SAN DIEGO – Experts in the field of Neisseria gonorrhoeae antimicrobial resistance are warily watching developments in China, where rates of nonsusceptibility to ceftriaxone are reportedly shooting through the roof.
In the United States at present, gonococcal resistance to ceftriaxone is exceedingly rare: well under 1% of isolates have elevated minimum inhibitory concentrations (MICs) to this cornerstone of empiric therapy. In Europe, the rate is about 3%. What’s really disturbing is that recent data from the World Health Organization Gonococcal Antimicrobial Surveillance Program indicate ceftriaxone nonsusceptibility rates in China are in the 20%-30%-plus range, Dr. Joseph Duncan said at the annual Interscience Conference on Antimicrobial Agents and Chemotherapy.
CDC
Neisseria gonorrhoeae's rate of nonsusceptibility to cefriaxone is about 20-30% in China, raising concerns about the spread of this type of resistance.
“This is very concerning for the potential spread of this type of resistance across the world at some point. It’s just ready to explode,” observed Dr. Duncan of the University of North Carolina, Chapel Hill.
Anytime gonococcal resistance rates to a drug reach about 5%, it spells trouble.
“Gonorrhea treatment is often syndromic. An isolated swab is taken, identified by Gram stain, you give them empiric therapy, and the patients walk out of the clinic and never come back. So you don’t want to have a 5% failure rate for your initial therapy,” he explained.
Neisseria gonorrhoeae has acquired resistance to virtually every antibiotic ever used to treat the infection. Treatment options are running out, which is why the Centers for Disease Control and Prevention has designated gonorrhea as an immediate public health threat requiring urgent and aggressive action.
The 2015 CDC Sexually Transmitted Disease Treatment Guidelines recommend only one front-line treatment for gonorrhea: dual therapy with ceftriaxone at 250 mg IM in a single dose plus azithromycin 1 g orally, also in a single dose. Given N. gonorrhoeae’s adaptability, experts believe that’s not a long-term solution.
After all, 5%-10% of gonococcal isolates in Europe and China are azithromycin-resistant, and while CDC surveillance data showed less than 1% of strains in the United States were azithromycin-resistant through 2013, preliminary data for 2014 show a concerning jump to 2.5%, according to Dr. Duncan’s fellow panelist Dr. Kimberly Workowski, professor of medicine at Emory University in Atlanta and lead author of the 2015 CDC STD guidelines.
Dr. Duncan described the state of the ongoing aggressive multipronged attempts to combat antimicrobial resistance in N. gonorrhoeae. This effort includes new antibiotics in the developmental pipeline, attempts to repurpose existing antibiotics, rapid point-of-care antibiotic susceptibility tests, and vaccine development.
He also highlighted the factors that have led to the bug’s capacity to acquire resistance to so many antibiotics having different mechanisms of action. One key factor is the organism’s sheer competence as expressed in genetic lability.
“This bacteria is continually sampling DNA from the environment. The organisms are constantly swapping genes and DNA segments with commensal Neisseria species. In fact, even human DNA sequences have been found inside the gonococcal genome,” Dr. Duncan said.
While high-level antibiotic resistance can be acquired in a single dramatic step, it can also come about through multiple smaller steps, each one yielding only low-level resistance. “This allows for the sort of creeping [minimum inhibitory concentration] that we’ve seen with the gonococcus, particularly with the extended-spectrum cephalosporin antibiotics,” Dr. Duncan continued.
Also, it’s apparent that even in the absence of antibiotics, other pressures can select for antibiotic-resistant strains. Dr. Duncan credited one of his mentors, William M. Shafer, Ph.D., of Emory University, with developing the hypothesis that fecal lipids might be an important driver of increased resistance rates. Supporting this hypothesis, he noted, is the finding in multiple studies that rectal gonococcal isolates consistently have a somewhat higher prevalence of resistance than those obtained from other sites.
Turning to the effort to curb antibiotic resistance, Dr. Duncan said the drug farthest along in the pipeline is solithromycin, a novel macrolide being developed by Cempra Pharmaceuticals in both oral and IV formulations. Solithromycin, a first-in-class fluoroketolide, is active against a broad range of Gram-positive organisms, among them Legionella, Chlamydia, Mycoplasma, and Ureaplasma, including macrolide-resistant strains. Its ability to bind to three ribosomal sites is thought to minimize development of resistance.
Two positive phase 3 clinical trials of solithromycin have been completed in patients with community-acquired bacterial pneumonia. A phase 3 trial in gonorrhea is ongoing after a positive phase 2 study.
Two bacterial topoisomerase inhibitors are in soon-to-be-completed phase 2 studies.
Delafloxacin, a new fluoroquinolone, was in a phase 3 clinical trial for gonorrhea that was terminated early due to ineffectiveness.