Stewardship / Resistance Scan for Feb 14, 2018

News brief

Italian researchers identify 26 E coli isolates with MCR-1 resistance gene

Italian scientists this week reported detecting the MCR-1 colistin-resistance gene in 26 Escherichia coli isolates among more than 19,000 Enterobacteriaceae that they tested as part of surveillance efforts in Romagna in northern Italy.

Writing in the International Journal of Infectious Diseases, the researchers describe how they started a surveillance program to investigate the extent of colistin resistance in the region. Colistin is an important last-resort antibiotic for treating multidrug-resistant (MDR) infections. MCR-1 was first identified in in E coli from pigs, pork products, and humans in 2015 and has now been detected in more than 30 countries.

Among 19,053 Enterobacteriaceae isolates collected from Aug 1, 2016, through Jul 31, 2017, the team identified 90 (0.47%) that were resistant to colistin, including the 26 (0.14%) E coli isolates harboring the MCR-1 gene. The gene resides on mobile sections of DNA called plasmids and can be transferred to other pathogenic bacteria, which increases the concern.

The authors conclude, "Since the prevalence rate of carbapenem resistant Enterobacteriaceae (CRE) in some hospital wards in our area is alarming, we underline the importance of a Surveillance Program to monitor the spread of the plasmid-mediated colistin resistance genes into MDR Gram-negative bacteria."
Feb 12 Int J Infect Dis study

MCR-1 found in Hong Kong fecal samples, including from healthy people

In related news, Hong Kong researchers who analyzed more than 600 fecal samples report that they have detected 14 instances of MCR-1-positive E coli isolates, according to a study yesterday in BMC Infectious Diseases.

They included all 672 samples submitted from routine analysis from Oct 31 to Nov 25, 2016, at a regional hospital. The samples were collected from 616 patients.

They detected the 14 MCR-1-positive samples from 14 separate people by employing polymerase chain reaction testing and whole-genome sequencing (WGS). Nine of the patients were healthy people seeing a physician for routine check-ups.

All the isolates were susceptible to carbapenems, but two produced extended spectrum beta-lactamase, another indication of antibiotic resistance. WGS revealed that the isolates belonged to at least 12 different sequence types and possessed diversified plasmid replicons, virulence, and acquired antibiotic resistance genes.

The authors write that MCR-1 detection in healthy individuals "is alarming considering wide diversity and high transmissibility of mcr-1 plasmids, which potentially facilitate emergence of pan-drug-resistant bacteria in future infection."
Feb 13 BMC Infect Dis study

FDA grants Fast Track designation to novel ESBL inhibitor

Biopharmaceutical company Allecra Therapeutics today announced that the US Food and Drug Administration (FDA) granted Fast Track designation to the company for its novel extended-spectrum beta-lactamase (ESBL) inhibitor, AAI101.

AAI101 is designed to overcome the resistance of ESBL-harboring gram-negative hospital pathogens to current antibiotic therapies. According to a company press release, the Fast Track designation means a planned phase 3 trial of AAI101 combined with the antibiotic cefepime for the treatment of serious hospital-acquired infections will now begin this summer.

The FDA grants Fast Track designation to facilitate the development and expedite the review of drugs with the potential to treat a serious or life-threatening conditions and fulfill an unmet medical need.

Cefepime/AAI101 is currently in phase 2 clinical development for use in complicated urinary tract infections, complicated intra-abdominal infections, and hospital- and ventilator-acquired bacterial pneumonia.
Feb 14 Allecra Therapeutics press release

Preliminary study shows new drug combo justified for some with MDR-TB

Two new drugs available for treating multi-drug resistant tuberculosis (MDR-TB) offer hope for the disease, and the combined use of bedaquiline and delamanid are seen as a promising option, but concerns about cardiotoxicity of both drugs have kept the World Health Organization from recommending them. However, a small early trial from Doctors Without Borders scientists suggests that, under some conditions, the drug combination is justified for patients who have few treatment options.

Writing in The Lancet Infectious Diseases yesterday, the team said they analyzed 28 patients who were treated with the drug combo in 2016 in Armenia, India, and South Africa. Over 6 to 12 months, the pateints receieved 400 mg of bedaquiline once a day for 2 weeks, then 200 mg of bedaquiline three times a week plus 100 mg of delamanid twice a day.

Preliminary results show that the combination appears to be safe and can lead to high rates of culture conversion in patients who have had little treatment success in the past. One death was reported in a patient with HIV who had severe immunosuppression.

The researchers concluded that while waiting for the results of clinical trials to come in, which could take 3 years, the findings support using the combination in those who have few other treatment options. "Our data suggest that broadly withholding such access over theoretical safety concerns is no longer justifiable," the team wrote.

In a commentary on study in the same journal, three European infectious disease specialists wrote that the drugs don't appear to cause additive or synergistic cardiac effects and confirmed that the cardiac effect of bedaquiline may be lower than previously thought. They said the study confirms that, under specific conditions, the combination can be justified in some patients with few other options. The conditions include adequate expertise, monitoring capacities, access to a quality-controlled lab, and support by an expert team.
Feb 13 Lancet Infect Dis study
Feb 13 Lancet Infect Dis commentary

News Scan for Feb 14, 2018

News brief

China reports first human infection from novel H7N4 avian flu

China has reported the world's first known novel H7N4 avian flu infection in a human, according to a report today from Hong Kong's Centre for Health Protection (CHP), which based its information on a notification from the mainland's National Health and Family Planning Commission.

The patient is a 68-year-old woman from Jiangsu province whose symptoms began on Dec 25. She was hospitalized on Jan 1 and was discharged on Jan 22. An investigation revealed she had contact with live poultry before she got sick. None of the woman's close contacts had any symptoms during the monitoring period.

A genetic analysis by the Chinese Center for Disease Control and Prevention found that all the H7N4 virus genes were of avian origin, the CHP said. It added that all novel influenza A infections are notifiable diseases in Hong Kong and that, based on seasonal patterns, it expects avian flu activity to be higher in the winter.
Feb 14 CHP statement

Five-season study finds flu VE similar for older, younger adults

Flu vaccination offers similar effectiveness for younger and older adults, but protection was very low for both groups against the problematic H3N2 strain, researchers from the US Centers for Disease Control and Prevention (CDC) and several institutions that are part of a surveillance network team that analyzes flu vaccine effectiveness (VE) reported yesterday in Vaccine.

Reports on flu vaccine protection in older adults have been inconsistent, and to get a better picture, the group looked at effectiveness over five flu seasons—2011-12 through 2015-16—comparing effectiveness in younger adults ages 18 to 49 with that of different age-groups of seniors. Of 20,022 adults seen for acute respiratory infections at the surveillance sites during those five seasons, 24% tested positive for influenza.

VE in those age 65 and older was not significantly lower than that of younger adults against any subtype. Against the 2009 H1N1 virus, VE was 49% and 48%, respectively, and against influenza B, VE was 62% and 55%, respectively. However, against H3N2, protection was low for both groups: 14% (and not statistically significant) for adults age 65 and older and 21% in the younger age-group. The investigators didn't find decreasing VE in adults age 75 and older compared with those 65 to 74.

The researchers didn't find any significant interaction of age and vaccination when they looked at prior vaccination status.

Though they didn't find lower VE in older adults, the team noted that immunogenicity studies have shown lower immune response in that age-group, with some showing waning response and VE over a single season. They said despite lower antibody response, the levels produced may still be enough to provide protection, perhaps along with antibodies from earlier years adding residual protection. The researchers said that improving flu VE for seniors and their younger peers still remains a priority.
Feb 13 Vaccine abstract

Fractional-dose yellow fever vaccine produces good immune response

A fractional dose of yellow fever vaccine, given to address shortages during a 2016 outbreak in the Democratic Republic of Congo (DRC), prompted a good immune response, researchers from the DRC and the CDC reported today in the New England Journal of Medicine.

The outbreak began at the end of 2015, starting in Angola and spreading to neighboring DRC. More than 7,000 suspected cases were reported between the two countries, 962 of them confirmed. The team recruited people from four age-groups at six sites in Kinshasa where the one-fifth-standard dose was given during the immunization campaign, which targeted 7.6 million children age 2 and older and nonpregnant adults.

The researchers measured yellow fever virus neutralizing antibody titers in blood samples obtained before vaccination, comparing them with samples taking at days 28 and 35 after vaccination. Of 716 people who completed follow-up, 98% had an immune response after vaccination. Of 493 who were seronegative at baseline, 98% showed evidence of seroconversion. However, in those who were seropositive at baseline, the percentage who had an immune response after vaccination was lower, at 66%.

The seroconversion was similar to earlier studies that measured the immune response of the full-dose yellow fever vaccine and in earlier clinical trials of the fractional dose that mainly included men. The team said they saw a slightly lower conversion rate in females than males, which has also been observed in clinical trials with the full-dose vaccine.

The authors concluded that the fractional dose is appropriate for response to yellow fever outbreaks and that more studies are needed to see if the method is protective in kids younger than 2, pregnant women, and people with HIV. They added that follow-up testing is under way to gauge protection up to 1 year after vaccination.
Feb 14 N Engl J Med report