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SAN DIEGO -- In what one participant called scientific "speed dating," physicians and researchers here got a rapid-fire look at 10 antibiotics that could be on pharmacy shelves within months.
The 90-minute symposium provides evidence that -- unlike past years -- the antibiotic pipeline is robust, delegates were told at the annual IDWeek meeting, sponsored jointly by the (IDSA), the (PIDS), the (SHEA), and the (HIVMA).
"We have new drugs for bad bugs," quipped co-moderator Cesar Arias, MD, PhD, of the University of Texas Medical School at Houston.
The new drugs include beta-lactamase inhibitors, a cephalosporin, an aminoglycoside, a fluoroquinolone, and a tetracycline, as well as several first-in-class medications. Themes that emerged during the discussion were twofold:
- The new drugs in established classes aim to overcome some of the safety issues of their predecessors
- And the approach to resistance is much more nuanced than it has been in the past, so that doctors will soon be able to choose medications that target specific mechanisms of resistance
Already available is delafloxacin (Baxdela), a new fluoroquinolone that won FDA approval in June for acute bacterial skin and skin structure infections (ABSSSI), according to Sue Cammarata, MD, of Melinta Therapeutics in Lincolnshire, Illinois.
Notably, she pointed out, clinical trials of the drug showed potency against both susceptible and resistant bacterial species that was comparable to what was seen with vancomycin/aztreonam. But there was no evidence of some of the side effects of earlier medications in the class, such as tendon rupture or peripheral nerve damage.
Next closest to the clinic is meropenem-vaboractam (Vabomere), which has FDA approval and should be available by the end of October, according to Michael Dudley, PharmD, of The Medicines Company in San Diego.
The novel part of the combination is vaboractam, which Dudley said is the first of a new class of beta-lactamase inhibitors -- drugs that block a common resistance mechanism to beta-lactam antibiotics and thereby restore their potency, often without an antibacterial mechanism of their own.
The combination has FDA approval for adults with complicated urinary tract infections (cUTIs) and acute pyelonephritis, Dudley said.
Further away is another beta-lactamase inhibitor, relebactam, which is being tested in combination with the beta-lactam imipenem, according to Amanda Paschke, MD, of Merck & Co. in Kenilworth, New Jersey.
The drug, designed to overcome beta-lactam resistance in Gram-negative pathogens, has shown promise in early-stage trials, including non-inferiority to comparator drugs in the phase II program, and is now in phase III studies, Paschke said.
Omadacycline is the first of a new class -- the aminomethylcyclines -- that are related to the tetracycylines, according to Paul McGovern, MD, of Paratek Pharmaceuticals in King of Prussia, Pennsylvania.
The company plans to seek approval for the drug early next year after it met all of the FDA and European endpoints in its phase III studies, Dudley said. Omadacycline has two formulations, oral and intravenous, and the company will be seeking indications for community acquired pneumonia and acute bacterial skin and skin structure infections (ABSSSI).
The Phase III trials have shown a "very high clinical efficacy" for the drug compared with standard treatments, he said.
Also new is fosfomycin for injection, according to Evelyn Ellis-Grosse, PhD, of San Diego's Zavante Therapeutics. An oral fosfomycin, sold as Monurol, is approved for uncomplicated urinary tract infections, but the injectable form is aimed at cUTIs, including acute pyelonephritis.
It's described as a first-in-class injectable epoxide antibiotic that functions by inhibiting cell-wall synthesis. In phase III studies, Ellis-Grosse said, the drug met the primary endpoint of statistical non-inferiority to piperacillin/tazobactam in patients with cUTIs.
Iclaprim, a diaminopyrimidine dihydrofolate reductase inhibitor, was designed to be more potent than trimethoprim, according to David Huang, MD, PhD, of Motif BioSciences in New York. The company is planning to seek FDA approval next year for ABSSSI, he said, after a phase III trial showed the drug was non-inferior to vancomycin at the early time point and test-of-cure endpoints.
The drug was initially submitted for approval in 2009 by the then-owner of the molecule, Arpida, but was rejected because of concerns over both its safety and efficacy.
Plazomicin, a next-generation aminoglycoside, outperformed its comparators in two phase III trials studying patients with, respectively, cUTIs and carbapenem-resistant Enterobacteriaceae infections, according to Ian Friedland, MD, of Achaogen in South San Francisco.
The drug met the planned non-inferiority margin for efficacy against meropenem in cUTIs and colistin in the CRE infections, but also showed statistical superiority, Friedland reported. The drug's safety profile was comparable to that of meropenem, but superior to that of colistin, mainly owing to a lower rate of renal events, he said.
The company is hoping to launch the drug in mid-2018.
The pleuromutilin antibiotics were discovered more than half a century ago but have been mostly restricted to animal use since then. Although topical pleuromutilins have been approved for human use, lefamutilin is the first systemic pleuromutilin to be developed for humans, according to Steven Gelone, PharmD, of Nabriva Therapeutics in King of Prussia, Pennsylvania.
It's currently being evaluated in two phase III trials in patients with community-acquired pneumonia and has shown non-inferiority against moxifloxacin (plus or minus linezolid) in the first of those, Gelone said. Interestingly, he reported, the drug has also shown activity against many sexually transmitted infections, including some that are now resistant to most medications.
Finally, the investigational siderophore cephalosporin cefiderocol has been shown to have efficacy against a range of Gram-negative pathogens and is stable in the face of all know beta-lactamases, according to Roger Echols, MD, of ID3C in Easton, Connecticut, making it useful against many carbapenem-resistant pathogens.
In a phase III trial in patients with cUTIs, with or without pyelonephritis, the drug was non-inferior to high-dose imipenem/cilastatin, Echols said, on a composite primary endpoint of clinical cure and microbiological eradication. But the statistical analysis suggested cefiderocol was actually superior.