Telavancin for the treatment of gram-positive infections

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Liapikou Adamantia MD
1st Respiratory Department of Sotiria Hospital, Athens, Greece

Laia Fernández-Barat MSc
Antoni Torres Martí MD, PhD
IDIBAPS (Institut d’Investigacions Biomèdiques August Pi i Sunyer), Barcelona, Spain
CIBERES (CIBER de Enfermedades
Respiratorias, 06/06/0028),
Barcelona, Spain
Department of Pneumology,
Institut Clínic del Tórax, Hospital Clínic, University of Barcelona, Spain

The development of drug resistance in gram-positive pathogens has become an increasing concern for the healthcare community. Pathogens identified as Staphylococcus species (spp.) and Enterococci spp. have become extremely challenging to eradicate. The emergence and spread of hospital and community-acquired methicillin-resistant Staphylococcus aureus (MRSA) has been documented worldwide, with its percentage exceeding 60% in some intensive care units.(1) The mainstay of treatment for MRSA infections remains vancomycin. Unfortunately, treatment failure and poor outcomes have been described with MRSA infections caused by isolates with high-vancomycin minimum inhibitory concentration (minimum inhibitory conentration (MIC≥)2mg/ml) so-called vancomycin-intermediate S. aureus (VISA) or glycopeptide-intermediate S. aureus (GISA) and heteroresistant isolates (heteroresistant vancomycin-intermediate S. aureus (hVISA)).(2) The S. aureus isolates with overt vancomycin resistance (VRSA) remain rare, with fewer than 20 cases observed.
As resistance continues to develop among the newer agents, an innovative class of antimicrobials known as lipoglycopeptides has emerged. One of them, telavancin (TLV), is the subject of this review, which covers its pharmacological properties, antibacterial activity, clinical efficacy and safety.

Chemistry
Telavancin (Vibativ; Theravance Inc) is a semisynthetic vancomycin derivative bearing both lipophilic and hydrophilic groups (Fig. 1).(3)
The hydrophilic (phosphomethyl) aminomethyl moiety is present at the 40 position of ring 7. The hydrophobic decylaminoethyl moiety is attached to the vancosamine sugar and it is the reason for the classification of TLV as a lipoglycopeptide. The decylaminoethyl lipophilic chain imparts to TLV the ability to bind to cell membranes, a feature which improves the antibacterial’s binding affinity for the D-Ala-D-Ala target site. The lipophilic side chain is also responsible for the activity of TLV against both MRSA phenotypes and non-VanA enterococci.(3,4)

Mechanism of action
The mechanism of action of TLV on susceptible bacteria exerts dual effects in eradicating pathogens.(4) Initially, TLV causes inhibition of bacterial cell wall synthesis by directly interfering with polymerisation and cross-linkage of the peptidoglycan layer, followed by disruption of bacterial cell membranes via depolarisation, leading to impaired barrier function5 and increasing permeability with leakage of cytoplasmic adenosine triphosphate and potassium ions.

Pharmacokinetics and pharmakodynamics
The activity of the drug in vitro is rapidly bactericidal and concentration-dependent, with the ratio of area under the time concentration curve to MIC (AUC/MIC) as the best predictor of activity in animal models to date.6 Preliminary results from an in vitro MRSA model suggest that free drug AUC/MIC ratios of 50–100 are associated with a 1- to 2-log decrease in bacterial counts and minimal resistance.(1)

TLV is extensively protein-bound (> 90%) and its elimination half-life ranges from 6.1 to 9.1 hours at doses above 5mg/kg, supporting once-daily dosing.

The concentration of TLV in skin blister fluid has been determined using a dose of 7.5mg/kg.(7) This study showed adequate TLV concentrations in blister fluid – 40% of plasma levels – with a high AUC/MIC ratio of the total and estimated free drug against gram-positive organisms,1 supporting the use of TLV in most soft tissue infections. In uninfected lung tissue, the estimated median AUC in epithelial lining fluid resulted in 75% of the free AUC in plasma.8 Unlike daptomycin, the in vitro activity of TLV was found to be unaffected by pulmonary surfactant.

It is noteworthy that TLV has the potential to kill non-growing bacteria. The post-antibiotic effect (PAE) of TLV against most gram-positive organisms ranges from four to six hours.(1,3,5) The primary mode of elimination of TLV is via the renal route, with up to 70% of the dose excreted in the urine as unchanged drug. TLV clearance was affected mainly by renal function, with 50% reduced clearance in patients with CrCl <30ml/min. Hepatic impairment does not appear to influence TLV clearance. The pharmacokinetic properties of TLV in paediatrics (<18 years of age) and pregnant females have not been studied.

Antimicrobial activity
TLV is a lipoglycopeptide antibiotic has been found to have bactericidal activity against clinically important gram-positive bacteria, such as Staphylococci (including MRSA, hVISA and VISA strains) and Streptococci (including penicillin-resistant Streptococcus pneumoniae (PRSP)) as well as gram-positive anaerobic and fastidious aerobic bacteria.

Several studies have shown that TLV had good activity against all isolates with MICs generally <1μg/ml. For both MSSA and MRSA, MIC90 breakpoints were in the range 0.25–1mg/l. However, the TLV MIC90 was slightly elevated in GISA species. At 1mg/l, TLV also possesses excellent Streptococci coverage, including multidrug-resistant strains.(1–3,5)

A surveillance report by Mendes and colleagues(9) provided an update on the activity of TLV and selected comparators tested against a contemporary (2009–2010) collection of European Staphylococcal isolates, TLV (MIC90, 0.25–0.5μg/ml) showed potent activity against Staphylococci, including against those exhibiting higher teicoplanin and/or vancomycin MIC values. When tested against MRSA, TLV was twofold more potent than daptomycin and four-to-eight-fold more active than vancomycin and linezolid.

TLV also has activity against Panton-Valentine leukocidin (PVL)-producing and non-producing community-acquired MRSA strains with a MIC90 of 0.5μg/ml, which is the same for vancomycin.(1)

TLV has potent in vitro activity against vancomycin susceptible enterococci; for susceptible E. faecalis, the MIC90 is 0.5–1μg/ml (compared with 2μg/ml for vancomycin). However, it was much less active against vanA-positive VRE (MIC90, 8–16μg/ml) and had modest activity against vanB-positive VRE (MIC90, 2μg/ml).
A variety of gram-positive anaerobes are inhibited by ≤ 2μg/ml TLV, including Actinomyces spp., Clostridium difficile, Clostridium clostridiforme, Clostridium innocuum, Clostridium ramosum, Eubacterium group, Lactobacillus spp., Propionebacterium spp., Peptostreptococcus spp., and Corynebacterium spp.(10) Vancomycin-susceptible E. faecalis and E. faecium are also susceptible to TLV, with MIC90 breakpoints of <1mg/l.

Clinical efficacy
Skin infections
The most common pathogen, S. aureus, is recognised in 44% of complicated skin and skin structure infections (SSSIs) in North America. Two randomised, double-blind, controlled trials, FAST and FAST 2, evaluated TLV against standard antimicrobial therapy for use in cSSSIs.(1,5)

The majority of the 195 patients were Caucasian males with soft tissue abscesses. S. aureus was isolated in around 50% of patients and half of these isolates were MRSA (FAST II). MRSA was eradicated in 92% of patients receiving TLV compared with 68% of patients receiving standard therapy (p = 0.04).

ATLAS 1 and 2 were two randomised, double-blind, phase III trials in which patients received either TLV 10mg/kg every 24 hours or vancomycin 1g every 12 hours for suspected or confirmed gram-positive cSSSIs. Most of the 1867 patients were Caucasian males and approximately 80% had subcutaneous abscesses or deep/extensive cellulitis. MRSA, the most common pathogen, was isolated in 579 microbiologically evaluable patients. Stryjewski et al11 reported that the cure rates in clinically evaluable patients were 87.9% (304/346) in the TLV group versus 86.5% (302/349) in the vancomycin group in the ATLAS 1 study (p = non-significant), 81 and 88.7% (354/399) in the TLV group versus 87.6% (346/395) in the vancomycin group in the ATLAS 2 study (p = non-significant).

Nosocomial pneumonia
The use of TLV was evaluated in two identical randomised, double-blind, comparator-controlled, parallel-group, phase III trials: the ATTAIN trials. The first data from the HAP trials (ATTAIN) were published in 2011 by Rubinstein et al(12) and further data were available and had been presented at scientific meetings. Patients received either TLV 10mg/kg every 24 hours or vancomycin 1g every 12 hours for up to 21 days. The primary efficacy endpoint for both ATTAIN trials was to assess the non-inferiority of TLV to vancomycin. A total of 1503 patients were enrolled to receive either vancomycin or TLV in combination with aztreonam or piperacillin–tazobactam if a polymicrobial infection was identified. Clinical cure was similar in both groups with significantly better cure rates obtained in TLV-treated high MIC isolates (<1mg/ml) MRSA episodes (treatment difference 12.5%; p<0.03). TLV demonstrated potent activity against recent gram-positive HAP isolates; MICs for all isolates ranged from 0.008 to 1μg/ml.
The secondary objective was to perform a pooled analysis of the superiority of TLV over vancomycin in patients with a confirmed MRSA infection (the most common gram-positive pathogen isolated). The clinical cure rates for the 159 MRSA patients were 86% for TLV vs 75% for vancomycin.

Safety and tolerability
Phase I clinical trials of TLV in 54 healthy adults found that the most common advers effects associated with its treatment were taste disturbance (75% vs 14% placebo) and headache (40% vs 29% placebo).6 Other reported adverse events included dizziness, foamy (soapy) urine, nausea and rash.(3) Electrocardiographic data from all trials demonstrated a prolongation in QTc (Fridericia corrected) interval associated with TLV treatment.

Moreover, TLV has been associated with infusion-related reactions similar to other glycopeptides antimicrobials, such as red man syndrome-like reactions, including flushing of the upper body, urticaria, pruritis, or rash.

Renal dysfunction was observed in 3% of TLV-treated patients and 1% of vancomycin-treated patients in the cSSSI trials(1,11) and in 10% of TLV treated patients and 8% of vancomycin-treated patients in the HAP trials.(12)

Nephrotoxicity has been noted with TLV, with increased serum creatinine levels of up to 1.5-times baseline values reported. Patients with severe renal dysfunction (CrCl <30ml/min) had a two-to-threefold increase in TLV exposure. The product information indicates that the TLV administration interval should be extended to every 48 hours in patients with CrCl between 10 and <30ml/min.(13)

The European Medicines Agency therefore concluded that telavancin should not be used in those who have acute renal failure. The additional post-marketing safety experience indicated that there had been a preponderance of reports of acute renal injury despite the careful advice provided in the US labelling.(13)

Regulatory affairs

• It was approved by the US Food and Drug Administration (FDA) in 2009 for the treatment of cSSSIs caused by gram-positive bacteria, including MRSA.(3)
• In Europe, on 2 September 2011, a marketing authorisation was granted for the treatment of adults with nosocomial pneumonia, including ventilator-associated pneumonia known or suspected to be caused by MRSA. Vibativ should be used only in situations where it is known, or suspected, that other alternatives are not suitable.(13)

Conclusions
With relatively few antimicrobial agents for serious gram-positive infections available, the need for alternative agents to vancomycin is clear. TLV has the potential to become a useful tool in the treatment of these infections. TLV is a rapidly bactericidal drug with multiple mechanisms of action against gram-positive cocci, including organisms with reduced susceptibility to vancomycin (for example, VISA, VRSA)

TLV is an excellent therapeutic option for patients with cSSSI caused by MRSA with or without elevated MIC to vancomycin because the once-daily treatment can be continued in an out-patient facility. Overall, TLV could benefit critically-ill patients with MRSA pneumonia who need a rapidly bacteriocidal agent with better penetration into lungs.

The safety profile of TLV is acceptable for the treatment of patients with severe infections produced by resistant organisms but more data are required to review its safety profile, and especially its administration in patients with renal impairment, critically-ill patients with comorbitidies and its activity in patients with healthcare-associated pneumonia.

References

1. Nannini EC, Stryjewski ME. A new lipoglycopeptide: telavancin. Expert Opin Pharmacother 2008;9(12):2197–207.
2. Howden BP et al. Reduced vancomycin susceptibility in Staphylococcus aureus, including vancomycin-intermediate and heterogeneous vancomycin-intermediate strains: resistance mechanisms, laboratory detection, and clinical implications. Clin Microbiol Rev 2010;23(1):99–139.
3. Astellas. www.astellas.us/therapeutic/product/disease.html (accessed 2 March 2012).
4. Higgins DL et al. Telavancin, a multifunctional lipoglycopeptide, disrupts both cell wall synthesis and cell membrane integrity in methicillin-resistant Staphylococcus aureus. Antimicrob Agents Chemother 2005;49(3):1 127–30.
5. Plotkin P et al. Telavancin (Vibativ), a new option for the treatment of gram-positive infections. Drug Forecast 2011;36:3 March 2011.
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7. Sun HK et al. Tissue penetration of telavancin after intravenous administration in healthy subjects. Antimicrob Agents Chemother 2006;50(2):788–90.
8. Lodise TP Jr et al. Telavancin penetration into human epithelial lining fluid determined by population pharmacokinetic modeling and Monte Carlo simulation. Antimicrob Agents Chemother 2008; 52(7):2300–304.
9. Mendes RE et al. Update on the telavancin activity tested against European staphylococcal clinical isolates (2009-2010). Diag Microbiol Infect Dis 2011;71(1):93–7.
10. Finegold S et al. In vitro activities of telavancin and six comparator agents against anaerobic bacterial isolates. Antimicrob Agents Chemother 2009; 53(9):3996–4001.
11. Stryjewski ME et al. Telavancin versus vancomycin for the treatment of complicated skin and skin-structure infections caused by Gram-positive organisms. Clin Infect Dis 2008;46 (11):1683–93.
12. Rubinstein E et al; ATTAIN Study Group. Telavancin versus vancomycin for hospital-acquired pneumonia due to gram-positive pathogens. Clin Infect Dis 2011;52(1):31–40.
13. European Medicines Agency. Vibativ. www.ema.europa.eu/docs/en_GB/document_library/EPAR__Summary for_the_public/human/001240/WC500115429.pdf (accessed 2 March 2012).