Meropenem and Vaborbactam
One of the new drugs discussed was the fixed-dose combination of meropenem and vaborbactam (Vabomere, Medicines Company), which was recently approved by the FDA for adults with complicated urinary tract infection or acute pyelonephritis. The combination acts on the Gram-negative bacteria — spreading throughout Europe and the United States — that produce beta-lactamase enzymes. An accelerated-development program helped the research move from the chemist’s lab to FDA approval in less than 8 years, Michael Dudley, PharmD, senior vice president, head of research and development, and coleader of The Medicines Company’s Infectious Disease Business, reported during his presentation. The combination should be available for use in a few weeks, he reported.
Intravenous and oral forms of delafloxacin ( Baxdela, Melinta Therapeutics) were approved by the FDA in June for adults with acute bacterial skin and skin structure infections caused by susceptible organisms. The agent is currently being assessed in a phase 3 trial of community-acquired bacterial pneumonia. The FDA designated delafloxacin a Qualified Infectious Disease Product for this indication, but has not yet approved it, said Sue Cammarata, MD, chief medical officer of Melinta Therapeutics.
Positive data, released in September, from a phase 3 global trial of lefamulin (Nabriva Therapeutics AG) for the treatment of community-acquired bacterial pneumonia have garnered attention. Strong results, flexible dosing, and the targeted spectrum of activity of lefamulin against the pathogens most commonly associated with community-acquired bacterial pneumonia — including multidrug-resistant strains — have led Nabriva Therapeutics to pitch the agent as an alternative to current gold-standard therapy, said Steven Gelone, PharmD, who is chief scientific officer of the company. Lefamulin has also shown activity against some of the most common sexually transmitted infections, Dr Gelone added.
Fosfomycin, an antibiotic used in Europe for more than 45 years, has broad Grampositive and Gram-negative activity. In a pivotal trial of patients with complicated urinary tract infections, including acute pyelonephritis, fosfomycin for injection ( ZOLYD, Zavante Therapeutics), also known as ZTI-01, met the primary end point of statistical noninferiority to a piperacillin–tazobactam combination. The formulation has been granted Fast Track and Qualified Infectious Disease Product designations by the FDA for the indications of complicated urinary tract infections, hospital-acquired bacterial pneumonia, ventilator-associated bacterial pneumonia, skin infections, and complicated intra-abdominal infections. Zavante Therapeutics is expected to submit a New Drug Application to the FDA early next year, said Evelyn Ellis-Grosse, PhD, chief scientific officer of the company.
The first siderophore cephalosporin to reach late-stage development has a distinctive mechanism for penetrating Gram-negative pathogens, including some that are highly resistant to colistin- and carbapenem-resistant strains of Pseudomonas aeruginosa, Acinetobacter baumannii, and Enterobacteriaceae. Cefiderocol (Shionogi) has no appreciable activity against Gram-positive organisms, noted Roger Echols, MD, an infectious disease specialist in Easton, Connecticut, who is a consultant for Shionogi
The agent is being tested in two phase 3 trials of serious bacterial infections caused by multidrug-resistant Enterobacteriaceae, including carbapenem-resistant Enterobacteriaceae. Plazomicin (Achaogen) could play a role in the treatment of bloodstream infections due to carbapenem-resistant Enterobacteriaceae, and might have potential long-term clinical benefits for patients with complicated urinary tract infections or acute pyelonephritis, said Ian Friedland, MD, chief medical officer of Achaogen, who reported that the company will submit a New Drug Application soon.
Oral and intravenous once-daily formulations of omadacycline (Paratek Pharmaceuticals) are in late-stage development for the treatment of community-acquired bacterial infections. New Drug Applications for oral and intravenous formulations of omadacycline for the treatment of acute bacterial skin and skin structure infections and community-acquired bacterial pneumonia will likely be submitted early next year, said by Paul McGovern, MD, vice president of clinical and medical affairs at Paratek. The drug will likely be available to clinicians by the end of 2018, he added.
This dihydrofolate reductase inhibitor was developed to be more potent than trimethoprim and to overcome trimethoprim-resistant bacteria. Because iclaprim (Motif BioSciences) concentrates at sites of infection — the skin and the lungs — the company is pursuing skin structure infections and hospital-acquired pneumonia indications, said by David Huang, MD, PhD, chief medical officer at Motif BioSciences. Unlike vancomycin, a standard antibiotic used to treat hospitalized patients with Grampositive infections, there is no evidence of nephrotoxicity with iclaprim, he reported. Iclaprim was granted Qualified Infectious Disease Product and Fast Track designations by the FDA, and a New Drug Application will likely be submitted for skin infections early next year. Iclaprim was recently granted orphan drug status by the FDA for the treatment of Staphylococcus aureus lung infections in patients with cystic fibrosis.
With the addition of relebactam, a novel beta-lactamase inhibitor, strains of Gramnegative bacteria that are resistant to imipenem, an established carbapenem, become more susceptible to that drug. Ongoing phase 3 studies of the combination, under development by Merck, are assessing patients with infections resistant to imipenem and those with hospital-acquired bacterial pneumonia or ventilator-associated bacterial pneumonia, said Dr Paschke.
Intravenous and oral formulations of eravacycline (Tetraphase Pharmaceuticals) — a novel, fully synthetic fluorocycline antibiotic — are being developed for the treatment of serious bacterial infections, including those caused by pathogens resistant to multiple drugs. Eravacycline was granted Qualified Infectious Disease Product and Fast Track designations by the FDA, and is being tested in late-stage trials for the treatment of complicated intra-abdominal infections, said Patrick Horn, MD, PhD, chief medical officer at Tetraphase Pharmaceuticals. A New Drug Application will likely be submitted early next year, he added.