Telavancin: a novel semisynthetic lipoglycopeptide agent to counter the challenge of resistant Gram-positive pathogens

Abstract

Telavancin (TD-6424), a semisynthetic lipoglycopeptide vancomycin-derivative, is a novel antimicrobial agent developed by Theravance for overcoming resistant Gram-positive bacterial infections, specifically methicillin-resistant Staphylococcus aureus (MRSA). The US Food and Drug Administration (USFDA) had approved telavancin in 2009 for the treatment of complicated skin and skin structure infections (cSSSIs) caused by Gram-positive bacteria, including MRSA (S. aureus, Streptococcus agalactiae, Streptococcus pyogenes, Streptococcus anginosus group, or Enterococcus faecalis). Telavancin has two proposed mechanisms of action. In vitro, telavancin has a rapid, concentration-dependent bactericidal effect, due to disruption of cell membrane integrity. Telavancin has demonstrable in vitro activity against aerobic and anaerobic Gram-positive bacteria. Telavancin and vancomycin have similar spectra of activity. Gram-negative bacteria are usually non-susceptible to telavancin. Telavancin has been successfully tested in various animal models of bacteremia, endocarditis, meningitis, and pneumonia. Phase II Telavancin versus Standard Therapy for Treatment of Complicated Skin and Soft-Tissue Infections due to Gram-Positive Bacteria (FAST 1 and FAST 2) and phase III [Assessment of Telavancin in Complicated Skin and Skin Structure Infections 1 (ATLAS 1 and ATLAS 2)] clinical trials have been conducted for evaluating telavancin’s efficacy and safety in cSSSIs. Phase III clinical trials have been carried out for evaluating telavancin’s safety and efficacy in nosocomial pneumonia [Assessment of Telavancin for Treatment of Hospital acquired Pneumonia 1 and 2 (ATTAIN 1 and ATTAIN 2)]. A phase II randomized, double-blind, clinical trial has been carried out for evaluating telavancin’s safety and efficacy in uncomplicated S. aureus bacteremia [Telavancin for Treatment of Uncomplicated S. aureus Bacteremia (ASSURE)]. Pacemaker lead–related infective endocarditis due to a vancomycin intermediate S. aureus (VISA) strain (non-daptomycin susceptible) was successfully treated with parenteral telavancin for 8 weeks. Telavancin extensively binds to serum albumin (~93%) and has a relatively small volume of distribution. Telavancin is not biotransformed by any cytochrome P₄₅₀ microsomal enzymes and excreted mainly in the urine. Though well-tolerated, worrisome adverse effects, including renal dysfunction and QTc prolongation are of potential concern. Given its extensive binding to plasma proteins, long half-life, and a long post-antibiotic effect, it represents a promising addition to the therapeutic armamentarium in combating infections caused by resistant Gram-positive pathogens, namely, MRSA.

Introduction

Bacteria are extremely adept at modifying themselves to changing environmental challenges. Antibacterial drugs, unlike other medications, hit at mutating targets. Hence, their antibacterial effectiveness diminishes over time. Resistance to antibiotics is a potential looming threat, and the resistance level of certain microbes has steadily increased.¹ Due to cumbersome and prolonged research and development timelines for new drug approvals, bacteria have outwitted human effectiveness to counter the serious threat of emerging resistance to antibacterials.² The astronomical expenses associated with new drug development have also pushed pharmaceutical firms to prioritize their drug development projects and selectively dwell on those drug development ventures that have a greater possibility for a return on committed development investment while shelving others. Hence, a large number of pharmaceutical companies have relinquished or are now pursuing antimicrobial research with perceptibly less vigor and interest. Expensive difficult science in concert with the perception of a ‘hostile’ regulatory system is to blame for this current bleak scenario. Only a handful of pharmaceutical frontrunners are exhibiting their bravado in doggedly pursuing antibacterial drug development. Only five new antibiotics were approved from 2003 to 2007, while 16 were approved in the years 1983–1987.³ The Food and Drug Administration (FDA) approved two new antibiotics in 2009.⁴ Drying-up of the antibiotic pipeline has led to a grim reality for the medical community.³

Staphylococcus aureus is a commensal bacterium in 25% of humans and is found predominantly in the nose, throat, armpit, and groin, where it causes no harm.⁵ This opportunistic pathogen is a common cause of hospital-acquired infection (HAI). Methicillin-resistant S. aureus (MRSA) is important as its infection leads to high rates of morbidity and mortality in affected hospitalized patients despite significant advancements in medical care. The incidence of MRSA infection has been showing an upward trend around the world.^6–9 The etiologic organisms have been identified as S. aureus strains with an oxacillin minimum inhibitory concentration (MIC) of at least 4 µg/ml. MRSA strains are prevalent in hospitals and have acquired the mecA gene (coding for the low-affinity binding protein PBP-2a) on genetic cassettes called SCCmec rendering them resistant to all the beta-lactams, inclusive of methicillin, flucloxacillin, carbapenems, and cephal-osporins (ceftobiprole being the exception).^10,11 Traditionally, MRSA has been considered a major nosocomial pathogen in healthcare facilities, but in the past decade, it has been observed emerging in the community as well.¹² Infections due to MRSA have been classified as either nosocomial [hospital acquired (HA-MRSA) or community acquired (CA-MRSA)]. Risk factors known for patients with hospital-associated MRSA (HA-MRSA) infections include recent hospitalization, dialysis, nursing-home residence, and other comorbid conditions, such as diabetes, chronic renal failure, and chronic pulmonary diseases, which bring them into contact with healthcare settings.¹² Infection is considered to be HA-MRSA if positive cultures result from samples drawn after 72 h of admission. On the other hand, cases considered CA-MRSA include those in which positive cultures have been drawn outside the hospital or drawn within 72 h of admission or in cases in which MRSA was diagnosed in an outpatient setting with no previous contact with the healthcare environment.^6,13 HA-MRSA has been implicated in skin and wound infections, bloodstream infection (inclusive of central venous catheter-related infections), pneumonia (inclusive of ventilator-associated pneumonia), osteomyelitis, endocarditis (inclusive of pacemaker lead–induced endocarditis), lung abscesses, and pyomyositis. Patients with CA-MRSA infections have often lacked risk factors known for patients with HA-MRSA infections. Injecting drug users could be a major reservoir for CA-MRSA transmission.¹² Many of the CA-MRSA infections are limited to superficial skin and skin structure infections. However, CA-MRSA can cause severe systemic infections, including pneumonia and bloodstream infection.¹³

In 1956, a new glycopeptide antibacterial compound, vancomycin, was ushered into therapy to tackle the emerging menace of penicillinase-producing staphylococci. Thereafter, product impurity–related adverse events and introduction of beta lactamase–resistant penicillins and cephalosporins in the 1960s resulted in a steep decline in the prescription of parenteral vancomycin. The 1980s and 1990s witnessed a renewed enthusiasm in prescription of vancomycin owing to the pharmaceutical development of a more purified product as also the requirement of countermeasures for the emerging and spreading MRSA challenge.^14,15 Vancomycin is used as the first-line agent against MRSA. In Europe and the United States, telavancin is also approved as a useful alternative for patients with difficult-to-treat, hospital-acquired MRSA pneumonia when there are very few alternatives. However, vancomycin-resistant strains have made an emergence. Some of these strains exhibit an intermediate sensitivity to vancomycin. They are termed as vancomycin intermediate S. aureus (VISA) and heteroresistant VISA (hVISA), comprising strains manifesting vancomycin resistance.¹⁶ Staphylococci exhibiting complete vancomycin resistance [vancomycin-resistant S. aureus (VRSA)] are rare.¹⁷ Some antibiotics like linezolid, tigecycline, daptomycin, and quinupristin/dalfopristin are effective against VRSA.¹⁸ Given the current scenario of increasing numbers of Gram-positive microorganisms resistant to vancomycin, novel antimicrobial molecules, active against Gram-positive bacteria, preferentially exhibiting a multitude of mechanisms of action, need to be actively researched and introduced into clinical practice. Antibacterial drug development is spurred by resistance trends aiming at development of modified analogs of known scaffolds to reinforce them against class-specific resistance mechanisms.

Telavancin (TD-6424) is a lipoglycopeptide derivative of vancomycin. It was developed by Theravance as a novel agent for resistant Gram-positive bacterial infections, especially MRSA.¹⁹ In 2009, USFDA approval for telavancin for the treatment of complicated skin and skin structure infections (cSSSIs) due to Gram-positive bacteria, including MRSA (S. aureus, Streptococcus agalactiae, Streptococcus pyogenes, Streptococcus anginosus group, or Enterococcus faecalis)^20,21 came through. This article reviews the chemical nature, mechanism of action, antimicrobial coverage, pharmacokinetics (PKs), pharmacodynamics (PDs), clinical efficacy, and tolerability profile of telavancin.

Chemical nature

Telavancin arose out of semisynthetic modification of vancomycin (which is documented to be a glycopeptide antimicrobial entity). The hydrophilic and hydrophobic moiety (Figure 1) appended to the glycopeptide backbone in telavancin helps in comprehending many of the unique PK and PD parameters of telavancin. In the telavancin molecule, there is a hydrophobic (decylaminoethyl) side chain which is linked to a vancosamine sugar. Also a hydrophilic (phosphonomethyl aminomethyl) group is linked on the 4′ position of amino acid 7 of the heptapeptide core.²² The linked lipophilic decylaminoethyl substituent to this molecule enables us to identify this antibacterial agent as a lipoglycopeptide. The hydrophobic decylaminoethyl side chain introduced on the vancosamine sugar bolsters tethering of the agent onto the cell membranes of bacteria, which substantially reinforces the antimicrobial action of telavancin toward MRSA and the vanA gene-containing enterococci.²³ On the other hand, the polar phosphonomethyl aminomethyl group attached to the resorcinol moiety reinforces the half-life-extending effect of the lipophilic side chain, permitting the agent to be conveniently dosed once per day.²³

Figure 1.

Chemical structure of telavancin hydrochloride which is a semisynthetic derivative of vancomycin. The lipophilic decylaminoethyl side chain (contributing towards prolonged half-life and membrane anchoring) is highlighted by the black arrow. The hydrophilic (phosphonomethyl aminomethyl) group is highlighted by the blue arrow.

Chemically telavancin may be christened as vancomycin, N3″-[2-(decyl-amino)ethyl]-29-[[(phosphono-methyl)-amino]-methyl] hydrochloride. The empirical formula of telavancin is C₈₀H₁₀₆C₁₂N₁₁O₂₇P·xHCl (where x = 1–3). Telavancin has a free-base molecular weight of 1755.6 Da. Telavancin hydrochloride exists as an off-white to slightly colored amorphous powder, which is very lipophilic and sparingly soluble in water.²⁴

Mechanism of action

Telavancin has been credited with two proposed mechanisms of action. Like vancomycin, telavancin exhibits bactericidal activity via interaction with C-terminal d-alanyl-d-alanine residue on bacterial cell wall peptidoglycan precursors. As a consequence of this interaction, polymerization of peptidoglycan (transglycosylation) and subsequent, cross-linking (transpeptidation) steps of cell wall synthesis are effectively tampered with. Telavancin powerfully inhibits peptidoglycan biosynthesis at the transglycosylase step, hence it is 10 times stronger than vancomycin at inhibition of peptidoglycan synthesis in intact MRSA cells. Since telavancin disturbs the integrity of the bacterial cell-membrane, in vitro, a concentration-dependent bactericidal effect is seen within 10 min.^19,24,25

A second mechanism of action has been proposed. It involves bacterial cell-membrane depolarization, resulting in perturbation of bacterial cell-membrane function. This dual mechanism of action is of particular interest, since few other glycopeptides are believed to work in this manner.¹⁹ Although the mechanism of cell membrane disruption by telavancin is not well-understood, it is speculated that this depends on interactions of the lipophilic decylaminoethyl moiety of telavancin with the lipid bilayer of the bacterial cell membrane.^19,26 This lipophilic entity promotes telavancin’s affinity for lipid II, a molecular member of the bacterial cell membrane. This enhanced affinity permits telavancin to gain ready access into the bacterial cell in order to disrupt the transglycosylation mechanism of cell wall synthesis instead of the bacterial cell wall transpeptidation mechanism, where vancomycin preferentially binds.²⁷ In S. aureus, there are reports that lipid II binding is imperative for telavancin to produce membrane depolarization on a flow cytometry assay. However, this may not reflect the key step in bacterial membrane perturbation.²⁸ Membrane depolarization may be further linked to loss of cytoplasmic adenosine triphosphate (ATP) and potassium ions. This alternate mode of action operates specifically in bacterial cell-membranes, and not in mammalian cells, and may be responsible for faster bactericidal effect of telavancin, in contrast to vancomycin.

Telavancin has affinity for the cell membrane and septum, which are known to be the active site of cell wall synthesis in the bacterial cytoplasm. This was determined by employing fluorescence microscopy in MRSA isolates.²⁹ Telavancin has been reported to possess higher binding to the bacterial septum in comparison to vancomycin. In all, 61% of telavancin-treated bacterial cells were documented to possess septal drug binding. However, only 13% of cells exposed to vancomycin were found to possess septal drug binding. Both agents displayed binding to the bacterial outer cell wall with vancomycin possessing a higher affinity for this site. Employing the d-alanyl-d-alanine ligand N, N′-diacetyl-l-Lys-d-alanyl-d-alanine as a marker for uncross-linked cell wall residues, researchers detected that vancomycin had 4–6 times stronger affinity for cell wall in comparison to telavancin.²³ Telavancin binds to the bacterial outer cell wall in a concentration-dependent manner, hence decreased binding to the cell wall is observed at lower concentrations. However, binding to the bacterial cell septum takes effect in a concentration-independent manner.²⁹ Bacterial cell lysis is not the reason for the rapid bactericidal effect observed with telavancin.²⁸ A plausible explanation is that telavancin causes bacterial membrane potential disruption, with consequent escape of intracellular ions such as K⁺, and ATP, leading to cell death.²³ A study with S. aureus (n = 8) documented that, in vitro, telavancin retains its bactericidal nature irrespective of the extracellular or intracellular location of the microorganism.³⁰

Spectrum of activity and synergy

In vitro activity

In vitro, telavancin has demonstrable activity against aerobic and anaerobic Gram-positive bacteria (Table 1).^31–37 Telavancin and vancomycin have similar spectra of activity. However, the MICs for telavancin are approximately 2- to 8-fold lower in comparison to vancomycin against susceptible test organisms. The MICs of telavancin against susceptible aerobic and anaerobic Gram-positive bacteria have been shown in Table 2 in comparison with other lipoglycopeptides (viz., dalbavancin and oritavancin), a cyclic lipopeptide (daptomycin), an oxazolidinone compound (linezolid), and vancomycin.^38–70

Table 1.

Activity (in vitro) of Telavancin against selected aerobic and anaerobic Gram-positive organisms.

Organism(s)	No. of isolates	MIC50 (µg/ml)	MIC90 (µg/ml)	Range (µg/ml)
Aerobic
Staphylococcus aureus (MSSA)	10,563	0.12−0.5	0.25−0.5	<0.015−1
Coagulase-negative staphylococci	839	0.06	0.5	0.06−1
Enterococcus faecalis (vancomycin-susceptible)	2687	0.25−0.5	0.5−1	0.06−2
Enterococcus faecium (vancomycin-susceptible)	1267	0.06−0.25	0.12−0.5	0.03−2
Streptococcus pneumoniae	1029	0.015	0.03	<0.001−0.06
Beta-hemolytic streptococci	790	0.03−0.125	0.06−0.125	<0.001−0.25
Viridans group streptococci	257	0.03−0.06	0.06−0.12	<0.001−1
Listeria monocytogenes	10	0.125	0.125	0.125−0.125
Anaerobic
Actinomyces spp.	45	0.125−0.25	0.25	0.125−0.25
Clostridium bolteae	16	4	8	0.5−8
Clostridium clostridioforme	31	1−4	8	0.25−8
Clostridium difficile	29	0.25	0.25	0.125−0.5
Clostridium innocuum	32	1−2	2−4	1−4
Clostridium perfringens	27	0.06	0.125−0.25	0.06−0.25
Clostridium ramosum	26	0.25−0.5	0.25−1	0.25−8
Other clostridial spp	109	<0.12−0.25	0.25	<0.12−1
Eubacterium lentum	10	0.25	0.25	0.125−0.25
Lactobacillus spp	26	0.25	0.25−1.25	<0.015−2
Peptoniphilus asaccharolyticus	10	0.03	0.06	0.03−0.06
Peptostreptococcus anaerobius	10	0.06	0.25	0.05−0.25
Propionibacterium acnes	12	0.125	0.125	0.06−0.125
Resistant organisms
S. aureus
MRSA	4680	0.12−0.25	0.25−0.5	0.06−1
CA-MRSA	134	0.25−0.5	0.25−0.5	0.25−1
hVISA	2	NA	NA	0.25−0.5
VISS	76	0.5	1	0.125−1
VRSA	6	NA	NA	2−4
Methicillin-resistant coagulase-negative Staphylococci	2758	0.25−0.5	0.25−1	0.06−2
Enterococcus species
Vancomycin-resistant	69	2−4	4−8	0.25−8
E. faecalis (NP)
Vancomycin-resistant	338	1−2	2−4	0.12−8
E. faecium (NP)
vanA genotype	521	4−8	16	<0.015−32
vanB genotype	53	0.25−0.5	2	0.06−4
Penicillin-resistant S. pneumoniae	301	0.015	0.015−0.03	0.008−0.12
MDR S pneumonia	60	0.015	0.03	0.008−0.12

CA-MRSA, community-acquired methicillin-resistant Staphylococcus aureus; hVISA, heteroresistant vancomycin intermediate S. aureus; NP, phenotype not specified; MDR, multidrug resistant; MRSA, methicillin-resistant S. aureus; MSSA, methicillin-susceptible S. aureus; VISS, vancomycin-intermediate staphylococcal species (S. aureus, Staphylococcus epidermidis, Staphylococcus haemolyticus); VRSA, vancomycin-resistant S. aureus.

Table 2.

Pharmacokinetic parameters of telavancin in healthy adult volunteers.

Parameters	Dose
	Single dose	Multiple doses
	10 mg/kg over 2 h	7.5 mg/kg/day over 2 h for 3 days (n = 8)	7.5 mg/kg/day over 1.5 h for 7 days (n = 6)	7.5 mg/kg/day over 0.5 h for 7 days (n = 6)	10 mg/kg/day over (n = 5) 1 h for days (n = 20)
Maximum concentration (Cmax) (mg/l)	87.5 ± 6.0	84.8 ± 5.3 [16.0 ± 2.0]	96.7 ± 19.8	151 ± 17	116 ± 13
Tmax (h)		1.0 ± 0.0 [9.3 ± 2.4]			1.0 ± 0.0
Cmin (µg/ml)					8.11 ± 2.28
t1/2 (h)	7.5 ± 0.6	6.28 ± 0.78 [6.91 ± 0.53]	8.83 ± 1.71	9.11 ± 2.33	7.41 ± 1.08
AUC0–24 (µg·h/ml)	858 ± 109	604 ± 83 [241 ± 33]	700 ± 114	1033 ± 91	785 ± 111
Vdss (ml/kg)	115 ± 6	98.0 ± 14.8	105 ± 20	119 ± 18	122 ± 22
Clss (ml/h/kg)	11.8 ± 1.4	11.8 ± 2.1	10.9 ± 1.6	12.2 ± 1.1	13.0 ± 1.9
MRT		6.57 ± 0.42 [10.3 ± 0.6]

AUC, area under the concentration-versus-time curve; Cl_ss (ml/h/kg) = clearance at steady state; MRT, mean residence time; t_1/2 (h), half-life; V_dss (ml/kg), apparent volume of distribution at steady state; [ ], values in parentheses (box brackets) indicate parameters of telavancin in blister fluid.

Data are mean ± SD.

Methicillin-susceptible S. aureus (MSSA) and MRSA are sensitive to the antibacterial activity of telavancin. MIC of telavancin for MRSA has been reported to be ⩽0.06–2 mg/l, whereas that for MSSA is 0.12–2 mg/l.^31,33,34 Telavancin’s MICs against vancomycin-susceptible E. faecalis and Enterococcus faecium are ⩽0.06–2 mg/l and 0.015–0.5 mg/l, respectively.^31,32

Plasmid-mediated resistance to vancomycin most frequently arises from spread of the vanA operon in E. faecium and less commonly by the vanB operon. vanA and vanB operons are less commonly found in E. faecalis. Other related van operons may also infrequently arise in E. faecium and E. faecalis. vanA and vanB operons mediate resistance to glycopeptides by altering the C-terminal d-Ala-d-Ala dipeptide of peptidoglycan to d-Ala-d-Lac, for which vancomycin displays low affinity.^71,72 vanA and vanB operons are composed of a series of genes each with defined activities. vanA-type resistance, and to a lesser extent vanB-type resistance, is common among enterococci owing to the transmissibility of these operons. Interspecies gene transfer is also possible and clinically important, but uncommon. Expression of vanA and vanB operons is induced by the presence of vancomycin. Telavancin resistance arises in enterococci harboring the vanA operon; also by operon induction, however, enterococci with vanB remain susceptible to telavancin.^72,73 Hence, some vancomycin-resistant enterococci (VRE) are also susceptible to telavancin.

Telavancin’s MICs against vancomycin-resistant E. faecalis and E. faecium are ⩽0.025–6 mg/l and 0.015–16 mg/l, respectively. For 29 isolates of vancomycin-resistant E. faecium as well as 29 isolates of vancomycin-resistant E. faecalis, the MIC₉₀ (MIC needed to inhibit 90% strain growth) is 1/64 (~0.015625) times the MIC₉₀ of vancomycin (viz., 4 mg/l versus >256 mg/l).³¹ Many species of streptococci (including multidrug-resistant and penicillin-resistant strains) are susceptible to telavancin.^31,35,36 Telavancin is more active against VISA and hVISA compared to vancomycin, given the fact that MIC₉₀ of vancomycin is 8 times more than that of telavancin (1 mg/l versus 8 mg/l) for 50 isolates of glycopeptide-intermediate staphylococcus species (GISS) and heteroresistant GISS.³¹

Other bacteria susceptible to telavancin include Bacillus anthracis (MIC, ⩽0.03–0.5 mg/l) and Listeria species (MIC, 0.125 mg/l).^31,74 Telavancin is known to exert activity against S. aureus harbored intracellularly inside murine THP-1 and human J774 macrophage cell lines.³⁰ Biofilm-generating S. aureus and Staphylococcus epidermidis are also susceptible to the antibacterial effects of telavancin.⁷⁵ Actinomyces species (MIC, 0.125–0.25 mg/l), Clostridium difficile (MIC, 0.125–0.5 mg/l), and many other anaerobic bacteria are susceptible to telavancin.³⁷ Gram-negative bacteria are usually non-susceptible to telavancin.

In vivo activity

Telavancin has been tested in various relevant animal models of infection, namely, bacteremia, endocarditis, meningitis, and pneumonia with success.

1. Bacteremia. In a MRSA bacteremia model in neutropenic mice, telavancin demonstrated superior efficacy in comparison to vancomycin.⁷⁶ Telavancin of 40 mg/kg administered as two subcutaneous injections spaced 12 h apart was found to be superior to 110 mg/kg of vancomycin also administered in a similar fashion. Those animals receiving telavancin had a significantly higher 14-day survival compared with vancomycin-treated animals (14/15 versus 0/15; p < 0.05).

2. Endocarditis. In a rabbit model of S. aureus endocarditis, telavancin exerted bacteriocidal effect against a MRSA strain (COL) and a VISA strain (HIP5836) at a concentration of 5 µg/ml. Vancomycin was bacteriostatic at 5 µg/ml and bacteriocidal at 10 µg/ml against COL. Vancomycin was bacteriostatic at 10 µg/ml against HIP5836. In the VISA model, significantly more effective results (reduction in vegetation levels and higher frequency in vegetation sterilization) were produced by telavancin (30 mg/kg twice daily IV for 4 days) compared to vancomycin (30 mg/kg twice daily IV for 4 days).⁷⁷ Another comparative study has reported the efficacy of telavancin and daptomycin in an experimental rabbit endocarditis model caused by two clinically derived daptomycin-resistant MRSA strains. Telavancin treatment significantly reduced MRSA densities in all target tissues and increased the percentage of these organs rendered culture negative as compared to untreated control or daptomycin-treated animals. These results demonstrate that telavancin has potent in vivo efficacy against daptomycin-resistant MRSA isolates in this invasive endovascular infection model.⁷⁸

3. Meningitis. In a rabbit model of induced meningitis (penicillin-resistant pneumococci or MSSA), the efficacy of telavancin in clearing penicillin-resistant pneumococci was greater than vancomycin or ceftriaxone. In the case of MSSA-induced meningitis rabbit model, the efficacy of telavancin was demonstrated to be better than vancomycin. However, the results were statistically insignificant.⁷⁹

4. Neutropenia. In a murine animal model of MRSA-associated pneumonia with neutropenia, telavancin was demonstrated to be non-inferior in comparison with vancomycin or linezolid.⁸⁰

Synergy

No antagonism has been reported when telavancin was administered along with piperacillin-tazobactam, cefepime, imipenem, or ciprofloxacin for infections caused by single isolates of MRSA, VISA, VRSA, S. agalactiae, vancomycin-susceptible E. faecalis, vancomycin-resistant E. faecium, and daptomycin-resistant S. aureus. Against isolates of VISA, when telavancin + piperacillin-tazobactam or telavancin + imipenem combinations were employed, synergistic activity was demonstrable. In the instance of a VRSA isolate, synergistic effect was recorded when telavancin was administered along with piperacillin-tazobactam, cefepime, or imipenem.⁸¹

Pharmacokinetics

Lipoglycopeptides being high molecular weight compounds are associated with poor absorption when administered by the oral route. Telavancin is available as a lyophilized powder formulation intended for reconstitution and consequent administration by intravenous (IV) injection. It exhibits linear and predictable PKs over 7.5–15 mg/kg dose range when infused over 30–120 min. For the intervention of systemic infections, slow IV infusion of telavancin is warranted in order to reduce the incidence of potential infusion-associated adverse drug reactions (like pruritus, flushing, and pain).⁸²

It was observed that administration of multiple ascending doses of telavancin in healthy subjects was associated with a linear PK profile from 1 to 12.5 mg/kg, in terms of area under the curve (AUC) and maximum concentration (C_max) values.⁸² When telavancin was infused at a dosage of 10 mg/kg over a period of 2 h in healthy adults, it was found that the mean peak serum concentration was 87.5 µg/ml and the area under the serum concentration time curve (AUC_0–∞) was 858 µg/(h·ml) (Table 2). The plasma clearance and mean half-life (t_1/2) values were 11.8 ml/h/kg and 7.5 h, respectively (Table 2). The fact that PK values do not vary substantially even after administration of several doses of telavancin have been documented in the scientific literature.^82,83 No gender-related differences have been noted in relation to the PK parameters of telavancin.⁸³ Telavancin has been documented to have a longer post-antibiotic effect in comparison to vancomycin in a study on its efficacy assessment which was explored in an immunocompromised murine MRSA bacteremia model.^76,84

Telavancin is extensively bound to plasma proteins, namely, serum albumin (~93%). The volume of distribution of telavancin is relatively small at 115 ml/kg. Upon administration of three doses of telavancin (7.5 mg/kg every 24 h) in eight healthy subjects, the mean AUC and C_max in the plasma and blister fluid (which was chemically induced) was found to be 604 and 241 µg/h·ml and 85 and 16 µg/ml, respectively. In comparison with that in the plasma, the mean AUC ratio reported in the scientific literature for telavancin was 40% in blister fluid.⁸⁵ Decent permeation of telavancin (10 mg/kg) into the epithelial lining fluid (ELF) of the lungs and macrophages of the alveoli have been documented in healthy volunteers during the dosing interval.⁸⁵ Telavancin has superior penetration into lung tissue in comparison to vancomycin. The AUC ratio of the alveolar ELF and the free drug levels in plasma of telavancin is 0.73 while that for vancomycin is 0.39.²¹ Telavancin is beneficial in the management of pneumonia as about three-fourths of the plasma protein–unbound fraction of telavancin is capable of permeating into the alveolar space. In the ELF, mean concentrations of telavancin were found to peak at 8 h (3.7 µg/ml) and thereafter, declined to 0.9 µg/ml at 24 h. The aforementioned concentrations were commensurate with computed free (unbound) plasma levels.^86,87 Telavancin extensively penetrates in the alveolar macrophages; the maximum concentrations being 45 µg/ml and occurring at 12 h after dosing.⁸⁶ In contrast to daptomycin, the effect of pulmonary surfactant on the activity of telavancin in the pulmonary tissues has not been documented so far.⁸⁸

The biotransformation pathway of telavancin has not been unraveled yet. Telavancin is not known to be biotransformed by any cytochrome P₄₅₀ microsomal enzymes.²⁴ A few hydroxylated metabolites of telavancin have been encountered in the urine.⁸⁹ Clearance of telavancin from the body is mainly by the renal route, with 65% (7.5 mg/kg) to 72% (15 mg/kg) excreted as the parent compound following multiple doses.³⁰ Its minor primary (7-hydroxy) metabolite is also present in the urine in a range of 3–6% of the dose. Clearance of telavancin is unaltered in healthy aged subjects but is substantially reduced in adults with compromised renal function (creatinine clearance < 30 ml/min).⁹⁰ Just 6% of telavancin is cleared after a 4-h hemodialysis treatment, though its t_1/2 and AUC_0–∞ are doubled in adults in whom hemodialysis is necessary.⁹¹ Removal of telavancin is mainly effected by continuous venovenous hemofiltration, and increasing the rate of ultrafiltration (UF) considerably accentuates its clearance. Clearance was independent of hemofilter type. At higher UF flow, continuous venovenous hemofiltration clearance surpasses the total clearance documented in patients with no abnormality in their renal function. In patients getting continuous venovenous hemofiltration, it is imperative to adjust the dose of telavancin.⁹² Significant variability in the PK disposition of telavancin has not been found in subjects having Child-Pugh class B (moderate) hepatic impairment.⁹³ The dosage of telavancin is 10 mg/kg every 24 h if the estimated creatinine clearance is >50 ml/min. It is stepped-down to 7.5 mg/kg in case the creatinine clearance is 30–50 ml/min. Furthermore, the dose is lowered to 10 mg/kg every 48 h in case the clearance is <30 ml/min.⁹⁴ Since, telavancin is not a substrate for any cytochrome P₄₅₀ microsomal enzyme, one would not anticipate significant drug interactions with telavancin. However, medical literature does not enlighten us much on this aspect.

Simple diffusion is the mechanism by which most drugs negotiate the placental barrier. Various factors influencing transplacental flux of substances are molecular size, molecular weight, ionic charge, lipid solubility, and circulating concentrations of free (protein-unbound) fraction. In one study, telavancin being more lipophilic and more extensively bound to plasma proteins (93%) compared to vancomycin (50%) was retained by the dually perfused lobule (placenta) and was transferred to the fetal circuit in reduced amounts.⁹⁵ One or more placental efflux transporters are known to be instrumental in effecting placental transfer of telavancin.⁹⁶ One previous report has documented telavancin’s inhibitory action on P-glycoprotein-mediated digoxin flux.⁹⁷

Pharmacodynamics and resistant organisms

Telavancin exerts swift (reduction in bacterial density >3log₁₀ colony forming unit (CFU)/ml at concentrations of ⩾4-fold MIC within a span of 8 h in time-kill studies) and concentration-dependent bacteriocidal activity against both intracellular and extracellular S. aureus in vitro and in vivo, in contrast to linezolid and vancomycin.^30,34,98 Pace et al.³⁴ have reported that the post-antibiotic effect of telavancin against S. aureus was much longer [6 h for MRSA and 4 h for MSSA and glycopeptide-intermediate S. aureus (GISA)] when compared to vancomycin (1 h for MRSA, MSSA and GISA) or nafcillin. Studies in murine neutropenic thigh (immunocompromised by cyclophosphamide pretreatment) models have shown that the PK-PD variable which best represents the antimicrobial outcome (optimal efficacy and therapeutic index) of telavancin is the AUC/MIC ratio.⁹⁹ In this study, telavancin was determined to be effective and potent against all the tested strains, inclusive of nafcillin-resistant (MRSA 33591) and vancomycin-resistant (VREF A256) strains. In the immunocompromised murine neutropenic thigh model, telavancin was determined to be considerably more potent when compared with comparator agents (viz., nafcillin, vancomycin, and linezolid) on an ED₅₀ and ED_stasis basis against MRSA 33591 and/or MSSA. Upon addition of 95% serum or a 40-mg/ml concentration of albumin, the increment in the MIC of telavancin against MRSA 33591 was consistent with the kinetics of extensively protein-bound telavancin. The observed increment in MIC (5- to 10-times) was lesser than the predicted value for an entity which is 95% plasma protein bound. This may be due to the fact that telavancin acts, partly, through a membrane effect unrelated to the extent of protein binding. This study also demonstrated that telavancin’s antibacterial activity is minimally influenced by the variability of an animal’s immune status.⁹⁹ In an in vitro kinetic model of the dynamics of telavancin’s antimicrobial effect on MSSA and MRSA, the minimum AUC/MIC ratio causing >3log₁₀ killing associated with no regrowth was found to be 50 (which corresponded to a dose of 10 mg/kg) and with an AUC/MIC ratio of 404, maximal killing was observed.¹⁰⁰ In this study, the existence of human albumin and serum in the broth did not variably influence the bacteriocidal property of telavancin. Telavancin was also deemed competent in killing both strains of S. aureus (MSSA and MRSA) that were non-growing. Nongrowing bacteria are profoundly tolerant to antibiotics.

Studies in various experimental animal infection models and humans have documented the potential antimicrobial clinical utility of telavancin.

1. Murine Immunocompromised Bacteremia Model. Reyes et al.⁷⁶ reported that in an immunocompromised mice model of robust bacteremia inoculated intraperitoneally with MRSA (ATCC 33591), telavancin significantly improved survival (7% mortality for telavancin versus 100% mortality for vancomycin) and exhibited superior reductions in the bacterial titers of MRSA in blood and spleen, in comparison to vancomycin. Hegde et al. reported that in an immunocompromised mice model of robust bacteremia inoculated intraperitoneally with glycopeptide-intermediate S. aureus (GISA; HIP5836 or Mu50) or heterogeneous vancomycin-intermediate S. aureus (hVISA; Mu3), telavancin administration led to significantly larger reductions in blood and spleen GISA and hVISA bacterial titers, in comparison with vancomycin. This happened despite similar free AUC/MIC ratio for both the drugs.¹⁰¹

2. Murine Pneumonia Model. Telavancin administration in a murine pneumonia model resulted into greater clearance of microorganisms (MRSA; ATCC 33591) from the lungs in contrast to vancomycin and linezolid. In this study, greater survival benefit was also noted in the mice treated with telavancin in comparison with vancomycin and linezolid.⁸⁰ Hegde et al.¹⁰² reported that in a immunocompromised murine model suffering pneumonia due to MSSA (ATCC 29213) telavancin treatment was associated with greater reduction in microbial load in comparison to three other comparator agents (viz., nafcillin, linezolid, and vancomycin). Crandon et al.¹⁰³ analyzed the comparative efficacies of telavancin versus vancomycin against 13 MRSA strains. Out of these, five were hospital-associated MRSA (HA-MRSA), and two were community-associated MRSA (CA-MRSA), two hVISA, and four VISA isolates with vancomycin MIC’s of ⩾1 µg/ml in a model of lung infection in neutropenic mice. Both the agents tested were found to be equiefficacious against the hVISA isolates. Against VISA strains, telavancin treatment resulted in significantly reduced bacterial loads in contrast to vancomycin for one out of four isolates after 24 h and for three out of four isolates after 48 h of exposure. Antimicrobial resistance is increasingly being encountered in pneumococci. In a study on experimental murine pneumococcal pneumonia (induced by intratracheal administration of S. pneumoniae), telavancin was found to be as active as ceftriaxone and vancomycin in reducing the pneumococcal loads in lung tissues.¹⁰⁴

3. Rabbit model of aortic valve endocarditis. Telavancin and vancomycin were compared in a model of aortic valve endocarditis by MRSA (strain COL) or VISA (strain HIP 5836) induced in New Zealand White rabbits. In this study, telavancin was found to be as efficacious as vancomycin for sterilization of the vegetations on the aortic valve against MRSA (MIC of telavancin, 1.0 µg/ml; MIC of vancomycin, 2 µg/ml) and superior than vancomycin against VISA (MIC of telavancin, 4 µg/ml; MIC of vancomycin, 8 µg/ml). Also, telavancin was effective in sterilizing vegetations in 4 out of 6 VISA-infected rabbits.⁷⁷ Miro et al.¹⁰⁵ examined the comparative efficacy of telavancin versus vancomycin in an experimental rabbit endocarditis model due to two GISA strains (ATCC 700788 & HIP 5836). In this study, after a 2-day treatment period, telavancin treatment led to greater vegetation sterilization in comparison with vancomycin. Xiong et al.¹⁰⁶ studied telavancin’s efficacy against MRSA strain resistant to daptomycin (REF2145) in vivo in a well-characterized rabbit model of infective endocarditis induced by catheters. Telavancin administration led to a mean reduction of >4.5log₁₀ CFU/g in vegetations, spleen, and kidneys in comparison to rabbits which were either untreated or treated with daptomycin. Moreover, telavancin treatment resulted in a considerably superior outcome in terms of the percentage of tissue cultures which were sterile (100% in kidney and spleen and 87% in vegetations; p < 0.0001) in comparison with other treatment groups.

4. Rabbit Meningitis Model. Penetration of telavancin into inflamed and noninflamed meninges was found to be 2% and 1%, respectively, in a rabbit model of meningitis following two injections given intravenously (at 30 mg/kg of body weight). It was found that telavancin was more efficacious than vancomycin in combination with ceftriaxone against a penicillin-resistant pneumococcal strain (WB4) in this model, and produced a substantial reduction in the viable cell count (−6.12 log). However, against a MSSA strain (1112), telavancin was slightly more efficacious than vancomycin in the same rabbit meningitis model.⁷⁹ Telavancin effectively sterilized the cerebrospinal fluid in 6 of 10 rabbits by 8 h. However, effective sterilization of the cerebrospinal fluid by vancomycin was seen in only 3 of 10 rabbits by 8 h.

5. Rabbit Osteomyelitis Model. Telavancin (administered 30 mg/kg every 12 h for a period of 4 weeks) ensured effective sterilization in 12 out of 15 (80%) tibial MRSA infections (due to strain 168-1) in a localized S. aureus osteomyelitis induced by the percutaneous route in rabbit left lateral tibial metaphysis. Telavancin was equally efficacious in comparison to linezolid and vancomycin in this study.¹⁰⁷

6. Elimination of Staphylococci from Peritoneal Dialysis Fluid. Clouse et al.¹⁰⁸ evaluated the comparative efficacies of telavancin, vancomycin, and cefazolin in eliminating MSSA isolates (ATCC 29213) and MRSA isolates (ATCC 33592) from simulated peritoneal dialysis fluid in vitro. Statistically significant superior bacterial kill for both MSSA and MRSA was obtained with telavancin treatment compared to the comparator agents in this study.

7. Staphylococcal Biofilm Model. In a Sorbarod biofilm model of staphylococcus, telavancin was substantially effective in bringing down the number of bacteria eluted from the biofilms against isolates of S. aureus (MSSA (ATCC 29213), MRSA (ATCC 33591), coagulase-negative staphylococci, and GISA) and compares favorably with the other agents tested (viz., vancomycin, teicoplanin, linezolid, and moxifloxacin).⁷⁵

8. Anaerobic Infections. Goldstein et al.³⁷ reported that telavancin exhibited good activity in vitro (<1 µg/ml) for a wide range of Gram-positive anaerobic bacteria and unusual anaerobes, namely, Actinomyces species, the Peptostreptococcus group, Propionibacterium species, and Clostridium species (C. perfringens and C. difficile). There was a 2- to 4-fold greater activity against most anaerobe strains over vancomycin. Against C. clostridioforme, telavancin was less active compared to vancomycin and had comparable activity to daptomycin and linezolid. Vancomycin, linezolid, and daptomycin-resistant Lactobacillus species were found to be telavancin-susceptible (⩽0.25 µg/ml). Isolates of Lactobacillus casei were found non-susceptible to vancomycin and telavancin. In another in vitro study on 460 anaerobic bacterial isolates, telavancin produced exceptional activity against Gram-positive anaerobes (MIC₉₀, 2 µg/ml). In this study, telavancin was found to be the most potent agent against C. difficile (MIC₉₀, 0.25 µg/ml).¹⁰⁹ Telavancin displays greater antimicrobial activity against Clostridium spp. in comparison to vancomycin, dalbavancin, and oritavancin.¹¹⁰ The relative lack of efficacy against Gram-negative anaerobes, which make up the major chunk of the native bowel flora, makes telavancin an excellent choice for therapy of C. difficile intestinal infections and also for the treatment of other pathologies, namely, autism, wherein the role of certain intestinal clostridia is evident.¹⁰⁹ Telavancin administration is not associated with any major impact on the microflora of the human intestines ecologically.¹¹¹

Clinical trials and human studies

Complicated skin and skin structure infections

Skin and skin structure infections (SSSIs) lead to frequent hospitalization and antibiotic administration.^112–114 Uncomplicated cSSSIs involving the epidermis and dermis comprise folliculitis, superficial cellulitis, simple abscesses, furunculosis, and minor wound infections. Complicated cSSSIs involving deeper structures, namely, fascia, muscle, and/or subcutaneous tissues comprise infected burn wounds and ulcers, deep space wound infections, and skin abscesses (complicated).

Some phase II (like FAST 1 and FAST 2) and some phase III [like Assessment of Telavancin in Complicated Skin and Skin Structure Infections 1 and 2 (ATLAS 1 and ATLAS 2)] clinical trials have been conducted for evaluating telavancin’s efficacy and safety in complicated skin and skin structure infections (cSSSIs).

FAST 1 trial

This was a phase II randomized trial.¹¹⁵ It was double-blind, multicentric, controlled trial evaluating telavancin versus standard antibacterial therapy for cSSSIs. Patients having a creatinine clearance <50 ml/min and a corrected QT (QTc) interval >470 ms were excluded from this study. Oral antimicrobial formulations were not allowed during the trial. However, in case enrolled patients were in need of Gram-negative or anaerobic coverage during the trial, aztreonam use with or without metronidazole was allowed. Success rates of telavancin were same as that of standard therapy, not only in the evaluation at the end-of-therapy but also at the test-of-cure (TOC) visit. In the clinically evaluable population (n = 141) and the all-treated population (n = 167), both therapeutic arms resulted in cures in 66 patients at the evaluations for TOC (79% for telavancin versus 80% for standard therapy; p = 0.53).

At the baseline evaluation, S. aureus was isolated in the telavancin arm (n = 50) and in the standard therapy (n = 52). At the TOC visit, cure was attained in 40 patients (80%) who were treated with telavancin and in 40 patients (77%) who were administered standard therapy.

At the baseline evaluation, cultured MRSA was detectable in 48 patients. In all, 82% of these patients in the telavancin arm achieved cure while cure was achieved in 69% in the standard therapy arm were cured. Of all the patients who were evaluable by microbiological means in both the telavancin therapy and standard therapy arms (n = 112), 75% patients (n = 42) were cured from the baseline pathogen at end-of-therapy (p = 0.83).

Eradication of pathogens was achieved in 44 (80%) patients receiving telavancin therapy versus 46 (82%) patients receiving standard therapy during the TOC assessments (p = 0.83). Eradication of MRSA was achieved in 16 (84%) patients receiving telavancin therapy versus 14 (74%) patients receiving standard therapy during the TOC assessments.

FAST 2 trial

This was a phase II randomized trial.¹¹⁶ It was a multicentric, double-blinded, controlled trial evaluating telavancin versus standard antibacterial therapy for cSSSIs. In FAST 2 Trial, dosage adjustments to telavancin were resorted to in the recruited patients based on their renal function. Patients having a corrected QT (QTc) interval more than 500 ms were omitted from this study. Like in FAST 1 Trial, oral antimicrobial formulations were not allowed during the trial. However, in case enrolled patients were in need of Gram-negative or anaerobic coverage during the trial, aztreonam use with or without metronidazole was permitted.

Similar success rates were reported in FAST 2, which like FAST 1 compared telavancin versus standard therapy. In all, 82 (82%) patients in the telavancin arm and 81 (85%) patients in the standard therapy arm of the all-treated population (n = 196) achieved cures (p = 0.37).

A total of 74 (96%) patients in the telavancin arm and 72 (94%) patients receiving standard therapy of the clinically evaluable population (n = 154) achieved cures (p = 0.53) at the TOC visit. Also, 62 (97%) patients receiving telavancin and 53 (93%) patients in the standard therapy arm achieved cures (p = 0.37) in the microbiologically evaluable population during the same visit.

At the baseline evaluation, in the all-treated group, cultured MRSA was detectable in 53 patients. In all, 86% of these patients in the telavancin arm achieved cure, while 75% in the standard therapy arm were cured of MRSA. In the all-treated group, 121 patients were found to be microbiologically evaluable. A total of 57 (89%) patients in the telavancin arm and 44 (77%) patients in the standard therapy arm were adjudicated to be cured of the infecting pathogen at the completion of treatment (p = 0.09). In all, 94% of patients allocated to telavancin and 83% patients in the standard treatment arm were judged to be cured of the infection at the end-of-treatment as well as at follow-up visits.

At the baseline evaluation, cultured MRSA was detectable in 91 patients who were microbiologically evaluable. In all, 96% of the patients in the telavancin arm achieved cure, while 90% in the standard therapy arm were cured. A total of 92% patients allocated to telavancin therapy and 78% patients allocated to standard therapy were cured of the infection (p = 0.07).

The rate of MRSA eradication was significantly higher in the telavancin arm (96%) compared with the standard therapy one (68%) (p = 0.04).

ATLAS trials (ATLAS 1 and 2)

ATLAS 1 and 2 were two similar randomized, double-blinded, multicentric, controlled (active control), non-inferiority phase III clinical trials.¹¹⁷ They were conducted for the assessment of the efficacy and safety of telavancin (at a dose of 10 mg/kg every 24 h) in treating cSSSI when compared with vancomycin (at a dose of 1 g given every 12 h). The number of patients who enrolled in both these trials was 1867. When necessary, adjustment of vancomycin doses was based on individual patients’ creatinine clearance and standard operating procedures at each participating institution. Oral antimicrobial formulations were not allowed during the trial. However, in case enrolled patients were in need of Gram-negative or anaerobic coverage during the trial, aztreonam use with or without metronidazole was permitted.

After data pooling was done from ATLAS 1 and 2 clinical trials, 745 patients received telavancin treatment and 744 patients were treated with vancomycin. Cure was attained in 88.3% of the patients in the telavancin arm and 87.1% of the patients in the vancomycin arm out of the population which could be evaluated clinically.

At the baseline evaluation, 579 clinically evaluable patients were having MRSA infection, and the cure rates achieved in them were 86.4% and 90.6% with vancomycin and telavancin treatments, respectively. Eradication rates for patients with MRSA isolates were 89.9% and 85.4% with telavancin and vancomycin, respectively. Eradication of the baseline pathogen was achieved for all patients at the TOC visit. The therapeutic response achieved with telavancin treatment (90%) was higher than that achieved with vancomycin treatment (85%).

Discontinuation of the therapy by patients on account of the adverse effects was somewhat more in the telavancin arm than in the vancomycin arm. In all, 8% of the patients on telavancin discontinued the therapy on account of adverse effects, while 6% of those on vancomycin discontinued the therapy on account of adverse effects. The differences between these two treatment arms were not statistically significant. Patients suffering from diabetic foot ulcers, osteomyelitis, gangrene, necrotizing fasciitis, and burns involving more than 20% of the body surface were omitted from this study. The external validity of these studies would have been raised if such patients were included since such infections are deemed to be therapeutically challenging.

Wilson et al. retrospectively subanalyzed the ATLAS trials for telavancin’s effectiveness in surgical site infections.¹¹⁸ This subanalysis evaluated a total of 194 patients (in whom a Gram-positive organism was identified) of which 101 and 93 subjects received telavancin and vancomycin, respectively. From 95 patients S. aureus could be isolated and in 42 patients MRSA was identified. In all, 10 days was the median treatment duration in both treatment arms. The cure rates were 77.2% and 69.9% in the telavancin and the vancomycin groups, respectively. The cure rates in patients with MRSA infections were 85.7% and 71.4% in the telavancin and vancomycin groups, respectively. In all, 12% of patients on telavancin therapy and 10% of patients on vancomycin therapy did not continue treatment on account of adverse effects.

Two phase III ATLAS trials demonstrated non-inferiority of telavancin compared with vancomycin for cSSSIs. Data from these trials were retrospectively evaluated according to 2013 USFDA guidance on acute bacterial skin and skin structure infections (ABSSSI). This post hoc analysis included patients with lesion sizes of ⩾75 cm² and excluded patients with ulcers or burns (updated all-treated population; n = 1127). Updated day 3 (early) clinical response was defined as a ⩾20% reduction in lesion size from baseline and no rescue antibiotic. Updated TOC clinical response was defined as a ⩾90% reduction in lesion size, no increase in lesion size since day 3, and no requirement for additional antibiotics or significant surgical procedures. Day 3 (early) clinical responses were achieved in 62.6% and 61.0% of patients receiving telavancin and vancomycin, respectively [difference, 1.7%, with a 95% confidence interval (CI) of −4.0–7.4%]. Updated TOC visit cure rates were similar for telavancin (68.0%) and vancomycin (63.3%), with a difference of 4.8% (95% CI, −0.7–10.3%). Adopting current FDA guidance, this analysis corroborates previous non-inferiority findings of the ATLAS trials of telavancin compared with vancomycin.¹¹⁹

Nosocomial pneumonia (hospital-acquired pneumonia, ventilator-associated pneumonia, and healthcare-associated pneumonia)

Phase III clinical trials have been carried out for evaluating telavancin’s safety and efficacy in nosocomial pneumonia [Assessment of Telavancin for Treatment of Hospital acquired Pneumonia 1 and 2 (ATTAIN 1 and ATTAIN 2)].

ATTAIN trials (ATTAIN 1 and 2)

ATTAIN 1 and 2 were two similar, phase III clinical trials which were randomized, double-blinded, multicentric, controlled (comparator drug), and non-inferiority trials designed for evaluating telavancin’s safety and efficacy (at a dose of 10 mg/kg every 24 h for upto 21 days) and vancomycin (at a dose of 1 g every 12 h for upto 21 days) in treating patients having clinical signs and symptoms of hospital-acquired pneumonia (HAP), ventilator-associated pneumonia, and healthcare-associated pneumonia.^120–123 Here, 1503 patients (⩾18 years of age, recruited from 38 countries and 274 centers) were randomized to the two treatment arms. When necessary, adjustment of telavancin and/or vancomycin doses was based on individual patients’ creatinine clearance. Antimicrobial formulations were not allowed during the trial. However, in case enrolled patients were in need of polymicrobial coverage during the trial, aztreonam or piperacillin/tazobactam use was permitted.

After data pooling was done from ATTAIN 1 and 2 clinical trials, cure rates achieved with telavancin treatment was 82% compared to 81% with vancomycin among the clinically evaluable patients. In patients having ventilator-associated pneumonia, administration of telavancin resulted in a better cure rate, but which was not significant statistically, when compared to vancomycin (80.3% versus 67.6%).¹²² The differences noted between the therapy groups for all the parameters were statistically significant.

It was first approved by the USFDA in 2009 for the treatment of complicated skin and skin structure infections, and in 2013, it was approved for the treatment of hospital-acquired and ventilator-associated bacterial pneumonia (HABP/VABP) caused by susceptible isolates of S. aureus when alternative treatments are not suitable. This most recent approval was based on two phase III studies, the ATTAIN trials. These identically designed trials assessed the clinical efficacy and safety of telavancin with that of vancomycin in the treatment of HABP/VABP due to Gram-positive organisms, with a focus on infections caused by MRSA.

When HABP/VABP is caused by Gram-positive and Gram-negative pathogens or both (mixed infections), the adequacy of Gram-negative coverage (GNC) can confound the assessment of a Gram-positive agent under study. This analysis examines the influence of Gram-negative infections and the adequacy of GNC on clinical efficacy and all-cause mortality in the telavancin HABP/VABP phase III ATTAIN trials. This post hoc analysis evaluated 3 patient groups from ATTAIN: (1) Gram-positive–only infections, (2) Gram-positive–only and mixed infections-adequate GNC, and (3) Gram-negative–only infections and mixed infections with inadequate GNC. For each, clinical efficacy at test of cure and all-cause mortality at day 28 was compared for telavancin and vancomycin. In the ATTAIN safety population, there were 16 more deaths in the telavancin arms than in the vancomycin arms. Of these, 13 were in patients with Gram negative–only infections (n = 9) or with mixed infections and inadequate GNC (n = 4), and all had estimated baseline creatinine clearances of <30 ml/min. Based on this analysis, clinical response and all-cause mortality could be confounded because there were more patients with Gram-negative pathogens at baseline and more patients received inadequate treatment of these Gram-negative infections in the telavancin groups.¹²⁴

Uncomplicated S. aureus bacteremia

ASSURE trial

A phase II randomized, double-blind, clinical trial has been carried out for evaluating telavancin’s safety and efficacy in uncomplicated S. aureus bacteremia [Telavancin for Treatment of Uncomplicated S. aureus Bacteremia (ASSURE)].¹²⁵ Recruited patients received either telavancin or the standard therapy [which could be vancomycin or an antistaphylococcal penicillin (viz., cloxacillin, nafcillin, or oxacillin)] and clinical cure was assessed at 84 days. All subjects with MRSA bacteremia were cured in both treatment arms. In each treatment group, one patient each (suffering from MSSA bacteremia) were non-responders to the respective treatment interventions. Adverse events were encountered more with telavancin (90%) in comparison to the standard treatment (72%). Discontinuation of therapy due to adverse events was 7% in both intervention groups.

Pacemaker lead related VISA infective endocarditis

Marcos and Camins reported a case of pacemaker lead–related infective endocarditis due to a VISA strain (non-daptomycin susceptible) successfully treated with parenteral telavancin for 8 weeks in terms of microbiological and clinical cure.¹²⁶

MRSA osteomyelitis

MRSA has emerged as an important etiologic agent of osteomyelitis.¹²⁷ Twilla et al. reported four cases of successfully treated MRSA osteomyelitis with prolonged parenteral telavancin administration and surgical intervention. One subject had renal function impairment, while in the other three patients, there was no impairment of renal function.¹²⁸

Adverse effects

The most frequent adverse effects observed with telavancin administration were dysgeusia (including metallic taste), nausea, vomiting, headache, foamy urine, renal impairment, and QTc prolongation (Tables 3 and 4). Rapid infusion of telavancin has the potential to induce ‘red-man syndrome’ like reaction, and hence, it is advised that it be infused slowly preferably over 1 h.¹²⁹

Table 3.

Summary of Adverse Events (AE’s) reported in patients administered Telavancin in Clinical Trials.

	Frequency (%)
	FAST I		FAST 2		ATLAS 1 & 2		ASSURE
	Telavancin	Standard therapy	Telavancin	Standard therapy	Telavancin	Standard therapy	Telavancin	Standard therapy
Nausea	15	13	16	6	27	15	3	10
Vomiting	10	4	8	6	14	7	3	10
Headache	11	10	8	4	14	13	10	10
Foamy urine	NR	NR	NR	NR	13	3	NR	NR
Insomnia	NR	NR	13	3	10	9	7	3
Constipation	4	6	5	7	10	7	NR	NR
Diarrhea	NR	NR	6	5	7	8	0	7
Pruritus	NR	NR	6	8	3	6	3	7
Dizziness	NR	NR	NR	NR	6	6	NR	NR
Psychiatric disorders	12	10	NR	NR	NR	NR	NR	NR
Dyspnea	8	1	NR	NR	NR	NR	3	7
Paresthesia	5	0	NR	NR	NR	NR	NR	NR
Taste disturbance	NR	NR	14	0	33	7	10	0
Chills	NR	NR	6	2	4	2	NR	NR
Rash	NR	NR	NR	NR	4	5	7	10
Infusion site pain	NR	NR	NR	NR	4	4	NR	NR
Fatigue	NR	NR	NR	NR	4	3	NR	NR
Infusion site erythema	NR	NR	NR	NR	3	3	7	3
Decreased appetite	NR	NR	NR	NR	3	2	NR	NR
Anxiety	NR	NR	NR	NR	3	2	NR	NR
Renal dysfunction	NR	NR	NR	NR	3	1	NR	NR
Acute renal failure	NR	NR	NR	NR	NR	NR	7	0
Urinary tract infection	NR	NR	NR	NR	NR	NR	14	0
Abdominal pain	NR	NR	NR	NR	2	3	NR	NR
Pyrexia	NR	NR	NR	NR	NR	NR	14	7
Anemia	NR	NR	NR	NR	NR	NR	10	7
Deep vein thrombosis	NR	NR	NR	NR	NR	NR	10	3
Hypokalemia	NR	NR	NR	NR	NR	NR	10	3
Agitation	NR	NR	NR	NR	NR	NR	7	3
Hematuria	NR	NR	NR	NR	NR	NR	3	7
Atelectasis	NR	NR	NR	NR	NR	NR	7	3
Phlebitis	NR	NR	NR	NR	NR	NR	3	7
Blood urea increased	NR	NR	NR	NR	NR	NR	7	0
Eosinophilia	NR	NR	NR	NR	NR	NR	0	14
Catheter site infection	NR	NR	NR	NR	NR	NR	0	7

ATLAS, Assessment of Telavancin in Complicated Skin and Skin Structure Infections; ASSURE, Telavancin for Treatment of Uncomplicated S. aureus Bacteremia; NR, not reported.

Table 4.

Laboratory abnormalities in the all-treated population in ATLAS 1 and 2 and ASSURE clinical studies.

Parameters	Variables
	Frequency (%)
	ATLAS 1 and 2		ASSURE
	Telavancin	Standard	Telavancin	Standard
Hematocrit
<30% in male patients	1	1	25	0
⩽28% in female patients	4	2	0	0
Eosinophilia (eosinophil count >500 cells/ml)	2	2	NR	NR
Leukopenia (leukocyte count ⩽2000 cells/ml)	1	2	0	0
Platelet count ⩽75 × 109 platelets/l	<1	0	0	0
AST level ⩾3 × ULN	2	3	17	0
ALT level ⩾3 × ULN	2	4	5	6
Alkaline phosphatase ⩾1.5 × ULN	NR	NR	12	5
Potassium concentration
<3 mEq/l	2	<1	8	0
>5.5 mEq/l	2	2	4	16
Serum creatinine concentration
Baseline creatinine
<1.5 mg/dl	NR	NR	22	0
⩾1.5 mg/dl and at least 50% greater than baseline	6	2	14	25
1.5–1.9 mg/dl	3	2	NR	NR
2.0–2.9 mg/dl	2	<1	NR	NR
⩾3.0 mg/dl	<1	<1	NR	NR
Increase in QTc
Interval >60 ms	1	<1	NR	NR
QTc Interval >500 ms	<1	<1	NR	NR

ALT, alanine aminotransferase; AST, aspartate aminotransferase; ATLAS, Assessment of Telavancin in Complicated Skin and Skin Structure Infections; ASSURE, Telavancin for Treatment of Uncomplicated S. aureus Bacteremia; NR, not reported; ULN, upper limit of normal.

Creatinine ⩾1.5 mg/dl was seen in 5% of 103 patients in the FAST 2 clinical trial at the cessation of treatment with telavancin. However, drug discontinuation resolved all reported renal dysfunction issue.¹¹⁶ A phase III trial comparing telavancin and vancomycin for complicated skin and soft tissue infections showed that the rate of nephrotoxicity or acute renal insufficiency was 6% (n = 822) for telavancin versus 2% (n = 856) for vancomycin at the end of therapy.¹¹⁷ Stryjewski et al.¹¹⁷ documented that the serum creatinine levels rose by ⩾1.5 mg/dl and were ⩾50% above the baseline in 6% of participants in the phase III ATLAS clinical trials. This increase in serum creatinine values was reversible; they came back to baseline levels. The increment in the telavancin-treated patients was greater than that in the 2% of patients who experienced a rise in their serum creatinine levels with vancomycin. Dosage adjustments are required in renal failure cases. In some of the patients, acute renal insufficiency was attributed not to telavancin exposure but rather to underlying disease (systemic lupus erythematosus), simultaneous administration of IV contrast dye or gentamicin, and other nephrotoxic agents [diuretics and nonsteroidal anti-inflammatory drugs (NSAIDs)]. The etiology of the foamy urine (occurring in 13% of ATLAS Trial patients) was attributed to the excretion of cyclodextrin, a solubilizing agent, present in the IV formulation of telavancin. It was observed to be of mild intensity, and the nature of the urine reverted to normal following cessation of telavancin administration. No interventions or discontinuations from the trials were necessitated as a result of these adverse events.^26,85,130 In another retrospective cohort study, 7 out of 21 (33.3%) patients receiving telavancin developed acute renal insufficiency associated with a median treatment duration of 9 days for its development. Many of the patients in this study were suffering from comorbidities and were administered telavancin for non-approved indications.¹³¹

Telavancin has a tendency to induce slight QTc prolongation similar to that observed for vancomycin.¹³² It occurs in <1% of the patients. Corrected QT interval (QTc) prolongation was 4.6 ms in patients treated with telavancin versus 9.5 ms in those patients treated with moxifloxacin. In the cSSSI trials, QTc outliers (QTc interval prolongation >60 ms) were similar in the vancomycin and telavancin arms, with two patients in the vancomycin arm and one in the telavancin arm exceeding a QTc of 500 ms (Table 4). No adverse cardiac events accruing out of QTc interval prolongation were noted. Cardiac mortality between the two treatment arms was not at variance.^{116,117,132,133}

Telavancin can interfere with coagulation assays leading to an increase in International Normalized Ratio (INR), prothrombin time (PT), and activated partial thromboplastin time (aPTT) values.^21,134,135

Telavancin is classified as a class C teratogenic drug. Animal experiments have documented decreased fetal weights and increased incidence of digit and limb malformations.²¹ There is a paucity of human data in this context. So pregnancy tests are imperative in women of reproductive age before initiating telavancin. In pregnant woman, potential benefits and risks should be weighed before use.^21,134 Like many other antibiotics, C. difficile–associated diarrhea can be caused by this agent.¹³⁴

Pediatric safety has not yet been established for telavancin, and USFDA has not yet granted approval of its use in children and nursing mothers.²⁴

Drug interactions

CYP3A4/5 isozymes are inhibited by telavancin. However, midazolam (which is a CYP3A4/5 substrate) metabolism is not known to be affected by telavancin.¹³⁶ Safe co-administration of telavancin with aztreonam and piperacillin/tazobactam may be possible as no clinically relevant drug interactions have been documented as yet in this context.¹³⁷ Telavancin is extensively bound to plasma proteins (~90%), and hence, it is possible that drug interactions may occur due to displacement of other highly plasma protein–bound drugs and vice versa. The metabolism of telavancin is not affected by enzyme inducers/inhibitors as it is minimally biotransformed inside the human body. One or more placental efflux transporters are known to be instrumental in effecting placental transfer of telavancin.⁹⁶ Telavancin’s inhibitory action on P-glycoprotein-mediated digoxin flux has been documented in one report.⁹⁷

Current status

Telavancin is available as a lyophilized powder in single use vials containing 250 or 750 mg of the drug. An application had been filed with the FDA in January 2009 for use in nosocomial pneumonia.¹³⁸ In October 2008, an application for marketing authorization of telavancin for treatment of cSSSI was withdrawn by Astellas Pharma in Europe as the Committee for Medicinal Products for Human Use (CHMP) of European Medicines Agency (EMA) expressed reservations over its adverse effects and invited more data.¹³⁹ In October 2009, another application for use of telavancin in cSSSIs and nosocomial pneumonia was filed with the EMA.¹³⁹ In September 2009, telavancin was approved by the USFDA for treatment of cSSSIs and by EMA for treatment of adult patients with HAP due to MRSA.^140,141 In Europe, telavancin has made a comeback on 18 March 2014 for the indication of diagnosed or likely MRSA nosocomial pneumonia (including ventilator-associated pneumonia), where use of existing alternative agents are not deemed suitable.¹⁴²

Conclusion

Telavancin, a semisynthetic lipoglycopeptide derivative of vancomycin, is a rapidly bacteriocidal antibiotic approved for use in cSSSIs and HAP caused by susceptible Gram-positive microorganisms. Telavancin has demonstrable in vitro activity against aerobic and anaerobic Gram-positive bacteria. Its spectrum of coverage includes MSSA, MRSA, VISA, and hVISA strains of S. aureus. Some VRE are also susceptible to the antimicrobial actions of telavancin. Many species of streptococci (including multidrug-resistant and penicillin-resistant strains) are susceptible to telavancin. Telavancin is more active against VISA and hVISA compared to vancomycin. Telavancin has an interesting dual mechanism of action – namely, inhibition of bacterial cell wall peptidoglycan chain synthesis (due to inhibition of transpeptidation and transglycosylation mechanisms) and perturbation of cell membrane barrier function due to membrane potential dissipation.¹⁴³ It has a more specific action at the division septum, the site of active cell wall synthesis, because of its avid binding to lipid II. In relation to its bacteriostatic comparators (linezolid and tigecycline) for use in Gram-positive infections, telavancin is bacteriocidal. Very little is known about biotransformation of telavancin in vivo. The primary route of unmetabolised telavancin clearance is through the kidneys (66–77% of total plasma clearance).

In murine models of bacteremia and in in vitro and rabbit models of infective endocarditis, telavancin demonstrated greater efficacy than vancomycin and similar or greater efficacy than daptomycin. The in vitro as well as in vivo efficacy of telavancin has been reflected positively in clinical cure rates obtained in phase III clinical trials for cSSSI and HABP/VABP.^123,144 Clinical experience includes bacteremic patients with catheter-associated infections, HAP, osteomyelitis, and endovascular infections, which showed comparable clinical cure rates between telavancin and vancomycin, although the findings were based on very small sample sizes. ATTAIN Trial data have documented the significantly improved cure rates obtained with telavancin over vancomycin in patients with monomicrobial S. aureus pneumonia and a vancomycin MIC value ⩾1 µg/ml. There is thus a potential empiric therapeutic utility of telavancin in clinical scenarios due to MRSA isolates with MIC values ⩾1 µg/ml. The European approval for telavancin for MRSA-induced nosocomial pneumonia is a shot in the arm for determining its specific therapeutic utility.¹⁴² Another promising definitive therapeutic utility of telavancin over vancomycin along with a beta-lactam agent could be in clinical scenarios of S. aureus bacteremia.

Although telavancin is generally well-tolerated, some worrisome adverse effects, including nephrotoxicity and worsening renal impairment have been encountered with its use and QTc prolongation is of potential concern. Renal adverse events have been more frequently reported in patients with baseline comorbid conditions and/or in patients taking concomitant medications known to predispose them to renal dysfunction. Renal function should be monitored in all patients receiving telavancin, and dosage adjustments are required in patients whose CrCl is ⩽50 ml/min. Warnings and precautions have been advised for patients with moderate to severe renal impairment (CrCl ⩽ 50 ml/min) because of the observed increased mortality rates in HABP/VABP and decreased clinical response in cSSSI with telavancin compared with vancomycin.¹³¹ The use of telavancin in patients with preexisting moderate-to-severe renal function should be considered only if the benefits of treatment outweigh the risks or in the absence of other suitable alternatives.¹⁴⁵ Lipoglycopeptides as a class, representing three agents (dalbavancin, oritavancin, and telavancin), all show in vitro potency greater than vancomycin. However, their long half-lives and complex PKs may preclude these agents being used in critically ill patients. In addition, the black box warning associated with telavancin would further reduce its current role. Nevertheless, these agents provide some alternatives in difficult-to-treat infections when no other options are available.^146,147

Given its extensive binding to plasma proteins, its long half-life, and its long post-antibiotic effect, it represents a promising addition to the therapeutic armamentarium against infections produced by resistant Gram-positive pathogens, namely, MRSA. Given the relentless pace of development of Gram-positive bacterial resistance to antibiotics, further evaluation of telavancin in clinical trials with a range of intended indications against standard comparator agents will probably determine its ultimate therapeutic niche in the future.