A comparison of available and investigational antibiotics for complicated skin infections and treatment-resistant Staphylococcus aureus and Enterococcus

Journal of Drugs in Dermatology, Jan, 2007 by Noah Scheinfeld

The FDA approved daptomycin for treating skin and skin structure infections but daptomycin failed to meet statistical noninferiority criteria in a clinical trial for severe community-acquired pneumonia and thus does not possess an indication for severe community-acquired pneumonia. Daptomycin has exhibited an unusual pattern of activity in pulmonary animal models with efficacy in Staphylococcus aureus hematogenous pneumonia and inhalational anthrax but no activity against Streptococcus pneumoniae in simple bronchial-alveolar pneumonia. Daptomycin was shown to interact in vitro with pulmonary surfactant, resulting in inhibition of antibacterial activity. This effect was specific to daptomycin and consistent with its known mechanism of action. This represents the first example of organ-specific inhibition of an antibiotic.

Linezolid (27-29)

Linezolid is an oxazolidinone that covers all important Gram-positive pathogens. Linezolid can be administered intravenously or orally with 100% bioavailability. It is approved to treat community-acquired and nosocomial pneumonia, complicated and uncomplicated skin and soft tissue infections, and infections caused by MRSA and VRE, including cases with concurrent bacteraemia and VREF. Randomized multicenter clinical trials involving patients infected with various types of serious Gram-positive infections showed that clinical cure rates with linezolid were similar to those with vancomycin or teicoplanin. Linezolid commonly causes gastrointestinal side effects and can rarely cause thrombocytopenia and myelosuppression. Linezolid is a particularly attractive medication compared to vancomycin in patients who have impaired renal function, poor or no intravenous access, require outpatient therapy, or who have been unable to tolerate glycopeptides. Resistant organisms and treatment failures have been reported when linezolid has been used. As it is available in oral form and has coverage that is wider than vancomycin and quinupristin-dalfopristin, its increasing use will continue rise.

Tigecycline (30,31)

Tigecycline is derived from minocycline, which is a tetracycline and a glycylcycline. Tigecycline is given intravenously and has demonstrated activity against a variety of Gram-positive and Gram-negative bacterial pathogens, many of which are resistant to existing antibiotics. Tigecycline has been approved by the FDA for treatment of cSSSI and complicated intraabdominal infections (cIAI) based on its (1) successful completion of phase III trials involving treatment of cSSSI, in which it was found to be at least equally effective to intravenous vancomycin and aztreonam and (2) successful completion of phase III trials involving treatment of cIAI in which it was found to be at least equally effective to intravenous imipenem and cilastatin. Tigecycline side effects are primarily digestive in nature. It should be a valuable addition to the armamentarium to treat even the most resistant pathogens.

Dalbavancin (32,33)

Dalbavancin is a new lipoglycopeptide antibacterial possessing in vitro activity against a variety of Gram-positive pathogens that include methicillin-susceptible and methicillin-resistant Staphylococcus aureus. It has demonstrated favorable minimum inhibitory concentration ranges compared with those of currently available agents. Dalbavancin is highly protein bound (>90%), which may contribute to its prolonged half life of 149 to 300 hours. Because of this long half life, it can be used once-weekly. It does not seem to have greatly increased coverage compared to vancomycin. The efficacy and tolerability of dalbavancin have been demonstrated in a wide variety of animal infection models. Clinical success and safety have been shown in phase II and III trials for skin and soft tissue infections and a phase II trial for catheter-related bloodstream infections. In these trials with vancomycin, linezolid, and various beta-lactams, comparable results have been reported. In June 2006, Pfizer received an approvable letter from the FDA for dalbavancin and expects approval and launch in 2007.