Nicola M. Parry, BVSc, MRCVS, MSc, DACVP, FRSPH, ELS

The US Food and Drug Administration (FDA) has now released final guidance on how to synchronize development of antimicrobials and antimicrobial susceptibility test (AST) devices, according to Ribhi Shawar, PhD, ABMM, FAM, branch chief at the Division of Microbiology Devices, in the Office of In Vitro Diagnostics and Radiological Health at FDA’s Center for Devices and Radiological Health.

In a webinar on February 12, Dr. Shawar presented an overview of some key features of the new 

 which specific antimicrobial agents a particular pathogen is sensitive to. Although these devices are useful to help guide clinicians in appropriate selection of antimicrobials at the patient level, they can also help to detect emerging drug resistance and monitor overall antimicrobial susceptibility changes. As such, AST devices play a role in combating the growing threat of antimicrobial resistance.

Although the FDA regulates AST devices, Dr. Shawar noted that they follow a different pathway to market than the drugs do.

And although increasing numbers of antimicrobials are more quickly reaching the drug approval stage, AST device development has not kept pace, and the devices frequently are not cleared until long after the drug is approved.

 in approving AST devices can impact patient care because a lack of susceptibility testing data may prevent clinicians using newly-approved antimicrobial agents that might more appropriately treat a patient’s multidrug-resistant organism 

The new guidance document aims to reduce this delay, said Dr. Shawar, by helping drug companies and medical device manufacturers to synchronize the processes to allow simultaneous approval of an antimicrobial and its corresponding AST device.

In particular, the document discusses how the two industries can interact to coordinate development of a new antimicrobial drug and its corresponding AST device. It also describes the important factors to consider when submitting applications for the 2 products, with a goal of simultaneous approval.

Overall, the FDA now wants more coordination in the early development stages, and the guidance specifically recommends that medical device companies should submit a 510(k) for their AST device about 4 to 5 weeks before the antimicrobial is expected to be approved.

However, the document also emphasizes that FDA will continue to independently make review decisions for AST devices and antimicrobial drugs, added Dr. Shawar. Existing regulatory requirements and timelines for drug or device review and approval or clearance remain unchanged, he said.

In concluding, he stressed how improved coordination of these two development processes has better synchronized the approvals of an antimicrobial and its corresponding AST device.

Before coordinated development activities, the time between antimicrobial approval and AST device clearance could be up to 40 months. However, since introducing coordinated development, this timeline has significantly decreased to 1 to 2 months, said Dr. Shawar.

This earlier availability of AST devices will help to improve both patient care and antimicrobial stewardship, he said.

Articles

The FDA has finalized its guidance on how to synchronize development of antimicrobials and antimicrobial susceptibility test devices.

FDA Guidance Synchronizes Launch of Antimicrobial and AST Device

Scientists used a portable DNA sequencing tool to investigate a 2018 Lassa fever outbreak in Nigeria, according to a recent study published online in the journal 

This allowed them to effectively guide the public health response to the outbreak as it was unfolding in real time.

“Results showed no strong evidence of a new strain emerging nor of person-to-person transmission,” Liana. E. Kafetzopoulou, from Public Health England, Porton Down, and the University of Liverpool, United Kingdom, and colleagues write.

Instead, “rodent contamination was the main source,” they note.

 of significant public health significance, including leptospirosis, hantavirus pulmonary syndrome, rat-bite fever, salmonellosis, 

 is an acute and frequently fatal hemorrhagic illness that occurs in West Africa. It is caused by 

 virus, a member of the arenavirus family, which is transmitted to humans via the urine or feces of infected rats.

The symptoms of Lassa fever are similar to those of Ebola virus disease, and include fever, weakness, muscle pain, and seizures. However, many infected people do not develop symptoms.

The 2018 Lassa fever outbreak in Nigeria was the largest on record, resulting in 376 confirmed cases as of March 18. In comparison, only 102 confirmed cases had been reported during the same period in 2017, the authors say.

Because of this sudden rise in cases, experts were concerned about the possibility of emergence of a new, highly transmissible strain of the virus.

With this in mind, Kafetzopoulou and colleagues analyzed patient samples during the outbreak to better understand the reason behind the sudden upsurge in cases.

The investigators used the Oxford Nanopore MinION device to perform viral genome sequencing while the outbreak was ongoing.

This new portable metagenomic technology allowed them to rapidly sequence the genetic code of Lassa virus samples collected from 120 affected patients. The investigators confirmed the presence of Lassa virus in all samples, and were able to perform real-time analysis of the viral genomes from 36 of these during the outbreak, and from the remaining samples after the outbreak.

Overall, the results confirmed extensive diversity among the viral strains, as well as mixing of the strains with those from previous years. According to the authors, this was most suggestive of independent zoonotic transmission events via rodents, and not indicative of a new emergent strain that was spreading quickly between people.

By obtaining these results in real time during the outbreak, experts in the region were better able to appropriately allocate public health resources, thus focusing the response on rodent control, environmental sanitation, and safe food storage.

“Further research is needed to evaluate whether improved diagnostics and disease awareness and/or ecological and climate factors promoting transmission are the drivers behind the changing epidemiology of Lassa fever in Nigeria,” the authors concluded.

A new portable metagenomic technology allowed investigators to perform real-time analysis of viral genomes during a 2018 Lassa fever outbreak in Nigeria.

Mobile Genomics Device Guides Response to Lassa Fever Outbreak

Dolutegravir monotherapy should no longer be used as HIV maintenance therapy, according to Bart J.A. Rijnders, MD, PhD, and Casper Rokx, MD, PhD, both from Erasmus Medical Center, Rotterdam, the Netherlands.

After dolutegravir-based combination antiretroviral therapy (cART) was approved for treatment of HIV-1 in the United States in 2013, and in Europe in 2014, evaluation of dolutegravir maintenance monotherapy initially made sense, say Drs. Rijnders and Rokx in a recent article 

But knowledge of the effectiveness of dolutegravir antiretroviral monotherapy for HIV has significantly evolved in recent years. Despite promising early results, subsequent prospective clinical trials showed that dolutegravir monotherapy is inferior to combination antiretroviral therapy for long-term HIV treatment. Additionally, its use is associated with viral rebounds and emergences of integrase resistance.

Drs. Rijnders and Rokx highlight data from the recently published French randomized 

 study. Investigators on this study aimed to determine whether a switch to dolutegravir monotherapy would be noninferior to continuing dolutegravir-based triple-therapy in maintaining virological suppression.

At 24 weeks, the investigators found that dolutegravir monotherapy was noninferior compared with triple-therapy, with 94% of the participants receiving monotherapy having a viral load below 50 c/ml compared with 96% of those receiving triple therapy. Virological rebound above 50 c/ml occurred in 2 patients receiving monotherapy, and in none of those receiving triple-therapy.

However, between weeks 24 and 48 of follow-up, 5 more cases of virologic rebound occurred in patients receiving dolutegravir monotherapy. And 2 of these cases involved participants developing new integrase inhibitor resistance mutations.

“Because the risk of virological failure with resistance increases overtime, we recommend avoiding dolutegravir monotherapy as a maintenance strategy among people living with chronic HIV infection,” the investigators emphasized.

And, according to Drs. Rijnders and Rokx, further analysis of data from the MONCAY study, and also from the DOMONO study, has shown that the risk of viral rebound during monotherapy was greater in patients who had a lower CD4 nadirs and a higher HIV-DNA. These 2 factors indicate a more advanced disease state with a larger HIV reservoir, they said. This suggests that maintenance dolutegravir monotherapy may have a role in treating a subgroup of HIV-1 patients with a smaller, less genetically diverse HIV reservoir, they added.

Drs. Rijnders and Rokx also discussed the recently published Swiss randomized 

 study. Investigators on this study aimed to determine whether dolutegravir monotherapy would maintain viral suppression better in people who had begun treatment during the acute phase of their HIV infection, and whether a smaller HIV reservoir and reduced viral diversity would lower the risk of viral rebound when antiretroviral treatment was switched to monotherapy.

The investigators focused on simplification of HIV therapy among patients who had been successfully treated with combination antiretroviral therapy for at least 48 weeks since primary HIV-1 infection, and who were then randomized to DTG monotherapy.

A total of 101 participants were randomized to either continue 3-drug combination antiretroviral therapy (n = 33) or switch to dolutegravir monotherapy (n = 68). The results showed that dolutegravir monotherapy was inferior to combination antiretroviral therapy, with 100% of participants in both study arms maintaining viral suppression.

The investigators noted that success of simplification strategies using dolutegravir monotherapy was likely determined by early start of treatment with subsequent low latent HIV-1 reservoir size, low viral diversity, and low immune activation. “It suggests that trials evaluating simplification strategies should stratify between patients first treated during primary and chronic infection,” they stressed.

“Where do we go from here with dolutegravir or other future monotherapy studies?,” asked Drs. Rijnders and Rokx.

Although they emphasized that dolutegravir as HIV maintenance monotherapy should no longer be used, they noted that 1 exception may be in a specific subset of patients, as studied in EARLY-SIMPLIFIED, or in patients with favorable reservoir and host characteristics that we must first gain a better understanding of.

“We therefore think that studies on monotherapy remain acceptable from an ethical point of view provided that the drug has a (very) high genetic barrier against the development of resistance and that a stringent set of common-sense rules are followed to protect the patient’s safety,” they concluded.

Despite promising early results, dolutegravir monotherapy should no longer be used as HIV maintenance therapy, a new study concludes.

Dolutegravir Monotherapy for HIV No Longer Recommended: Study

Investigators have now detected Marburg virus in West Africa for the first time, a December 21, 2018, 

 from the US Centers for Disease Control and Prevention (CDC) reports. The deadly virus was isolated from fruit bats in Sierra Leone.

 is related to Ebola virus. Both belong to the 

 with high fatality rates in humans and nonhuman primates.

Transmission of Marburg virus predominantly occurs via close contact, as well as via infected blood and other body fluids. It can also occur by infected semen.

The Egyptian fruit bat or Egyptian rousette (

) is the natural reservoir host of Marburg virus. The bats shed the virus in their saliva, urine, and feces while feeding on fruit. And people become exposed to the virus when they eat fruit that has been contaminated by infected bats, or if they are bitten by infected bats while capturing them to eat.

Because fruit bats infected with Marburg virus do not to show obvious signs of illness, and because of their ability to fly across great distances, these bats play an important role in transmitting the infection.

According to the CDC, 5 Egyptian rousette fruit bats in Sierra Leone tested positive for active infection with Marburg virus. This discovery came during the course of 2 studies that began in 2016 after the large Ebola outbreak in West Africa.

Both studies set out aiming to identify the reservoir of Ebola virus. One is led by the CDC and Njala University in Freetown, Sierra Leone. The other is led by the University of California, Davis, and the University of Makeni in Sierra Leone, and is funded by the United States Agency for International Development.

The CDC statement indicates that testing of 4 of the Marburg virus-positive bats identified genetically diverse strains, suggesting that the virus has been in Sierra Leone bat colonies for many years. In addition, 2 of these 4 strains are genetically similar to the one linked with the largest and deadliest Marburg outbreak that occurred in Angola in 2005. And this marks the first report of these Angolan strains in bats, CDC says.

At the time of the CDC statement, there had been no reported cases of human Marburg virus in Sierra Leone. Nevertheless, the presence of the virus in fruit bats in the area now poses a public health threat to the people there.

“This discovery is an excellent example of how our work can identify a threat and help us warn people of the risk before they get sick,” Jonathan S. Towner, PhD, who led the CDC team in one of the projects, concluded in the statement.

Investigators have identified Marburg virus in Sierra Leone bats, marking the first time the hemorrhagic fever has been discovered in West Africa.