl]aminomethyl) group on the 4′ position of amino acid 7.14 The addition of the lipophilic decylaminoethyl substituent to the molecule classifies this agent as a lipoglycopeptide. Figure 1. Open in new tabDownload slide Chemical structures of telavancin and vancomycin. Figure 1. Open in new tabDownload slide Chemical structures of telavancin and vancomycin. Telavancin has two proposed mechanisms of action (Figure 22). The first mechanism is similar to vancomycin’s and involves highly specific, noncovalent binding to the terminal d-Ala-d-Ala stem peptides of both lipid II and immature, un-cross-linked glycan strands.15 This binding shields substrates from transglycosylases and transpeptidases; thus, peptidoglycan polymerization and cross-linking steps are inhibited. The second proposed mechanism of action involves depolarization of the bacterial membrane, resulting in disruption of the functional integrity of the bacterial membrane. It is speculated that this secondary mechanism of action depends on the interaction of the lipophilic decylaminoethyl moiety of telavancin with the lipid bilayer of the bacterial cell membrane.16 The effect of telavancin on membrane potential in bacterial cells was observed at a concentration of approximately 16 mg/L; this concentration is higher than telavancin’s minimum inhibitory concentration (MIC) against most gram-positive isolates.15 This dual mechanism of action is of particular interest, since few other glycopeptides are believed to work in this manner. Figure 2. Open in new tabDownload slide Mechanisms of action of telavancin. The top panel demonstrates normal cell-wall synthesis of a gram-positive bacterium with the production of peptidoglycan strands from lipid II by transglycosylase and the cross-linking of glycan strands by transpeptidase. The center panel demonstrates telavancin inhibiting transglycosylase and transpeptidase, thus inhibiting the polymerization of peptidoglycan from lipid II and cross-linking of peptidoglycan strands into the bacterial cell wall. The third panel demonstrates telavancin’s secondary mechanism of action, whereby telavancin noncovalently binds to a membrane-bound molecule of lipid II in a recently divided gram-positive bacteria (inset) and the lipophilic decylaminoethyl moiety of the molecule interacts directly with the bacterial cell membrane. This interaction results in increased membrane permeability and depolarization of the bacterial cell membrane. Illustration by Taina Litwak, CMI. Figure 2. Open in new tabDownload slide Mechanisms of action of telavancin. The top panel demonstrates normal cell-wall synthesis of a gram-positive bacterium with the production of peptidoglycan strands from lipid II by transglycosylase and the cross-linking of glycan strands by transpeptidase. The center panel demonstrates telavancin inhibiting transglycosylase and transpeptidase, thus inhibiting the polymerization of peptidoglycan from lipid II and cross-linking of peptidoglycan strands into the bacterial cell wall. The third panel demonstrates telavancin’s secondary mechanism of action, whereby telavancin noncovalently binds to a membrane-bound molecule of lipid II in a recently divided gram-positive bacteria (inset) and the lipophilic decylaminoethyl moiety of the molecule interacts directly with the bacterial cell membrane. This interaction results in increased membrane permeability and depolarization of the bacterial cell membrane. Illustration by Taina Litwak, CMI. Spectrum of activity In vitro activity Telavancin is active against gram-positive aerobic and anaerobic bacteria (Table 11).17,–23 Its spectrum of activity is similar to that of vancomycin but is characterized by an MIC that is generally two to eight times lower for most organisms tested. Table 2 2 compares the MICs of telavancin with those of dalbavancin, daptomycin, linezolid, oritavancin, and vancomycin against gram-positive aerobic and anaerobic bacteria.24,–56 Table 2. Susceptibility of Gram-Positive Organisms to Telavancin and Selected Antimicrobials MIC90(mg/mL)a Organism Dalbavancin Daptomycin Linezolid Oritavancin Telavancin Vancomycin aMIC90 = minimum inhibitory concentration for 90% of strains, based on two isolates from Michigan and Pennsylvania. bR = organism is resistant to the antimicrobial agent. Enterococcus faecalis17,18,24,–39     Vancomycin susceptible 0.06 1–2 1–4 1 0.5–1 1–4     Vancomycin resistant 32 0.5–4 2–4 2 4 Rb Enterococcus faecium17,18,24,–39     Vancomycin susceptible 0.12 1–4 2–4 0.12–0.5 0.25–0.5 1.5–2     Vancomycin resistant 32 1–4 2–4 1–2 4 R Staphylococcus aureus2,3,17,20,24,–26,28,–51     Methicillin susceptible 0.06–0.5 0.5–1 2–4 1–2 0.25–1 0.5–2     Methicillin resistant 0.06–1 0.25–1 1–4 2 0.5–2 0.5–2 Coagulase-negative staphylococci17,24,–26,30,35,–38,40,–49,51,52     Methicillin susceptible 0.06–0.5 0.25–2 2 0.5–2 0.25–0.5 1–2     Methicillin resistant 0.06–0.5 0.5–1 1–2 2–4 0.5–1 1–2 Gram-positive anaerobes23,28,53,–56     Clostridium difficile 0.25 1 16 0.016–2 0.25 2     Clostridium perfringens 0.125 0.5 2 0.016–2 0.125 0.5     Propionibacterium species 0.5 2 1 0.032–0.125 0.125 0.5 MIC90(mg/mL)a Organism Dalbavancin Daptomycin Linezolid Oritavancin Telavancin Vancomycin aMIC90 = minimum inhibitory concentration for 90% of strains, based on two isolates from Michigan and Pennsylvania. bR = organism is resistant to the antimicrobial agent. Enterococcus faecalis17,18,24,–39     Vancomycin susceptible 0.06 1–2 1–4 1 0.5–1 1–4     Vancomycin resistant 32 0.5–4 2–4 2 4 Rb Enterococcus faecium17,18,24,–39     Vancomycin susceptible 0.12 1–4 2–4 0.12–0.5 0.25–0.5 1.5–2     Vancomycin resistant 32 1–4 2–4 1–2 4 R Staphylococcus aureus2,3,17,20,24,–26,28,–51     Methicillin susceptible 0.06–0.5 0.5–1 2–4 1–2 0.25–1 0.5–2     Methicillin resistant 0.06–1 0.25–1 1–4 2 0.5–2 0.5–2 Coagulase-negative staphylococci17,24,–26,30,35,–38,40,–49,51,52     Methicillin susceptible 0.06–0.5 0.25–2 2 0.5–2 0.25–0.5 1–2     Methicillin resistant 0.06–0.5 0.5–1 1–2 2–4 0.5–1 1–2 Gram-positive anaerobes23,28,53,–56     Clostridium difficile 0.25 1 16 0.016–2 0.25 2     Clostridium perfringens 0.125 0.5 2 0.016–2 0.125 0.5     Propionibacterium species 0.5 2 1 0.032–0.125 0.125 0.5 Open in new tab Table 2. Susceptibility of Gram-Positive Organisms to Telavancin and Selected Antimicrobials MIC90(mg/mL)a Organism Dalbavancin Daptomycin Linezolid Oritavancin Telavancin Vancomycin aMIC90 = minimum inhibitory concentration for 90% of strains, based on two isolates from Michigan and Pennsylvania. bR = organism is resistant to the antimicrobial agent. Enterococcus faecalis17,18,24,–39     Vancomycin susceptible 0.06 1–2 1–4 1 0.5–1 1–4     Vancomycin resistant 32 0.5–4 2–4 2 4 Rb Enterococcus faecium17,18,24,–39     Vancomycin susceptible 0.12 1–4 2–4 0.12–0.5 0.25–0.5 1.5–2     Vancomycin resistant 32 1–4 2–4 1–2 4 R Staphylococcus aureus2,3,17,20,24,–26,28,–51     Methicillin susceptible 0.06–0.5 0.5–1 2–4 1–2 0.25–1 0.5–2     Methicillin resistant 0.06–1 0.25–1 1–4 2 0.5–2 0.5–2 Coagulase-negative staphylococci17,24,–26,30,35,–38,40,–49,51,52     Methicillin susceptible 0.06–0.5 0.25–2 2 0.5–2 0.25–0.5 1–2     Methicillin resistant 0.06–0.5 0.5–1 1–2 2–4 0.5–1 1–2 Gram-positive anaerobes23,28,53,–56     Clostridium difficile 0.25 1 16 0.016–2 0.25 2     Clostridium perfringens 0.125 0.5 2 0.016–2 0.125 0.5     Propionibacterium species 0.5 2 1 0.032–0.125 0.125 0.5 MIC90(mg/mL)a Organism Dalbavancin Daptomycin Linezolid Oritavancin Telavancin Vancomycin aMIC90 = minimum inhibitory concentration for 90% of strains, based on two isolates from Michigan and Pennsylvania. bR = organism is resistant to the antimicrobial agent. Enterococcus faecalis17,18,24,–39     Vancomycin susceptible 0.06 1–2 1–4 1 0.5–1 1–4     Vancomycin resistant 32 0.5–4 2–4 2 4 Rb Enterococcus faecium17,18,24,–39     Vancomycin susceptible 0.12 1–4 2–4 0.12–0.5 0.25–0.5 1.5–2     Vancomycin resistant 32 1–4 2–4 1–2 4 R Staphylococcus aureus2,3,17,20,24,–26,28,–51     Methicillin susceptible 0.06–0.5 0.5–1 2–4 1–2 0.25–1 0.5–2     Methicillin resistant 0.06–1 0.25–1 1–4 2 0.5–2 0.5–2 Coagulase-negative staphylococci17,24,–26,30,35,–38,40,–49,51,52     Methicillin susceptible 0.06–0.5 0.25–2 2 0.5–2 0.25–0.5 1–2     Methicillin resistant 0.06–0.5 0.5–1 1–2 2–4 0.5–1 1–2 Gram-positive anaerobes23,28,53,–56     Clostridium difficile 0.25 1 16 0.016–2 0.25 2     Clostridium perfringens 0.125 0.5 2 0.016–2 0.125 0.5     Propionibacterium species 0.5 2 1 0.032–0.125 0.125 0.5 Open in new tab Table 1. Susceptibility of Susceptible and Multidrug-Resistant Gram-Positive Organisms to Telavancin Organism No. Isolates MIC90a(mg/L) MICb(mg/L) a = mimimum inhibitory concentration required to inhibit 90% of isolates. MIC90 bMIC = mimimum inhibitory concentration. cR = organism is resistant to the antimicrobial agent. dLactobacillus species include L. acidophilus (n = 2), L. catenaforme (n = 8), L. gasseri (n = 1), L. jensenii (n = 2), L. leichmannii (n = 1), L. rhamnosus (n = 1), and L. uli (n = 1). Enterococcus faecalis17,18     Vancomycin susceptible 458 1–2 0.06–2     Vancomycin resistant 50 4–16 0.25–6 Enterococcus faecium17,18     Vancomycin susceptible 120 0.25–0.5 ≤0.015–0.5     Vancomycin resistant 267 4–8 ≤0.015–16 Staphylococcus aureus17,19,20     Methicillin susceptible 77 0.5–1 0.12–2     Methicillin resistant 158 0.5–2 ≤0.06–2     Vancomycin intermediate 37 4 1–4 Staphylococcus species, coagulase negative17     Methicillin susceptible 30 0.5 0.125–1     Methicillin resistant 30 1 0.25–2 Streptococcus species17,21,22     S. pneumoniae 412 0.015–0.03 0.002–0.06     Beta-hemolytic streptococci 218 0.015–0.125 0.06–0.125     Viridans-group streptococci 102 0.12 0.001–1 Clostridium species23     C. clostridioforme 15 8 0.25–8     C. difficile 14 0.25 0.125–0.5     C. innocuum 15 4 2–4     C. perfringens 12 0.125 0.06–0.125     C. ramosum 16 1 0.25–8 Other gram-positive anaerobes23     Actinomyces species 45 0.25 0.125–0.25     Eubacterium species 33 0.25 0.03–1     Lactobacillus casei 6 Rc 32–64     Lactobacillus speciesd 16 0.25–1.25 <0.015–2     Propionibacterium species 34 0.125 0.06–0.25     Peptostreptococcus anaerobius 10 0.25 0.06–0.25 Corynebacterium species23     C. amycolatum 10 0.06 0.03–0.06     C. jeikeium 11 0.06 <0.015–0.03     Corynebacterium species group 10 0.03 <0.015–0.03 Organism No. Isolates MIC90a(mg/L) MICb(mg/L) a = mimimum inhibitory concentration required to inhibit 90% of isolates. MIC90 bMIC = mimimum inhibitory concentration. cR = organism is resistant to the antimicrobial agent. dLactobacillus species include L. acidophilus (n = 2), L. catenaforme (n = 8), L. gasseri (n = 1), L. jensenii (n = 2), L. leichmannii (n = 1), L. rhamnosus (n = 1), and L. uli (n = 1). Enterococcus faecalis17,18     Vancomycin susceptible 458 1–2 0.06–2     Vancomycin resistant 50 4–16 0.25–6 Enterococcus faecium17,18     Vancomycin susceptible 120 0.25–0.5 ≤0.015–0.5     Vancomycin resistant 267 4–8 ≤0.015–16 Staphylococcus aureus17,19,20     Methicillin susceptible 77 0.5–1 0.12–2     Methicillin resistant 158 0.5–2 ≤0.06–2     Vancomycin intermediate 37 4 1–4 Staphylococcus species, coagulase negative17     Methicillin susceptible 30 0.5 0.125–1     Methicillin resistant 30 1 0.25–2 Streptococcus species17,21,22     S. pneumoniae 412 0.015–0.03 0.002–0.06     Beta-hemolytic streptococci 218 0.015–0.125 0.06–0.125     Viridans-group streptococci 102 0.12 0.001–1 Clostridium species23     C. clostridioforme 15 8 0.25–8     C. difficile 14 0.25 0.125–0.5     C. innocuum 15 4 2–4     C. perfringens 12 0.125 0.06–0.125     C. ramosum 16 1 0.25–8 Other gram-positive anaerobes23     Actinomyces species 45 0.25 0.125–0.25     Eubacterium species 33 0.25 0.03–1     Lactobacillus casei 6 Rc 32–64     Lactobacillus speciesd 16 0.25–1.25 <0.015–2     Propionibacterium species 34 0.125 0.06–0.25     Peptostreptococcus anaerobius 10 0.25 0.06–0.25 Corynebacterium species23     C. amycolatum 10 0.06 0.03–0.06     C. jeikeium 11 0.06 <0.015–0.03     Corynebacterium species group 10 0.03 <0.015–0.03 Open in new tab Table 1. Susceptibility of Susceptible and Multidrug-Resistant Gram-Positive Organisms to Telavancin Organism No. Isolates MIC90a(mg/L) MICb(mg/L) a = mimimum inhibitory concentration required to inhibit 90% of isolates. MIC90 bMIC = mimimum inhibitory concentration. cR = organism is resistant to the antimicrobial agent. dLactobacillus species include L. acidophilus (n = 2), L. catenaforme (n = 8), L. gasseri (n = 1), L. jensenii (n = 2), L. leichmannii (n = 1), L. rhamnosus (n = 1), and L. uli (n = 1). Enterococcus faecalis17,18     Vancomycin susceptible 458 1–2 0.06–2     Vancomycin resistant 50 4–16 0.25–6 Enterococcus faecium17,18     Vancomycin susceptible 120 0.25–0.5 ≤0.015–0.5     Vancomycin resistant 267 4–8 ≤0.015–16 Staphylococcus aureus17,19,20     Methicillin susceptible 77 0.5–1 0.12–2     Methicillin resistant 158 0.5–2 ≤0.06–2     Vancomycin intermediate 37 4 1–4 Staphylococcus species, coagulase negative17     Methicillin susceptible 30 0.5 0.125–1     Methicillin resistant 30 1 0.25–2 Streptococcus species17,21,22     S. pneumoniae 412 0.015–0.03 0.002–0.06     Beta-hemolytic streptococci 218 0.015–0.125 0.06–0.125     Viridans-group streptococci 102 0.12 0.001–1 Clostridium species23     C. clostridioforme 15 8 0.25–8     C. difficile 14 0.25 0.125–0.5     C. innocuum 15 4 2–4     C. perfringens 12 0.125 0.06–0.125     C. ramosum 16 1 0.25–8 Other gram-positive anaerobes23     Actinomyces species 45 0.25 0.125–0.25     Eubacterium species 33 0.25 0.03–1     Lactobacillus casei 6 Rc 32–64     Lactobacillus speciesd 16 0.25–1.25 <0.015–2     Propionibacterium species 34 0.125 0.06–0.25     Peptostreptococcus anaerobius 10 0.25 0.06–0.25 Corynebacterium species23     C. amycolatum 10 0.06 0.03–0.06     C. jeikeium 11 0.06 <0.015–0.03     Corynebacterium species group 10 0.03 <0.015–0.03 Organism No. Isolates MIC90a(mg/L) MICb(mg/L) a = mimimum inhibitory concentration required to inhibit 90% of isolates. MIC90 bMIC = mimimum inhibitory concentration. cR = organism is resistant to the antimicrobial agent. dLactobacillus species include L. acidophilus (n = 2), L. catenaforme (n = 8), L. gasseri (n = 1), L. jensenii (n = 2), L. leichmannii (n = 1), L. rhamnosus (n = 1), and L. uli (n = 1). Enterococcus faecalis17,18     Vancomycin susceptible 458 1–2 0.06–2     Vancomycin resistant 50 4–16 0.25–6 Enterococcus faecium17,18     Vancomycin susceptible 120 0.25–0.5 ≤0.015–0.5     Vancomycin resistant 267 4–8 ≤0.015–16 Staphylococcus aureus17,19,20     Methicillin susceptible 77 0.5–1 0.12–2     Methicillin resistant 158 0.5–2 ≤0.06–2     Vancomycin intermediate 37 4 1–4 Staphylococcus species, coagulase negative17     Methicillin susceptible 30 0.5 0.125–1     Methicillin resistant 30 1 0.25–2 Streptococcus species17,21,22     S. pneumoniae 412 0.015–0.03 0.002–0.06     Beta-hemolytic streptococci 218 0.015–0.125 0.06–0.125     Viridans-group streptococci 102 0.12 0.001–1 Clostridium species23     C. clostridioforme 15 8 0.25–8     C. difficile 14 0.25 0.125–0.5     C. innocuum 15 4 2–4     C. perfringens 12 0.125 0.06–0.125     C. ramosum 16 1 0.25–8 Other gram-positive anaerobes23     Actinomyces species 45 0.25 0.125–0.25     Eubacterium species 33 0.25 0.03–1     Lactobacillus casei 6 Rc 32–64     Lactobacillus speciesd 16 0.25–1.25 <0.015–2     Propionibacterium species 34 0.125 0.06–0.25     Peptostreptococcus anaerobius 10 0.25 0.06–0.25 Corynebacterium species23     C. amycolatum 10 0.06 0.03–0.06     C. jeikeium 11 0.06 <0.015–0.03     Corynebacterium species group 10 0.03 <0.015–0.03 Open in new tab Telavancin is active against methicillin-susceptible S. aureus (MSSA) and MRSA (MIC, 0.12–2 and ≤ 0.06–2 mg/L, respectively).17,19,20 Activity against vancomycin-susceptible Enterococcus faecium and Enterococcus faecalis is also present, with MICs of ≤ 0.015–0.5 and 0.06–2 mg/L, respectively.17,18 Telavancin also displays activity against some vancomycin-resistant enterococci (VRE). The MIC of telavancin for vancomycin-resistant E. faecalis is 0.025–6 mg/L and for vancomycin-resistant E. faecium is ≤ 0.015–16 mg/L. The MIC required to inhibit the growth of 90% of strains (MIC90) of telavancin for 29 isolates of vancomycin-resistant E. faecalis and 29 isolates of vancomycin-resistant E. faecium is more than 64 times lower than the MIC90 of vancomycin (4 mg/L versus >256 mg/L).17 Telavancin is active against various species of streptococci (including penicillin-resistant and multidrug-resistant strains), with MICs of 0.002–0.06 mg/L for Streptococcus pneumoniae, 0.06–0.125 mg/L for β-hemolytic streptococci, and 0.001–1 mg/L for viridans-group streptococci.17,21,22 Preliminary reports on activity against VISA and hVISA indicate that telavancin has more activity against these organisms than vancomycin. Telavancin had an eightfold lower MIC90 than vancomycin (1 mg/L versus 8 mg/L) in a study of 50 isolates of glycopeptide-intermediate staphylococcus species (GISS) and heteroresistant GISS.17 For three isolates of VRSA, telavancin had an MIC of 2–4 mg/L, compared with 32–1024 mg/L for vancomycin.19 Telavancin has activity against Bacillus anthracis (MIC, ≤ 0.03–0.5 mg/L) and Listeria species (0.125 mg/L).17,57 Telavancin shows intracellular antibacterial activity in S. aureus-infected macrophages (murine THP-1 and human J774 cell lines) at pharmacologically relevant concentrations.58 Telavancin also demonstrates activity against biofilm-forming S. aureus and Staphylococcus epidermidis.59 Data suggest that telavancin does not have clinically useful activity against gram-negative bacteria.a a Data on file, Theravance Inc.; 2007. Goldstein et al.23 reported activity against Actinomyces species (MIC, 0.125–0.25 mg/L), Clostridium difficile (0.125–0.5 mg/L), and several other anaerobic bacteria. In vivo activity The efficacy of telavancin has been studied in several animal models of infection, including bacteremia, endocarditis, meningitis, and pneumonia. Bacteremia Telavancin proved superior to vancomycin in the treatment of MRSA bacteremia in neutropenic mice.60 Two subcutaneous doses of telavancin 40 mg/kg given 12 hours apart were more effective than two subcutaneous doses of vancomycin 110 mg/kg or placebo in reducing bacterial levels in blood and spleen tissue. Survival at 14 days was significantly higher among telavancin-treated animals (14/15) than among those given vancomycin (0/15) or placebo (0/15) (p < 0.05). Endocarditis Telavancin was efficacious in a rabbit model of S. aureus endocarditis.61 Rabbits treated with telavancin 30 mg/kg twice daily (the dosage required to achieve serum concentrations similar to those seen in humans receiving 7.5 mg/kg/day) achieved a greater reduction in vegetation levels and a higher frequency of vegetation sterilization than rabbits treated with vancomycin. The difference was significant for VISA but not MRSA infections. Meningitis After receiving two doses of telavancin (30 mg/kg), seven rabbits with meningitis induced by a single strain of penicillin-resistant pneumococci or of MSSA achieved a maximum concentration (Cmax) in cerebrospinal fluid (CSF) of 5.14 mg/L.62 These concentrations were above the MIC for both strains. The Cmax/MIC ratio ranged from 30 to 63 for the pneumococcus strain and from 0.9 to 1.9 for the MSSA strain. Penetration of the noninflamed meninges of two rabbits was less than 1%, with a CSF Cmax of 0.130 mg/L. Telavancin was more efficacious in eliminating penicillin-resistant pneumococci than vancomycin or ceftriaxone. Telavancin’s efficacy against MSSA-induced meningitis appeared to be better than that of vancomycin, but the results were not statistically significant. Pneumonia Telavancin was at least as effective as vancomycin or linezolid in the treatment of MRSA-associated pneumonia in neutropenic mice.63 Mice treated with telavancin at a dosage that produced an area under the concentration-versus-time curve (AUC) comparable to that achieved in humans had significantly greater reductions in lung bacterial levels at 48 hours than did mice given vancomycin or linezolid (p < 0.05). Synergy Data on the combination of telavancin with other antimicrobials are limited. One study evaluated the activity of telavancin alone or in combination with ciprofloxacin, cefepime, imipenem, or piperacillin–tazobactam against single isolates of MRSA, VISA, VRSA, Streptococcus agalactiae, vancomycin-resistant E. faecium, vancomycin-susceptible E. faecalis, and a strain of daptomycin-nonsusceptible S. aureus.64 No antagonism was observed. Synergy was observed for VISA isolates when a combination of telavancin and imipenem or telavancin plus piperacillin–tazobactam was evaluated. Synergy was also observed for a VRSA isolate when telavancin was used in combination with cefepime, imipenem, or piperacillin–tazobactam. Resistance Little is known about the incidence of inducible resistance to telavancin. One study evaluating multidrug-resistant enterococci, staphylococci, and streptococci found no spontaneous-resistance mutants of telavancin (defined as an MIC greater than four times that for the parent strain) after a 10-day serial passage in the presence of sub-MIC concentrations of telavancin.65 A similar study in which isolates were passaged serially for 20 days selected for mutants with eightfold increases in the MIC for two of the three VRE strains examined.66 Resistance was not observed for the isolates of MRSA (n = 7), MSSA (n = 1), or vancomycin-susceptible E. faecalis (n = 1) tested. Pharmacokinetics Telavancin has a short distribution phase after i.v. infusion and is distributed into the central and peripheral compartments.67 Table 33 summarizes the pharmacokinetics of telavancin in healthy volunteers.67,68 Table 3. Pharmacokinetics of Telavancin in Healthy Volunteers Mean ± S.D. Value for Indicated Dosage Variable 7.5 mg/kg/day over 2 hr for 3 Days68(n= 8) 10 mg/kg over 2 hr67(n= 5) 7.5 mg/kg/day over 1.5 hr for 7 Days67n( = 6) 12.5 mg/kg/day over 0.5 hr for 7 Days67(n= 6) aAUC = area under the concentration-versus-time curve. Maximum concentration (mg/L) 84.8 ± 5.3 87.5 ± 6.0 96.7 ± 19.8 151 ± 17 Elimination half-life (hr) 6.28 ± 0.78 7.5 ± 0.6 8.83 ± 1.71 9.11 ± 2.33 AUC (μg · hr/mL)a 604 ± 83 858 ± 109 700 ± 114 1033 ± 91 Clearance (mL/hr/kg) 11.8 ± 2.1 11.8 ± 1.4 10.9 ± 1.6 12.2 ± 1.1 Volume of distribution (mL/kg) 98.0 ± 14.8 115 ± 6 105 ± 20 119 ± 18 Mean ± S.D. Value for Indicated Dosage Variable 7.5 mg/kg/day over 2 hr for 3 Days68(n= 8) 10 mg/kg over 2 hr67(n= 5) 7.5 mg/kg/day over 1.5 hr for 7 Days67n( = 6) 12.5 mg/kg/day over 0.5 hr for 7 Days67(n= 6) aAUC = area under the concentration-versus-time curve. Maximum concentration (mg/L) 84.8 ± 5.3 87.5 ± 6.0 96.7 ± 19.8 151 ± 17 Elimination half-life (hr) 6.28 ± 0.78 7.5 ± 0.6 8.83 ± 1.71 9.11 ± 2.33 AUC (μg · hr/mL)a 604 ± 83 858 ± 109 700 ± 114 1033 ± 91 Clearance (mL/hr/kg) 11.8 ± 2.1 11.8 ± 1.4 10.9 ± 1.6 12.2 ± 1.1 Volume of distribution (mL/kg) 98.0 ± 14.8 115 ± 6 105 ± 20 119 ± 18 Open in new tab Table 3. Pharmacokinetics of Telavancin in Healthy Volunteers Mean ± S.D. Value for Indicated Dosage Variable 7.5 mg/kg/day over 2 hr for 3 Days68(n= 8) 10 mg/kg over 2 hr67(n= 5) 7.5 mg/kg/day over 1.5 hr for 7 Days67n( = 6) 12.5 mg/kg/day over 0.5 hr for 7 Days67(n= 6) aAUC = area under the concentration-versus-time curve. Maximum concentration (mg/L) 84.8 ± 5.3 87.5 ± 6.0 96.7 ± 19.8 151 ± 17 Elimination half-life (hr) 6.28 ± 0.78 7.5 ± 0.6 8.83 ± 1.71 9.11 ± 2.33 AUC (μg · hr/mL)a 604 ± 83 858 ± 109 700 ± 114 1033 ± 91 Clearance (mL/hr/kg) 11.8 ± 2.1 11.8 ± 1.4 10.9 ± 1.6 12.2 ± 1.1 Volume of distribution (mL/kg) 98.0 ± 14.8 115 ± 6 105 ± 20 119 ± 18 Mean ± S.D. Value for Indicated Dosage Variable 7.5 mg/kg/day over 2 hr for 3 Days68(n= 8) 10 mg/kg over 2 hr67(n= 5) 7.5 mg/kg/day over 1.5 hr for 7 Days67n( = 6) 12.5 mg/kg/day over 0.5 hr for 7 Days67(n= 6) aAUC = area under the concentration-versus-time curve. Maximum concentration (mg/L) 84.8 ± 5.3 87.5 ± 6.0 96.7 ± 19.8 151 ± 17 Elimination half-life (hr) 6.28 ± 0.78 7.5 ± 0.6 8.83 ± 1.71 9.11 ± 2.33 AUC (μg · hr/mL)a 604 ± 83 858 ± 109 700 ± 114 1033 ± 91 Clearance (mL/hr/kg) 11.8 ± 2.1 11.8 ± 1.4 10.9 ± 1.6 12.2 ± 1.1 Volume of distribution (mL/kg) 98.0 ± 14.8 115 ± 6 105 ± 20 119 ± 18 Open in new tab In vitro Telavancin is highly protein bound (approximately 93%) in vitro in the presence of serum.67 In the presence of human serum, the MIC of televancin increased two- to eightfold against 50 glycopeptide-intermediate and heteroglycopeptide-intermediate staphylococcal species, as well as against three VRSA strains.19 However, bactericidal activity was maintained at approximately four times the MIC in both the presence and absence of serum. Likewise, telavancin’s MIC against MRSA increased 5- to 10-fold in the presence of mouse serum and albumin, and one study with MRSA and MSSA found a mean MIC increase in medium supplemented with human serum and human albumin of 4.57-and 4.85-fold, respectively.19 Healthy volunteers A pharmacokinetic study in 27 healthy male volunteers identified a linear relationship between the telavancin dosage and mean Cmax.67 Six participants receiving a single dose of telavancin 10 mg/kg i.v. infused over 120 minutes achieved a mean ± S.D. Cmax of 87.5 ± 6.0 mg/L. Six participants receiving 7.5 mg/kg/day infused over 30 minutes for seven days had a mean ± S.D. Cmax of 96.7 ± 19.8 mg/L, and six participants receiving 12.5 mg/kg/day infused over 30 minutes for seven days had a mean ± S.D. Cmax of 151 ± 17 mg/L. The mean ± S.D. AUC from time zero to infinity in volunteers receiving a single 10-mg/kg dose infused over two hours was 858 ± 109 μg · hr/mL, while those receiving 12.5 mg/kg/day for seven days achieved an AUC at steady state (AUCss) of 1033 ± 91 μg · hr/mL. The mean ± S.D. AUCss after doses of 7.5 mg/kg/day for seven days was 700 ± 114 μg · hr/mL. The ratio of the AUC after the first dose to the AUCss after seven days of continuous drug administration was low: 1.05, 1.02, and 1.01 for doses of 7.5, 12.5, and 15 mg/kg, respectively, suggesting minimal accumulation of the drug if given once daily.67 The overall volume of distribution of telavancin (V) was approximately 115 mL/kg in healthy adults after a single dose of 10 mg/kg. Similar results were observed after seven days of therapy with telavancin 12.5 and 7.5 mg/kg/day (mean ± S.D. V, 105 ± 20 and 119 ± 18 mL/kg, respectively). Initial studies suggest that telavancin penetrates well into blister fluid. One study in eight healthy volunteers found a mean ± S.D. Cmax in blister fluid of 16 ± 2 μg/mL after three consecutive doses of 7.5 mg/kg.68 The maximum concentration in blister fluid was achieved a mean ± S.D. of 9.3 ± 2.4 hours after the first infusion, and the elimination half-life was similar between plasma and blister fluid. Overall, the estimated mean ± S.D. AUC of telavancin in blister fluid compared with plasma drug concentrations was 40.3% ± 5.8%. Telavancin penetrates the pulmonary epithelial lining fluid and alveolar macrophages. Twenty human volunteers receiving three doses of telavancin 10 mg/kg showed a mean peak telavancin concentration in the epithelial lining fluid of 3.8 mg/L (range, 2.0–5.6 mg/L) after eight hours.69 This is roughly equivalent to the vancomycin concentrations found in epithelial fluid. In 14 critically ill patients receiving a minimum of five days of vancomycin therapy, the mean vancomycin concentration in alveolar macrophages was 4.5 mg/L (range, 0.8–8.1 mg/L).70 Higher concentrations of telavancin have been achieved in alveolar macrophages, with a mean Cmax at 12 hours of 45 mg/L (range, 22–76 mg/L).69 Telavancin is excreted primarily by renal elimination. Approximately 70–80% of a dose is excreted in the urine, with 60–70% eliminated unchanged and the remainder as hydroxylated metabolites.a Telavancin’s mean ± S.D. half-life was 7.5 ± 0.6 hours in five male volunteers who were administered one 10-mg/kg dose over 120 minutes.67 The half-life allows for administration every 24 hours. The clearance of telavancin after a single 10-mg/kg dose was 11.8 mL/kg/hr, and the mean ± S.D. clearance was similar in healthy male volunteers given 7.5 and 12.5 mg/kg/day for seven days (10.9 ± 1.6 and 12.2 ± 1.1 mL/hr/kg, respectively).67 There is no published information on the extent of fecal elimination or hepatic metabolism in healthy people. Special populations Renal insufficiency An extended half-life of telavancin was observed in renally impaired patients receiving a dose of 7.5 mg/kg.71 In patients with mild renal impairment (creatinine clearance [CLcr], 51–80 mL/min; n = 4), moderate impairment (30–50 mL/min; n = 3), or severe impairment (<30 mL/min; n = 2), the half-life of telavancin was 11.8, 13.2, and 17.9 hours, respectively. Overall clearance of the drug decreased slightly in patients with mild renal impairment and decreased markedly in those with moderate to severe impairment (11, 9, and 6 mL/kg/hr, respectively). Patients with renal impairment are likely to have a higher volume of distribution than healthy volunteers. Telavancin was minimally removed by hemodialysis in six patients (about 6%), and the mean ± S.D. half-life of the drug was 19.7 ± 4.9 hours.72 In vitro continuous venovenous hemodialysis appears to readily eliminate telavancin. Using a polysulfone hemofilter with an ultrafiltrate flow of 1 L/hr resulted in a mean ± S.D. drug clearance of 7.10 ± 2.35 mL/min.73 This clearance is approximately half that in healthy individuals, so the telavancin dosage may need to be adjusted accordingly.67 A study comparing two commonly used hemodialysis membranes (AN69 and polysulfone) found that both membranes were effective in clearing the drug during continuous venovenous hemofiltration.74 Dosage adjustment for renal dysfunction is indicated, since this drug is primarily eliminated unchanged by the kidneys. In clinical trials, patients with a CLcr of less than 50 mL/min received adjusted dosages of telavancin.11,–13 Administration of telavancin 10 mg/kg every 48 hours (i.e., a 50% dosage reduction) has been recommended for patients with end-stage renal disease receiving hemodialysis; however, a supplemental dose after dialysis does not appear to be required.72 Hepatic insufficiency One study evaluated eight volunteers with Child–Pugh class B hepatic impairment and found no significant difference in telavancin elimination compared with patients with normal hepatic function.75 Therefore, a dosage adjustment may not be necessary for patients with hepatic dysfunction. Patients with severe hepatic impairment were not studied. The elderly A study of the pharmacokinetics of telavancin 10 mg/kg in healthy elderly volunteers (eight men and eight women; mean age, 71 years [range, 66–83 years]) found a half-life of approximately 11 hours, versus approximately 8 hours in healthy younger adults.67 While there seems to be no difference in the overall clearance of telavancin between elderly and younger adults (approximately 12 mL/kg/hr for both groups),67,76 healthy elderly persons may have an increased V. The same study demonstrated that elderly male and female participants had a mean ± S.D. V of 173 ± 12 and 161 ± 13 mL/kg, respectively.76 From these data, no dosage adjustment appears to be necessary for elderly patients with normal renal function. Obesity No data on the pharmacokinetics of telavancin in obese patients are available. Pharmacodynamics Bactericidal patterns Telavancin displays concentration-dependent bactericidal activity that is best predicted by the ratio of the AUC to the MIC.77 Telavancin demonstrated concentration-dependent killing of S. aureus both in vitro and in vivo. In vitro time–kill models showed that telavancin was bactericidal against Staphylococcus species at four times the MIC.19 Postantibiotic effect Telavancin exhibits a postantibiotic effect (PAE) of four to six hours against most gram-positive bacteria. One in vitro study examining the activity of telavancin in the treatment of MSSA, MRSA, and VISA found a PAE of at least four hours.20 This effect was considerably longer than that for vancomycin (approximately one hour) or nafcillin (no appreciable PAE). Clinical efficacy In a randomized, double-blind, controlled, Phase II clinical trial in 167 patients with a diagnosis of complicated skin and soft-tissue infection caused by suspected or confirmed gram-positive organisms (FAST I), telavancin 7.5 mg/kg/day i.v. was as effective as standard therapy (anti-staphylococcal penicillin or vancomycin) in achieving a clinical cure (p = 0.53).12 A second Phase II trial (FAST II) evaluated 195 patients with the same types of infections; telavancin 10 mg/kg i.v. every 24 hours (n = 100) was compared with an anti-staphylococcal penicillin 2 g i.v. every 6 hours (n = 7) or vancomycin 1 g i.v. every 12 hours (n = 88).11 The clinical cure rates among patients receiving at least one dose of study medication were not significantly different between the two groups, with 82% of patients receiving telavancin achieving a clinical cure and 85% of patients receiving penicillin (p = 0.37). Among clinically evaluable patients, telavancin achieved a 96% clinical cure rate (n = 77), versus 94% for penicillin (n = 77) (p = 0.53). The clinical cure rates for microbiologically evaluable patients with infections caused by S. aureus (n = 91) were similar between the telavancin and penicillin groups (96% and 90%, respectively) (p = 0.36). Clinical cure rates were similar among patients with confirmed MRSA infections (n = 45) (96% for telavancin and 90% for penicillin) (p = 0.42). Microbial eradication was similar among patients infected with S. aureus (92% for telavancin and 78% for penicillin (p = 0.07). In patients with MRSA infections, microbiological eradication was superior for telavancin (92%) versus vancomycin (68%) (p = 0.04). The manufacturer of telavancin has completed Phase III trials in patients with complicated skin and soft-tissue infections (the ATLAS I and II trials). A new drug application (NDA) was filed with FDA in December 2006. In the ATLAS studies, a total of 1867 patients were randomized to receive either telavancin 10 mg/kg i.v. every 24 hours or vancomycin 1 g i.v. every 12 hours (the dosage was adjusted according to the standard operating procedures of each study center).13 The primary endpoint was clinical cure at follow-up, with secondary endpoints being microbiological eradication, combined clinical and microbiological cure, and cure rate by pathogen. Among the 1489 patients who were clinically evaluable, telavancin had a higher but not statistically higher rate of success compared with vancomycin. Recruitment is under way for Phase III clinical trials comparing telavancin and vancomycin in the treatment of hospital-acquired pneumonia caused by gram-positive bacteria, including MRSA (ATTAIN 1 and ATTAIN 2). The manufacturer plans to enroll 625 patients in each trial, and the primary endpoint is clinical response.78 Safety Adverse effects The most common adverse effects of telavancin during the clinical trials were metallic taste, nausea, vomiting, headache, foamy urine, and Q-Tc-interval prolongation.11,12 Table 44 summarizes the adverse effects and laboratory test abnormalities observed in Phase II and III trials of telavancin versus standard therapy. Increases in serum creatinine (SCr) levels were more frequent in patients treated with telavancin.11,13 In Phase III clinical trials, renal adverse events occurred in 2.5% of patients receiving telavancin, compared with 0.5% of patients receiving vancomycin.13 A decrease in the platelet count was observed in six telavancin recipients at the end-of-therapy visit during the first Phase II trial.12 The decrease, from a mean ± S.D. of 296,000 ± 111,000 platelets/mm3 to 176,000 ± 101,000 platelets/mm3, was considered mild. The count did not fall below 107,000 platelets/mm3 in any patient, and the decline had resolved by 7–14 days after the end of treatment. No reductions in platelet counts were reported in any of the other clinical trials.11,13 Microalbuminuria occurred in 7% of patients receiving telavancin in the FAST I trial but was not associated with an increase in SCr.12 The frequency of microalbuminuria in the FAST II trial was 4% but did not differ significantly from the rate for the standard treatment.11 The cause of foamy urine, which occurred in 13% of patients in the ATLAS trials, is believed to be the solubilizing agent cyclodextrin contained in the telavancin formulation.13,68 This adverse event was mild and was limited to the period of therapy.68 Table 4. Frequency of Adverse Events and Laboratory Test Abnormalities in Clinical Trials of Telavancin11,–13 Frequency (%) FAST I (n= 167)12 FAST II (n= 195)11 ATLAS I and II (n= 1867)13 Item Telavancin (7.5 mg/kg/day) Standard Therapya Telavancin (10 mg/kg/day) Standard Therapya Telavancin (10 mg/kg/day) Standard Therapyb aStandard therapy included in antistaphylococcal penicillin every 6 hours or vancomycin 1 g every 12 hours. bStandard therapy consisted of vancomycin 1 g every 12 hours. cNR = not reported. dAST = aspartate transaminase, ALT = alanine transaminase. Adverse Events     Metallic taste NRc NR 14 0 33 7     Nausea 15 13 16 6 27 15     Vomiting 10 4 8 6 14 7     Headache 11 10 8 4 14 13     Foamy urine NR NR NR NR 13 3     Insomnia NR NR 13 3 10 9     Constipation 4 6 5 7 10 7     Diarrhea NR NR 6 5 7 8     Pruritus NR NR 6 8 6 13     Dizziness NR NR NR NR 6 6     Psychiatric disorders 12 10 NR NR NR NR Laboratory Test Abnormalities     Increase in serum creatinine conc. 8 2 5 0 0.5 2.5     Increases in AST and ALTd 16 18 10 33 NR NR     Hypokalemia NR NR 7 0 NR NR     Anemia 10 10 13 15 NR NR     Microalbuminuria 7 1 NR NR NR NR     Leukopenia 1 2 2 1 NR NR     Thrombocytopenia 7 0 0 1 NR NR     Eosinophilia NR NR 5 12 NR NR     Hypomagnesemia NR NR 3 4 NR NR     Dyspnea 8 1 NR NR NR NR     Paresthesia 5 0 NR NR NR NR Frequency (%) FAST I (n= 167)12 FAST II (n= 195)11 ATLAS I and II (n= 1867)13 Item Telavancin (7.5 mg/kg/day) Standard Therapya Telavancin (10 mg/kg/day) Standard Therapya Telavancin (10 mg/kg/day) Standard Therapyb aStandard therapy included in antistaphylococcal penicillin every 6 hours or vancomycin 1 g every 12 hours. bStandard therapy consisted of vancomycin 1 g every 12 hours. cNR = not reported. dAST = aspartate transaminase, ALT = alanine transaminase. Adverse Events     Metallic taste NRc NR 14 0 33 7     Nausea 15 13 16 6 27 15     Vomiting 10 4 8 6 14 7     Headache 11 10 8 4 14 13     Foamy urine NR NR NR NR 13 3     Insomnia NR NR 13 3 10 9     Constipation 4 6 5 7 10 7     Diarrhea NR NR 6 5 7 8     Pruritus NR NR 6 8 6 13     Dizziness NR NR NR NR 6 6     Psychiatric disorders 12 10 NR NR NR NR Laboratory Test Abnormalities     Increase in serum creatinine conc. 8 2 5 0 0.5 2.5     Increases in AST and ALTd 16 18 10 33 NR NR     Hypokalemia NR NR 7 0 NR NR     Anemia 10 10 13 15 NR NR     Microalbuminuria 7 1 NR NR NR NR     Leukopenia 1 2 2 1 NR NR     Thrombocytopenia 7 0 0 1 NR NR     Eosinophilia NR NR 5 12 NR NR     Hypomagnesemia NR NR 3 4 NR NR     Dyspnea 8 1 NR NR NR NR     Paresthesia 5 0 NR NR NR NR Open in new tab Table 4. Frequency of Adverse Events and Laboratory Test Abnormalities in Clinical Trials of Telavancin11,–13 Frequency (%) FAST I (n= 167)12 FAST II (n= 195)11 ATLAS I and II (n= 1867)13 Item Telavancin (7.5 mg/kg/day) Standard Therapya Telavancin (10 mg/kg/day) Standard Therapya Telavancin (10 mg/kg/day) Standard Therapyb aStandard therapy included in antistaphylococcal penicillin every 6 hours or vancomycin 1 g every 12 hours. bStandard therapy consisted of vancomycin 1 g every 12 hours. cNR = not reported. dAST = aspartate transaminase, ALT = alanine transaminase. Adverse Events     Metallic taste NRc NR 14 0 33 7     Nausea 15 13 16 6 27 15     Vomiting 10 4 8 6 14 7     Headache 11 10 8 4 14 13     Foamy urine NR NR NR NR 13 3     Insomnia NR NR 13 3 10 9     Constipation 4 6 5 7 10 7     Diarrhea NR NR 6 5 7 8     Pruritus NR NR 6 8 6 13     Dizziness NR NR NR NR 6 6     Psychiatric disorders 12 10 NR NR NR NR Laboratory Test Abnormalities     Increase in serum creatinine conc. 8 2 5 0 0.5 2.5     Increases in AST and ALTd 16 18 10 33 NR NR     Hypokalemia NR NR 7 0 NR NR     Anemia 10 10 13 15 NR NR     Microalbuminuria 7 1 NR NR NR NR     Leukopenia 1 2 2 1 NR NR     Thrombocytopenia 7 0 0 1 NR NR     Eosinophilia NR NR 5 12 NR NR     Hypomagnesemia NR NR 3 4 NR NR     Dyspnea 8 1 NR NR NR NR     Paresthesia 5 0 NR NR NR NR Frequency (%) FAST I (n= 167)12 FAST II (n= 195)11 ATLAS I and II (n= 1867)13 Item Telavancin (7.5 mg/kg/day) Standard Therapya Telavancin (10 mg/kg/day) Standard Therapya Telavancin (10 mg/kg/day) Standard Therapyb aStandard therapy included in antistaphylococcal penicillin every 6 hours or vancomycin 1 g every 12 hours. bStandard therapy consisted of vancomycin 1 g every 12 hours. cNR = not reported. dAST = aspartate transaminase, ALT = alanine transaminase. Adverse Events     Metallic taste NRc NR 14 0 33 7     Nausea 15 13 16 6 27 15     Vomiting 10 4 8 6 14 7     Headache 11 10 8 4 14 13     Foamy urine NR NR NR NR 13 3     Insomnia NR NR 13 3 10 9     Constipation 4 6 5 7 10 7     Diarrhea NR NR 6 5 7 8     Pruritus NR NR 6 8 6 13     Dizziness NR NR NR NR 6 6     Psychiatric disorders 12 10 NR NR NR NR Laboratory Test Abnormalities     Increase in serum creatinine conc. 8 2 5 0 0.5 2.5     Increases in AST and ALTd 16 18 10 33 NR NR     Hypokalemia NR NR 7 0 NR NR     Anemia 10 10 13 15 NR NR     Microalbuminuria 7 1 NR NR NR NR     Leukopenia 1 2 2 1 NR NR     Thrombocytopenia 7 0 0 1 NR NR     Eosinophilia NR NR 5 12 NR NR     Hypomagnesemia NR NR 3 4 NR NR     Dyspnea 8 1 NR NR NR NR     Paresthesia 5 0 NR NR NR NR Open in new tab During Phase III clinical trials, more adverse effects were reported in patients receiving telavancin than in patients receiving standard therapy.13 The rate of discontinuation of therapy due to adverse effects was nearly two times higher in the telavancin group (7% versus 4%). The most common adverse event leading to discontinuation of therapy was nausea (1%); all other adverse events leading to discontinuation occurred at rates of <1%. A Phase I study randomized 160 healthy men (n = 94) and women (n = 66) with a mean age of 27.8 years to receive telavancin 7.5 or 15 mg/kg/day, moxifloxacin 400 mg/day (as a positive control), or placebo.79 The mean increase in Q-Tc interval (with Fridericia correction) relative to placebo in patients receiving telavancin 7.5 or 15 mg/kg was 4.1 and 4.5 msec, respectively. This was statistically higher than for placebo recipients (p = 0.036) but less than half that seen in the moxifloxacin controls (9.2 msec). No dosage dependency was seen between the two telavancin dosages. The study concluded that the mean change from baseline in Q-Tc-interval duration of <5 msec for telavancin at a dosage beyond the clinical range suggests there should be minimal, if any, risk of cardiac-related events with this new antibiotic.61 In Phase III trials, slight Q-Tc-interval prolongation was noted in the telavancin group. Approximately 1% of patients in the telavancin-treated group had a Q-Tc-interval increase of greater than 60 msec, compared with 0.5% of vancomycin recipients.13 No cardiac adverse events associated with Q-Tc-interval prolongation were noted.11,–13 Drug interactions To date there have been no published studies evaluating drug–drug interactions involving telavancin. Dosage and administration In Phase II and III clinical trials evaluating telavancin for skin and soft-tissue infections, the drug was administered at a dosage of 10 mg/kg i.v. every 24 hours.11,13 Currently, telavancin is formulated only as an i.v. injection, and there is no indication that an oral formulation is feasible (Theravance, personal communication, 2007). The drug is administered by i.v. infusion over 60 minutes. Patients with renal dysfunction The tentative dosage in renal impairment is 7.5 mg/kg every 24 hours for a CLcr of 30–50 mL/min and 10 mg/kg every 48 hours for a CLcr of less than 30 mL/min.a Patients with hepatic dysfunction Available data indicate that dosage adjustment may not be necessary in patients with mild to moerate hepatic dysfunction (Child–Pugh class B).75 No data are available to aid in dosage recommendations for patients with severe hepatic dysfunction. Pregnant women The use of telavancin has not been evaluated in pregnancy. Geriatric patients Available data are limited but indicate that dosage adjustment may not be necessary in elderly patients with normal renal function.76 Place in therapy Telavancin is under review by FDA (NDA filed December 2006) for use in treating complicated skin and soft-tissue infections caused by gram-positive bacteria. The manufacturer is actively recruiting patients for Phase III clinical trials of this drug for the treatment of hospital-acquired pneumonia caused by MRSA. Telavancin has demonstrated two mechanisms of action involving interference with cell-wall synthesis and disruption of the functional integrity of the cell membrane. This compound has antimicrobial coverage similar to vancomycin’s, with MICs that are generally two- to eightfold lower for many gram-positive bacteria, including MRSA. This drug also demonstrates some activity against strains of VRE. Telavancin is highly protein bound and has a prolonged half-life that allows for once-daily administration. The drug penetrates well into the skin fluid and pulmonary epithelial lining fluid and accumulates well in alveolar macrophages. The drug has favorable pharmacodynamic properties, with more rapid bactericidal activity than vancomycin in vitro. In animal models, telavancin was effective in the treatment of soft-tissue infections, meningitis, endocarditis, and pneumonia. In clinical trials, telavancin was at least as effective as standard therapy for complicated skin and soft-tissue infections. Pre-clinical evaluations demonstrate that telavancin is more likely to be associated with increased SCr levels than vancomycin. Telavancin has shown activity against a number of gram-positive species, including S. aureus and enterococci. If approved for marketing, telavancin may offer an alternative to vancomycin for treating infections caused by β-lactam-resistant organisms and will join newer agents such as daptomycin, linezolid, and tigecy-cline as alternatives to vancomycin for gram-positive infections. In some cases, the agent displays activity against isolates that are resistant to vancomycin; however, in many cases vancomycin-resistant strains also display tolerance to telavancin. This may limit the drug’s utility against fully vancomycin-resistant bacteria and in cases of vancomycin treatment failure. The agent has favorable pharmacodynamic properties, but clinical data have yet to demonstrate that telavancin is superior to standard therapy. Once-daily administration may allow for more convenient administration and obviate the need to monitor serum concentrations. Two other glycopeptide derivatives have been under development for the treatment of drug-resistant gram-positive infections. Oritavancin (Targanta), a semisynthetic glycopeptide derived from a vancomycin analogue, has shown promise against MRSA, as well as potential activity against vancomycin-resistant strains of staphylococci and enterococci.24,25,80,–87 Oritavancin displays concentration-dependent bactericidal activity and has an extended half-life allowing administration every 24 or 48 hours.88,–91 Oritavancin is currently in Phase III clinical trials, and, although no formally published clinical trials are available, meeting presentations suggest that it is effective in the treatment of skin and soft-tissue infections.90,91 Dalbavancin (Pfizer), another compound structurally similar to the glycopeptide teicoplanin (which is approved for use in Europe), recently completed Phase III clinical trials for the treatment of complicated skin and soft-tissue infections, as well as a Phase II trial for catheter-related bloodstream infections.92,–95 The agent demonstrates activity against MRSA and other gram-positive organisms.26,27,40,–49 Dalbavancin has an extended half-life (9–12 days), which may allow for weekly administration.93,–97 An NDA was filed, and FDA approved the labeling of this compound in July 2006. 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TI - Telavancin: A novel lipoglycopeptide antimicrobial agent
JF - American Journal of Health-System Pharmacy
DO - 10.2146/ajhp070080
DA - 2007-11-15
UR - https://www.deepdyve.com/lp/oxford-university-press/telavancin-a-novel-lipoglycopeptide-antimicrobial-agent-jSXgLoFmHc
SP - 2335
VL - 64
IS - 22
DP - DeepDyve
ER -