Rapid diagnostic for gonorrhea wins $19 million federal prize competition to combat antibiotic resistance

A diagnostic test capable of accurately and reliably detecting the microorganism that causes gonorrhea and rapidly determining in under 30 minutes if the microorganism is susceptible to a single-dose antibiotic is the winner of the Antimicrobial Resistance (AMR) Diagnostic Challenge. Visby Medical, Inc., will receive $19 million as a prize for its winning diagnostic.

Colorized scanning electron micrograph of Neisseria gonorrhoeae bacteria, which causes gonorrhea. NIAID

According to the Centers for Disease Control and Prevention, more than 2.8 million antibiotic-resistant infections occur in the United States each year, and more than 35,000 people die as a result. The AMR Diagnostic Challenge is co-sponsored by the National Institutes of Health and the Biomedical Advanced Research and Development Authority (BARDA) of the HHS Office of the Assistant Secretary for Preparedness and Response, with each contributing $10 million over the course of the competition.

“Antibiotic-resistant bacteria are a growing and concerning public health risk against which we have few effective deterrents,” said NIH Director Francis S. Collins, M.D., Ph.D. “Challenge prizes spur innovation and we saw many innovative concepts throughout this competition. I want to congratulate Visby Medical for their winning technology, which could help reduce the unnecessary use of antibiotics, a major driver of antimicrobial resistance.”

“One of the challenges healthcare providers face in combating the growing threat of antimicrobial resistant infections is identifying which drugs will be effective in treating the initial infection, and fixing that problem starts with rapid, accurate, easy-to-use, point of care diagnostics,” said BARDA Acting Director Gary Disbrow, Ph.D. “Innovative technologies that can rapidly detect and diagnose drug resistant infections have the potential to measurably improve our response in a public health emergency caused by a drug resistant pathogen. Congratulations to Visby Medical on their winning technology.”

The company’s diagnostic, known as Patient-side, Disposable, Molecular PCR Diagnostic Device for Neisseria gonorrhoeae and Drug Resistance Markers, is a palm-size, single-use, disposable device for the detection of Neisseria gonorrhoeae (N. gonorrhoeae), the microorganism that causes gonorrhea. This diagnostic gives results quickly, allowing clinicians to treat patients immediately and with the correct medication. Gonorrhea is one of the most frequently seen sexually transmitted infections (STIs), which represent a major public health crisis worldwide and in the United States. There were more than 580,000 cases of gonorrhea reported nationwide in 2018 according to the CDC, a 63% increase from 2014.

This type of rapid testing that includes assessment of antibiotic susceptibility has not been available previously as a point-of-care diagnostic device. Antimicrobial resistance in gonorrhea is of increasing concern, and successful treatment of gonorrhea is becoming more difficult. Treatment options have been limited to two drugs, requiring an injection of one drug plus an oral antibiotic.

If approved by the U.S. Food and Drug Administration, the Visby Medical device could be useful in ensuring that patients with gonorrhea receive the right antibiotic so that they can immediately begin treatment, and will allow other antibiotics to be used for patients with drug resistant strains of N. gonorrhoeae.

The easy-to-use format of the device could be helpful in STI clinics, walk-in/urgent care clinics and other facilities without extensive hands-on laboratory staff. Ultimately, this device could have a significant impact in addressing the increasing incidence of gonorrhea and the increasing spread of drug resistant forms of this common STI in the United States and worldwide. Visby Medical currently is exploring how its proprietary technology platform could be adapted to aid in the development of diagnostics for SARS-CoV-2, the virus that causes COVID-19.

The winning diagnostic was chosen from a group of five semifinalists who each received $100,000 in Step 2 of the competition to develop and test prototypes to improve detection of drug-resistant bacteria or differentiate between a bacterial and viral infection. For more information on Visby Medical’s submission and the AMR Diagnostic Challenge, visit: https://dpcpsi.nih.gov/AMRChallenge.

Can vaccines help fight the rise of drug-resistant microbes?

 

The doctor gave vaccination needle .

Some of the most important medications doctors have at their disposal have been rendered ineffective by parasites, viruses, and bacteria that have evolved resistance against them, and the problem is poised to get worse.

Drug-resistant strains of gonorrhea, salmonella, Escherichia coli (E. coli) and many other disease-causing agents are flourishing around the world, and the consequences are disastrous—at least 700,000 people die globally as a result of antimicrobial resistance (AMR) annually, according to a 2016 review on antimicrobial resistance commissioned by former UK Prime Minister David Cameron.

It’s a perilous situation, but several new studies from researchers at Harvard T.H. Chan School of Public Health indicate that an important tool in the fight against AMR already exists: vaccines.

The Proceedings of the National Academy of Sciences (PNAS) recently devoted a special feature section to examine the role vaccines can play in stemming the tide of AMR. In general terms, vaccinations can help lessen the burden of AMR in two ways: First, they can protect against the direct transmission of drug-resistant infections. Second, they can lessen the chances of someone getting sick, which in turn reduces the likelihood that he or she will be prescribed antibiotics or other medications. The fewer medications someone takes, the less likely it is that microbes will evolve resistance to the drugs.

“Despite the increased attention paid to vaccination as a response to AMR in recent years, it remains underemphasized in many cases,” said David Bloom, Clarence James Gamble Professor of Economics and Demography, who co-authored an overview articlefor the PNAS feature. “Vaccination potentially confers considerable value with regard to its ability to slow the development of antimicrobial resistance and mitigate its worst effects.”

As Bloom notes, AMR is not a new problem. Bacteria have been evolving resistance to antibiotics since the first doses of penicillin were administered back in the 1940s. In the past few decades, though, the burden of AMR has skyrocketed and there’s emerging evidence that some drug-resistant bugs are more aggressive or transmissible than their drug-susceptible counterparts.

Among the many challenges is that any use of antimicrobials, including common antibiotics, drives the evolution of resistance, even if the drugs are being used appropriately, Bloom said. Efforts to curb AMR have mostly focused on developing new antibiotics and other drugs. That’s certainly part of the solution, he said, but developing new drugs is a slow, costly process and it’s only a matter of time before the targeted parasites or bacteria begin developing resistance to the new drugs.

Vaccines are appealing because they don’t just protect individuals against germs, they protect entire communities through “herd immunity” (the more people that are vaccinated, the harder it is for germs to spread). For instance, Bloom points to drops in drug-resistant pneumococcal disease in areas where pneumococcal conjugate vaccines have been widely administered. There is also evidence showing that pathogens are much less likely to develop resistance to vaccines than they are to antimicrobial treatment—making vaccines an important first-line defense against AMR.

Promising as this sounds, there’s still much to learn about vaccines and AMR, both on the biological side and on the implementation side. To that end, PNAS featured a paperled by JP Sevilla, research associate at Harvard Chan School, that discussed the need to create a framework to assess the economic value of vaccines with regard to their impact on AMR.

Based on what’s known now, it appears that vaccinations offer significant value by addressing AMR and its associated social and economic challenges. Failing to account for AMR in economic assessments of vaccinations could mean that we are undervaluing vaccination programs and consequently underinvesting in vaccine R&D and uptake.

“Addressing AMR doesn’t require making fundamental changes to already well-developed frameworks for economically evaluating vaccines. There’s a causal chain flowing from vaccination, to its health impacts, and the economic consequences of those impacts. The economic elements of the chain—measuring vaccination costs and the economic consequences of health impacts—are the easier part,” Sevilla said. “The hardest link and highest research priority is the non-economic middle: tracing through the causal impacts of vaccination on susceptible and resistant disease.”

Another PNAS paper, co-authored by Chan School’s Marc Lipsitch, professor of epidemiology, examined how vaccines may help protect the microbiome, the collection of trillions of microorganisms throughout the body. The study noted that the microbiome appears to play an important role in helping humans mount effective immune responses to pathogens. But antimicrobials, which are often broad spectrum and don’t just target the organism that’s causing illness, could alter the microbiome and make it less effective when it comes to spurring the immune system into action.

Further exploring the interplay between vaccines and the microbiome, a paper co-authored by Harvard Chan School PhD student Christine Tedijanto, showed the extent to which bacteria that are commonly found in the microbiome are exposed to antibiotics even when they are not the target of the medication. In other words, if a patient is prescribed antibiotics for a case of pneumonia caused by Streptococcus pneumoniae (S. pneumoniae), it’s likely the antibiotics will also affect E. Coli and other naturally occurring bacteria in the person’s microbiome that are not making the person sick. This in turn increases the likelihood that those untargeted bacteria may become resistant to the antibiotics.

Tedijanto’s study showed that vaccines can help mitigate this effect. She found that pneumococcal conjugate vaccination programs, which provide protection against S. pneumoniae infection, significantly reduce the amount of antibiotics E. Coli and Staphylococcus aureus (S. aureus) are exposed to even though they’re not directly targeted by the vaccine.

While there is significant potential for vaccines to help quell the burden of AMR, Bloom said that a robust and integrated set of solutions is needed, including the development of new vaccines, new antibiotics and other medications, as well as buy-in from policymakers, the global health community, and the public at large.

–Chris Sweeney

Photos: istock.com

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The article is published courtesy of Harvard T.H. Chan, School of Public Health

Novel antibiotic shows promise in treatment of uncomplicated gonorrhea

An investigational oral antibiotic called zoliflodacin was well-tolerated and successfully cured most cases of uncomplicated gonorrhea when tested in a Phase 2 multicenter clinical trial, according to findings published today in the New England Journal of Medicine. The National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, sponsored the clinical study.

This illustration depicts a three-dimensional (3D) computer-generated image of a number of drug-resistant, Neisseria gonorrhoeae diplococcal bacteria. U.S. Centers for Disease Control and Prevention – Medical Illustrator

Gonorrhea is a common sexually transmitted disease (STD) that affects both men and women, particularly young people ages 15 to 24 years. Gonorrhea is the second most commonly reported notifiable disease in the United States, with more than 550,000 cases reported in 2017. If untreated, gonorrhea infection can lead to pelvic inflammatory disease, ectopic pregnancy, infertility, and an increased risk of HIV infection. Pregnant women can pass the infection to their babies, who can become blind or develop life-threatening infections as a result.

Gonorrhea is caused by the bacterium Nesseria gonorrhoeae, which has progressively developed resistance to each of the antimicrobials used to treat it. As a result, in 2015, the U.S. Centers for Disease Control and Prevention revised gonorrhea treatment guidelines to recommend dual therapy with injectable ceftriaxone and oral azithromycin to reduce the emergence of resistance to ceftriaxone.

Zoliflodacin (formerly known as ETX0914 and AZD0914), developed by Entasis Therapeutics based in Waltham, Massachusetts, represents a new type of oral antibiotic that inhibits DNA synthesis in a different way than currently approved antibiotics.

“The rate of reported gonorrhea cases in the United States has increased 75 percent since the historic low in 2009, and antibiotic resistance has considerably reduced the number of treatment options for this disease,” said NIAID Director Anthony S. Fauci, M.D. “These encouraging research findings published today suggest that zoliflodacin has the potential to be a useful and easy-to-administer oral antibiotic for treating gonorrhea.”

The study took place from November 2014 through December 2015 and was led by Stephanie N. Taylor, M.D., of Louisiana State University Health Sciences Center in New Orleans. Study investigators recruited patients from sexual health clinics there and in Seattle; Indianapolis, Indiana; Birmingham, Alabama; and Durham, North Carolina. The trial enrolled 179 participants (167 men and12 non-pregnant women) ages 18 to 55 years with either symptoms of uncomplicated urogenital gonorrhea, untreated urogenital gonorrhea or sexual contact with someone with gonorrhea within 14 days before enrollment. Participants were randomly selected to receive either a single 2 or 3-gram dose of oral zoliflodacin or a 500-milligram (mg) dose of injectable ceftriaxone. Among the 117 per-protocol participants who were evaluated six days after treatment, 98 percent (48 of 49 participants) of those who received the 2-gram zoliflodacin dose, 100 percent (47 of 47 participants) of those who received the 3-gram dose, and all (21 of 21) of the participants in the ceftriaxone group were considered cured of their urogenital gonorrhea based on culture results.

Zoliflodacin cured all rectal gonorrheal infections (4 of 4 participants who received the 2-gram dose and 6 of 6 participants who received the 3-gram dose) as did ceftriaxone (3 of 3 participants). However, the investigational drug did not fare as well in treating patients with gonorrhea infections of the throat (pharyngeal): 67 percent of volunteers who received the 2- gram dose (4 of 6 participants) and 78 percent of those who received the 3-gram dose (7 of 9 participants) were cured. All of the participants (4 of 4) in the ceftriaxone group achieved a cure.

The investigational antibiotic was well tolerated with transient gastrointestinal upset the most commonly reported adverse effect. Microbiological evaluation of post-treatment clinical isolates did not demonstrate resistance to zoliflodacin.

In March 2018, NIAID completed a study to evaluate zoliflodacin’s pharmacokinetics, safety and tolerability as a single oral dose to serve as a bridge from the Phase 2 clinical trial formulation to the final formulation for Phase 3 testing. Results from that study have not yet been made public. Additionally, in September 2018 NIAID launched a Phase 1 study to evaluate the investigational drug’s cardiac effects, a standard safety test for new drugs such as this.

Zoliflodacin has been awarded fast track status by the U.S. Food and Drug Administration for development as oral treatment for gonococcal infections. It is expected to begin Phase 3 testing in the Netherlands, South Africa, Thailand and the United States next year.