• Bacterial Infections
• Drug Resistance
• Pneumonia
• Emerging Therapies

Aminoglycosides are a well-known class of drugs with proven efficacy; however, they are being used less frequently because of resistance, nephrotoxicity, and ototoxicity. George Zhanel, PhD, University of Manitoba, Winnipeg, Manitoba, Canada, discussed plazomicin (formerly ACHN-490), a new aminoglycoside that is used to treat gram-negative infections, which was evaluated against gentamicin, tobramycin, and amikacin. Dr. Zhanel believes plazomicin is a next-generation aminoglycoside that retains its activity against multidrug-resistant gram-negative and gram-positive bacterial strains that express all clinically relevant aminoglycoside-modifying enzymes. It is not active against organisms that harbor rRNA methyltransferases. Plazomicin is synergistic with daptomycin and ceftobiprole against a variety of MRSA phenotypes and with a variety of β-lactams (eg, cefepime, doripenem, imipenem, and piperacillin-tazobactam) and against P. aeruginosa (in vitro). At 15 mg/kg IV, plazomicin has a C_max of 113 μg/mL, an AUC_0–24 of 239 h·μg/mL, t_1/2 of 3.0 hr, and V_ss of 0.24 L/kg. Animal and human studies have not reported nephrotoxicity or ototoxicity [Zhanel G et al. Expert Rev Anti Infect Ther 2011. Submitted; Zhanel G et al. IDSA 2011]. Plazomicin is currently being investigated in a Phase 2 study to treat complicated urinary tract infections and acute pyelonephritis [NCT01096849].

Prabhavathi Fernandes, PhD, Cempra Pharmaceuticals, Chapel Hill, North Carolina, USA, presented information on macrolides and ketolides with improved antibacterial properties. Dr. Fernandes discussed several investigational programs: a novel series of azetidinyl ketolides that mitigate hepatotoxicity by minimizing hepatic turnover and time-dependent inactivation of CYP3A isoforms in the liver [Magee TV et al. J Med Chem 2009]; cethromycin, a ketolide antibiotic that has shown potent activity (similar to telithromycin) against macrolide-resistant bacterial strains but failed to obtain United States Food and Drug Administration approval for community-acquired bacterial pneumonia (CABP) and is now being pursued in superiority trials in simple drug-resistant respiratory infections; and modithromycin, a bridged bicyclic macrolide that is also similar in potency to telithromycin that is active against pneumococcal strains with erm and mef resistance but has a relatively high (8 μg/mL) MIC₉₀ for H. influenzae and a very long half-life. Dr. Fernandes concluded her presentation with solithromycin (CEM-101), an oral (Phase 2) and intravenous (Phase 1) fluoroketolide that is being evaluated for the treatment of CABP that has shown activity against S. pneumoniae, CA-MRSA, Enterococci, and M. avium and in animal models of malaria. MICs are similar to azithromycin for gram-negatives, but on average, solithromycin is 8 to 16 times more active for the gram-positive organisms and is active against azithromycin-resistant strains. Solithromycin has 67% oral bioavailability, as compared with 38% for azithromycin; is well distributed into tissues and cells; has a plasma half-life of approximately 7 hours; shows no significant effect against nACH receptors; and has been shown to be safe and well tolerated in Phase 1 studies [Still JG et al. Antimicrob Agents Chemother 2011]. In the recently completed Phase 2 trials, it has shown noninferiority to levofloxacin, with favorable safety and tolerability. Plans are underway for a Phase 3 oral trial and Phase 2 intravenous-oral trial in CABP in 2012.

Kelly Aubart, PhD, GlaxoSmithKline, Collegeville, Pennsylvania, USA, discussed GSK1322322, a novel peptide deformylase inhibitor that is in development for hospitalized CABP, acute bacterial skin, and skin structure infections. The new agent has good activity against gram-positive pathogens, including those that infect the skin and soft tissue, as well as the respiratory tract. It is potent in vivo and in vitro against a range of pathogens, including MRSA. GSK1322322 was safe and well tolerated in Phase 1 studies. A Phase 2 study in skin and soft tissue infections has recently been completed [NCT01209078].

• © 2011 MD Conference Express