December 01, 2013
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New antimicrobials on the horizon

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The emergence of antimicrobial resistance poses a serious challenge to health care practitioners. Management and control of multidrug-resistant organisms should include good infection control practices, good antimicrobial stewardship programs and novel antimicrobials with new mechanisms of action.

Since 2000, only four new classes of antibiotics have come on the market. These include oxazolidinones, pleuromutilin, lipopeptides and a diarylquinoline called bedaquiline (Sirturo, Janssen Therapeutics). Bedaquiline is the first new drug to be developed for tuberculosis in several decades and could improve the management of MDR-TB and extremely drug-resistant TB (XDR-TB) cases. Recognizing the need for new antibiotics, the FDA and the European Medical Association (EMA) have developed new policies to encourage development of new antimicrobials. In this review, we discuss only a few promising antibiotics that are on the horizon.

Beta-lactams and beta-lactamase inhibitors

There are new carbapenems in development that have expanded gram-positive activity while maintaining some gram-negative and anaerobic activity. Tomopenem (Daiichi Sankyo) has activity against methicillin-resistant Staphylococcus aureus and has been studied in phase 2 clinical trials for treatment of skin and skin structure infections (SSSIs). Razupenem (Meiji Seika) and ME1036 (Forest Laboratories) have activity against MRSA and vancomycin-resistant enterococci (VRE). Razupenem has undergone phase 2 clinical trials for SSSIs. ME1036 is in early development but will likely have a role in the treatment of severe pneumonia with bacteremia.

Obi Nnedu

George Pankey

A new oral carbapanem, Tebipenem (Meiji Seika), has undergone phase 2 clinical trials in Japan. It has activity against penicillin-resistant strains of Streptococcus pneumoniae, Haemophilus influenzae, Klebsiella pneumoniae, Moraxella catarrhalis and Escherichia coli. It will likely play a role in treatment of respiratory tract infections.

Avibactam (AstraZeneca) is a beta-lactamase inhibitor currently undergoing clinical trials as a combination with either aztreonam, ceftazidime or ceftaroline (Teflaro, Forest Laboratories). It is active against amp-C, extended-spectrum beta-lactamases (ESBLs) and K. pneumoniae carbapenemase (KPC) beta-lactamases. Ceftazidime/avibactam is currently undergoing phase 2 trials for treatment of ceftazidime-resistant isolates. Ceftaroline/avibactam just complicated phase 2 clinical trials in comparison to doripenem (Doribax, Janssen) for treatment of urinary tract infection.

Three other new beta-lactamase inhibitors are in development: MK-7655 (Merck); ME1071 (Meiji Seika); and RPX7009 (Rempex). MK-7655 and ME1071 have been studied combined with carbapenems and appear to expand the in vitro activity of the carbapenem against resistant strains of gram-negative rods. MK-7655 shows activity against class A and class C carbapenemases when combined with imipenem (Primaxin, Merck) in vitro. ME1071 inhibits metallo-beta-lactamases in vitro and has been studied as a combination with ceftazidime and carbapenems. RPX7009 has activity against KPC-producing K. pneumoniae isolates. The combination of RPX7009 and biapenem, a carbapenem, is currently in phase 1 clinical trials.

There also are new combinations with older beta-lactamase inhibitors such as ceftolozane/tazobactam (Cubist) that are undergoing investigation. Tazobactam is a beta-lactamase inhibitor that has been around as a combination with piperacillin. Ceftolozane is a relatively new cephalosporin that has activity against Pseudomonas aeruginosa and Enterobacteriaceae.

Ceftolozane/tazobactam has been successfully studied in phase 3 trials for UTIs, intra-abdominal infections and hospital-acquired pneumonia.

Ceftolozane/tazobactam will likely play an important role in the treatment of resistant Pseudomonas and Enterobacteriaceae.

Additional therapeutics in development

Dalbavancin (Durata Therapeutics) and oritavancin (The Medicines Company) are new glycopeptides that have undergone phase 3 trials. Both have lipophilic moieties that allow them to have substantially longer half lives than vancomycin, which allows less frequent dosing. Dalbavancin can be given once weekly, whereas oritavancin can be given once daily. Dalbavancin has undergone successful phase 3 trials for skin and soft tissue infections (SSTIs), and a new drug application has been submitted. Oritavancin is particularly promising because it has activity against vancomycin-intermediate S. aureus, vancomycin-resistant S. aureus, daptomycin-resistant strains of S. aureus and VRE. Oritavancin is currently undergoing phase 3 trials for acute bacterial SSSIs.

Five new fluoroquinolones are in development. These include finafloxacin (MerLion Pharmaceuticals), delafloxacin (Rib-X Pharmaceuticals), avarofloxacin (Furiex Pharmaceuticals), zabofloxacin (Pacific Beach BioSciences) and nemonoxacin (TaiGen Biotechnology). Generally, they offer the same spectrum of activity as existing quinolones with few exceptions. Nemonoxacin has activity against ciprofloxacin-resistant strains of MRSA and is being evaluated in phase 3 clinic trials for treatment of community-acquired pneumonia (CAP). Delafloxacin has activity against quinolone-resistant gram-negative organisms and is about to undergo phase 3 trials for bacterial SSSIs.

Eravacycline (Tetraphase) is a novel tetracycline that is available in oral and parenteral formulations. It has broad activity against gram-positive, gram-negative and anaerobic pathogens. Its spectrum of activity includes MRSA, methicillin-sensitive S. aureus (MSSA), streptococci, enterococci, ESBL/carbapenem-resistant strains of gram-negative rods, Bacteroides fragilis and Clostridium difficile. It maintains activity against pathogens that have tetracycline-specific efflux pumps. Eravacycline has been evaluated for treatment of community-acquired intra-abdominal infections in phase 2 trials and had similar outcomes in comparison to ertapenem (Invanz, Merck).

Omadacycline (Paratek Pharmaceuticals) is another new tetracycline that is being evaluated for the treatment of SSTI. It has activity against gram-negatives, gram-positives and anaerobes, including B. fragilis. Phase 2 trials have been completed for SSSIs showing comparable efficacy to linezolid (Zyvox, Pharmacia & Upjohn). Phase 3 trials are being planned.

Tedizolid (Trius Therapeutics) and radezolid (Rib-X Pharma) are two new oxazolidinones in the pipeline. Tedizolid has activity against resistant gram-positive organisms such as MRSA, VRE and linezolid-resistant strains of Enterococcus. Tedizolid has excellent oral bioavailability when given orally or parenterally and may have less antimitochondrial toxicity than linezolid. Tedizolid is currently undergoing phase 3 clinical trials for SSSIs. Radezolid maintains the gram-positive activity of other oxazolidinones and also has activity against some gram-negative organisms such as H. influenzae and M. catarrhalis. Radezolid may have a role for treating pneumonias. Radezolid has successfully completely phase 2 clinical trials for community CAP and SSSIs.

References:

Bassetti M. Ann Clin Microbiol Antimicrob. 2013;12:22.
Butler MS. J Antibiot (Tokyo). 2013;66:571-591.
Gordon YJ. Curr Eye Res. 2005;30:505-515.
Pucci MJ. Clin Micro Rev. 2013;26:792-821.

For more information:

Obi Nnedu, MD, MPH, is associate program director of the infectious disease fellowship program in the department of infectious diseases at Ochsner Health Systems in New Orleans. Nnedu can be reached at: onnedu@ochsner.org.
George Pankey, MD, is director of infectious diseases research and an infectious disease consultant at Ochsner Clinic Foundation, New Orleans. Pankey also is a member of the Infectious Disease News Editorial Board. He can be reached at: gpankey@ochsner.org.

Disclosure: Nnedu and Pankey report no relevant financial disclosures.