Drugs in the Pipeline for Gram-positive, C difficile, and Non-tuberculosis Mycobacterial Infections

A trio of speakers at ASM Microbe 2019 provided a look at the latest developments in drugs intended to quell gram-positive pathogens, including Clostridioides difficile (C diff) and non-tuberculosis (TB) mycobacterial infections.

Vancomycin-resistant Enterococcus faecium, the ever-present methicillin-resistant Staphylococcus aureus (MRSA), and penicillin-non-susceptible Streptococcus pneumoniae remain threats. “The clinical pipeline to these pathogens is dominated by derivatives of established classes. New drug classes to address resistance with existing classes are fewer and none of the new classes of antibiotics have translated into clinical development,” said Sushmita Lahiri, PhD, with Macrolide Pharmaceuticals (now Zikani Therapeutics), in Watertown, Massachusetts.

Eravacycline and omadacycline were recently approved by the US Food and Drug Administration (FDA). Iclaprim for the treatment of acute bacterial skin and skin structure infection (ABSSSI) was turned down by the FDA in February of this year, with more data needed. None of these drugs feature a novel mode of action.

Phase 2 trials are ongoing or planned for antibiotics targeting ABSSSI, bone and joint infections, as well as bacteremia caused by Staphylococcus, and ventilator-assisted pneumonia due to S aureus. Afabicin is noteworthy, as is a novel chemical class that targets NADH-dependent enoyl reductase (Fabl), an enzyme involved in fatty acid synthesis by bacteria. Many efforts have tried and failed to come up with an inhibitor of Fabl.

The list of phase 1 compounds is depressingly short. Interestingly, it includes a conjugate of an antibody to wall teichoic acid and rifamycin (DSTA-46375) that targets bacteremia caused by multidrug-resistant S aureus bacteremia. The use of antibodies has a checkered history. This may be changing with the upcoming phase 3 trial of tosatoxumab and some ongoing phase 2 trials. Antibody-based treatments may yet prevail.

One of the bedeviling gram-positive pathogens is C diff. The focus of drug development is shifting to prevention, according to Dale Gerding, MD, a research physician at Edward Hines Jr. VA Hospital in Hines, Illinois.

These efforts include the prevention of recurrent infections through the development of new antibiotics with a narrower spectrum of focus that are tailored to preserve the existing microbiota, immunologics including monoclonal antibodies, and microbial replacement using fecal microbiota transplantation (FMT) or biotherapeutics.

Treatment of C diff infections by rejigging the intestinal microbiota using FMT is an approach that is definitely gaining traction. Several oral formulations are commercially available. Earlier this year, however, 2 individuals receiving FMT died from multidrug-resistant organisms that originated from the FMT donors. In the aftermath of these deaths, as of July 15, the FDA will require screening of donors for multidrug-resistant organisms.

Another tact is to prevent the infections taking hold. Biotherapeutics have a place here, as do vaccines, probiotics, and neutralization of antibiotics in the gut to prevent alteration of the microbiome.

The jury is still out on the value of probiotics. Indeed, there are indications that probiotics could impede recovery of the microbiota rather than promote recovery.

Non-tuberculosis mycobacteria are another challenging target. New drugs are being explored and others are being repurposed, according to Charles Daley, MD, with the National Jewish Hospital in Denver. Emerging therapies that need to be assessed in more detail include host-directed therapies in the form of inhaled nitric oxide and granulocyte-macrophage colony stimulating factor and the use of bacteriophages.

The new drugs on the scene include bedquiline, delamanid, cyclines (tigecycline, omadacycline, and eravacycline), and SPR719. Rejigged drugs include an inhaled preparation of amikacin enclosed in liposomes, orally administered soft gels containing clofazimine, linezolid/tedizolid (although linezoid-related adverse events are an issue), beta-lactams (alone or other with inhaled compounds), and rifamycins.

“There is only 1 FDA-approved drug for the treatment of pulmonary Mycobacterium avian complex infections—amikacin liposome inhaled suspension. New and repurposed drugs show improved activity compared with some of our currently used drugs. We lack clinical trials to inform us how to use the drugs in combination regimens, although trials are planned,” Daley said.

The symposium, “Pipeline Drugs to Treat Gram-positive, C. difficile, and Non-TB Mycobacterial Infections,” was held June 22, 2019, at ASM Microbe in San Francisco, California.

Brian Hoyle, PhD, is a medical and science writer and editor from Halifax, Nova Scotia, Canada. He has been a full-time freelance writer/editor for over 15 years. Prior to that, he was a research microbiologist and lab manager of a provincial government water testing lab. He can be reached at hoyle@square-rainbow.com.

DISCLOSURES

Sushmita Lahri: none

Dale Gerding: consultancies with MGB BioPharma, Medpace, Merck, Rebiotix, and Actelion

Charles Daley: research funding from Insmed; member of advisory board of Insmed, Johnson and Johnson, Meiji, Paratek, and Spero

SOURCES

• Photos and tape of ASM presentations

PRESENTATIONS

Symposium S220: Pipeline Drugs to Treat Gram-positive, C. difficile, and Non-TB Mycobacterial Infections

• New Antibiotics in the Pipeline Targeting Gram-positive Pathogens; Sushmita Lahiri, PhD, Executive Director of Biology, Macrolide Pharmaceuticals (now Zikani Therapeutics), Watertown, Massachusetts
• Prevention is the Focus for New C. difficile Agents in Clinical Trials; Dale N. Gerding, MD, Edward Hines Jr., VA Hospital, Hines, Illinois
• New and Repurposed Drugs for the Treatment of NTM; Charles Daley, MD, National Jewish Health, University of Colorado, Denver, Colorado