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

Dalbavancin

Dalbavancin, a lipoglycopeptide, is a semisynthetic derivative of a teicoplanin-like natural glycopeptide. Dalbavancin binds to the terminal D-alanyl-D-alanine of the pentapeptide chain, which inhibits peptidoglycan cross-linking and leads to cell death. However, unlike vancomycin and teicoplanin, the lipophilic side chain of dalbavancin anchors the molecule to the bacterial membrane.[54] This interaction is theorized to account for the increased binding affinity of dalbavancin to the target D-ala-D-ala with resultant potent antimicrobial activity.

Dalbavancin's activity is solely against gram-positive pathogens. Dalbavancin has slow bactericidal activity against S. aureus, both methicillin-sensitive and -resistant.[55] Against S. aureus with reduced susceptibility to vancomycin and linezolid, dalbavancin generally retains activity; however, MIC values are elevated.[55,56] The increased potency of dalbavancin against staphylococci, especially coagulase-negative staphylococci, is due to the monoamide substituent at the peptide carboxy group.[54] Dalbavancin exhibits bactericidal activity against pneumococci, regardless of penicillin sensitivity.[54]

Dalbavancin has a low propensity for in vitro resistance development in staphylococci compared with the other glycopeptides.[54] Direct selection of single-step high-level resistance was not observed during in vitro experiments. In serial passage studies, the dalbavancin MICs increased twofold in S. aureus compared with four- and eightfold for vancomycin and teicoplanin.

A unique attribute of dalbavancin is its long half-life of 123 to 210 hours, which supports a once-weekly dosing regimen.[57] Steady-state concentrations are generally achieved in 2 to 3 days following administration. Single doses ≥ 500 mg provided plasma concentrations above the minimum bactericidal level for MRSA for at least 7 days. Approximately one third of dalbavancin is excreted unchanged in the urine, suggesting nonrenal routes of elimination. No dosage adjustment is required for patients with mild to moderate renal impairment; however, those with severe renal disease may require an adjustment to avoid increased drug exposure.[58,59]

The area under the time curve (AUC):MIC and maximum concentration (Cmax):MIC ratios were the PK-PD indices that best predicted dalbavancin activity against S. aureus and S. pneumoniae in the neutropenic murine thigh infection model.[60] An in vitro pharmacokinetic system predicted free drug AUC24:MIC value of 200 to 300 to be the best PK-PD target for patients with moderate to severe infections.[60]

Dalbavancin appears to be safe and well tolerated by patients in clinical studies. The most commonly reported adverse events included pyrexia, headache, and gastrointestinal symptoms. No auditory or vestibular toxicity, or "red man" syndrome was observed in study subjects. Dalbavancin has been shown to be devoid of major ecologic effects on normal intestinal microflora.[61]

Dalbavancin achieved noninferiority to linezolid for the treatment of cSSSIs in a phase III trial and was similar to vancomycin in a phase II study of the treatment of catheter-related bloodstream infections.[62,63] There are no clinical studies published to date evaluating dalbavancin for the treatment of HCAP. However, its broad spectrum of gram-positive activity, including MRSA, makes it an option for further investigation. Although dalbavancin is widely distributed in rat lung tissue, the penetration into the epithelial lining fluid in humans is unknown.[64] Without preclinical pharmacokinetic, animal model, or clinical data, the role of dalbavancin for the treatment of HCAP is unknown.

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