New Antibiotics for Healthcare-Associated Pneumonia

Elizabeth A. Neuner, Pharm.D.; David J. Ritchie, Pharm.D.; Scott T. Micek, Pharm.D.

Disclosures

Semin Respir Crit Care Med. 2009;30(1):92-101. 

In This Article

Telavancin

Telavancin is another investigational semisynthetic lipoglycopeptide derivative of vancomycin that inhibits cell wall synthesis by binding to peptidoglycan precursors containing the terminal D-ala-D-ala residue and preventing cross-linking. Enhanced binding affinity of the lipoglycopeptide to its target binding site and a second mechanism of action of perturbing the bacterial cell membrane may be responsible for its enhanced gram-positive potency relative to vancomycin.[65] Telavancin is highly active in vitro against both MSSA and MRSA and in time-kill assays demonstrates rapid, concentration-dependent bactericidal activity against staphylococci.[66] Against S. aureus with reduced susceptibility to glycopeptides, telavancin retains some activity but with elevated MICs.[67] Telavancin is active versus S. pneumoniae independent of penicillin susceptibility.[66]

The selection of spontaneous mutants resistant to high levels of telavancin has not occurred in in vitro testing.[68] In addition, serial passage experiments with telavancin failed to produce any resistant mutants of S. aureus.

Telavancin possesses approximately linear pharmacokinetics that support once-daily dosing.[69] Telavancin is highly protein bound, estimated at 93% in human plasma. Telavancin is distributed into lung tissue with epithelial lining fluid concentrations of approximately two- to eightfold above the MIC90 of S. aureus for 24 hours.[70] The primary elimination route is renal, and the elimination half life is 8 to 9 hours. It is anticipated that patients with moderate to severe renal dysfunction will require dosage adjustments. Unlike other glycopeptides, telavancin exhibits concentration-dependent activity. The PK-PD parameter best predictive of efficacy in an in vitro model was the AUC:MIC ratio.[71] A target AUC:MIC ratio of 50 resulted in bactericidal activity and prevented regrowth, whereas an AUC:MIC ratio of 400 achieved maximal killing.[71]

The effect of telavancin (7.5 mg/kg and 15 mg/kg doses) on the QTc interval was assessed in 160 healthy subjects.[72] Telavancin produced statistically significant prolongations in the QTc interval compared with placebo, but no subjects experienced a QTc > 500 millisecond nor were any adverse cardiovascular events observed. In phase II clinical trials, the mean QTc prolongation in the telavancin groups was 6.4 to 12.5 millisecond. Reported adverse events from clinical trials include taste disturbances, nausea, headache, and insomnia.

Two phase III studies (ATLAS-I and -II) demonstrated noninferiority to vancomycin for the treatment of cSSSIs.[73] In addition, two phase III, randomized, double-blind trials (ATTAIN-1 and -2) investigating telavancin for the treatment of HAP are completed.[74] In these studies, 1503 patients with HAP or VAP due to gram-positive pathogens were randomized to receive telavancin 10 mg/kg every 24 hours or vancomycin 1 g every 12 hours for a total of 7 to 21 days. Concomitant treatment with gram-negative antibiotics was allowed for polymicrobial infections. Telavancin was noninferior to vancomycin in a combined analysis of the primary efficacy outcome of clinical cure, 82.7% versus 80.9%. For patients with MRSA infections, the cure rates were 82% for telavancin versus 74% for vancomycin. In a subgroup analysis of patients with VAP, there was a trend toward higher clinical cure rates with telavancin compared with vancomycin, 80.3% versus 67.8%. The potent activity of telavancin against gram-positive organisms including MRSA in addition to the preliminary clinical trial results in the treatment of HCAP due to gram-positive organisms are promising.

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