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

Oritavancin

Oritavancin is a third glycopeptide in clinical development. In addition to inhibiting peptidoglycan synthesis, a second recently identified mechanism, involves the rapid disruption of both membrane potential and permeability.[75] These combined activities provide oritavancin with potent activity against a wide spectrum of gram-positive organisms. Oritavancin demonstrates activity against both MSSA and MRSA.[76] Importantly, oritavancin possesses activity against VISA and VRSA isolates.[77] Oritavancin has bactericidal activity against pneumococci, irrespective of the degree of penicillin resistance.[76] Resistance studies with vancomycin-susceptible and nonsusceptible S. aureus suggest the resistance potential for oritavancin is low.[78]

Distribution of oritavancin is best described by a three-compartment pharmacokinetic model that suggests rapid tissue accumulation and prolonged retention.[79] Oritavancin is slowly distributed into the epithelial lining and alveolar macrophages, and the epithelial lining fluid (ELF) concentrations are similar in magnitude to vancomycin.[80] Approximately 87% of oritavancin is bound to plasma proteins, elimination occurs slowly through renal clearance, and the estimated t1/2 is 195 hours.[79] Activity of oritavancin is concentration dependent, and T > MIC is the PK-PD parameter best predictive of efficacy in S. aureus bacteremia.[81] In a PK-PD study of oritavancin, a target of free-drug T > MIC of 22% was predictive of microbiological efficacy.

The high intracellular accumulation of oritavancin was shown in vitro to cause alterations in animal lysosome activity suggesting oritavancin has the potential to cause a mixed-lipid storage disorder; however, the clinical significance to humans is unknown.[82] Other adverse effects reported include transient elevations in hepatic transaminases and injection site reactions.

Oritavancin was compared with vancomycin in a phase II study for S. aureus bacteremia and displayed noninferiority to vancomycin/cephalexin for the treatment of cSSSIs.[83,84] Although preclinical studies show distribution into pulmonary tissue comparable to vancomycin, there are no studies evaluating oritavancin's safety and efficacy for the treatment of pneumonia. Activity against MRSA and S. aureus with reduced susceptibility to vancomycin, along with the intrapulmonary concentrations of oritavancin, lend support to the further investigation of oritavancin for the treatment of pneumonia.

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