ASP Scan (Weekly) for Jul 27, 2018

Iowa State AMR research center
Gram-negative ICU infections
Firm pares antibiotic R&D
Antibiotics for kids' LRTIs
Colistin resistance risk factors
Antifungal use in US hospitals
Pathogens in hurricane floodwaters
Antibiotic resistance in leeches
Candida auris uptick
MCR-1 on hospital surfaces
Antibiotic use in livestock
Forgotten antibiotics
ESBL colonization in travelers
Antibiotic redosing
Resistance trends in Swiss nursing homes
Antibiotic legislation nixed

Iowa State to host new antimicrobial resistance research center

Iowa State University will lead a new research institute to address antimicrobial resistance, with partners including the US Department of Agriculture (USDA), two other universities, and the Mayo Clinic, Iowa State said in a news release yesterday.

The Institute for Antimicrobial Resistance Research and Education will be based at the Ames campus and was created through a joint task force from the Association of Public & Land-Grant Universities and the Association of American Veterinary Medical Colleges. The center will receive $1.6 million in funds for its first 3 years and will seek to improve the health of people, animals, and the environment. Iowa State was chosen among eight applicants.

"Antimicrobial resistance touches each of us in our daily lives. This new institute provides a great resource for the entire country as we work to build strong, collaborative research and educational programs to mitigate this risk,” said Paul Plummer, DVM, associate professor of veterinary diagnostic and production animal medicine at Iowa State who will serve as the new center's director.

Iowa State researchers will coordinate efforts with scientists with the USDA Agricultural Research Service, the University of Nebraska-Lincoln, University of Nebraska Medical Center, the University of Iowa, and the Mayo Clinic.
Jul 26 Iowa State news release


ICU pathogens often gram-negative, mostly susceptible to antibiotics

An analysis of 6,091 bacterial isolates from the intensive care units (ICUs) of 75 US medical centers in 2015 through 2017 determined that 67% were gram-negative bacteria, and all but two pathogens demonstrated high susceptibility to common antibiotics, according to a study today in the Journal of Antimicrobial Chemotherapy.

Researchers from JMI Laboratories in North Liberty, Iowa, tested the samples, collected as part of the International Network for Optimal Resistance Monitoring program, for susceptibility to multiple antimicrobial agents using broth microdilution. The most common organisms were Staphylococcus aureus (30.0%), Pseudomonas aeruginosa (20.7%), Klebsiella (11.8%), Enterobacter (8.3%), Escherichia coli (7.1%), and Stenotrophomonas maltophilia (5.1%).

Gram-negative bacteria were isolated from 67.1% of the patients, the researchers noted, and P aeruginosa and Enterobacteriaceae represented more than 80% of gram-negative organisms.

The most effective agents against P aeruginosa were colistin (99.8% susceptible), ceftazidime/avibactam (96.8% susceptible in 2015-17 and 96.2% in 2017) and ceftolozane/tazobactam (96.5% in 2017). The most effective drugs against Enterobacteriaceae were ceftazidime/avibactam (100.0% susceptible), amikacin (99.4%) and meropenem (97.6%). S maltophilia and Acinetobacter baumannii, in contrast, showed high resistance rates to most antimicrobials tested.
Jul 27 J Antimicrob Chemother abstract


Drug firm cuts R&D efforts against gram-negative MDR bacteria

Drug developer Achaogen announced in a news release yesterday that it is cutting antibiotic research and development (R&D) to focus on commercializing Zemdri (plazomicin) and other efforts, further narrowing the drug development pipeline.

The company, based in South San Francisco, Calif., and geared toward developing agents against multidrug-resistant gram-negative bacteria, said it is restructuring to focus on selling Zemdri in the United States after Food and Drug Administration approval for the drug's treatment of complicated urinary tract infections and on pursuing approval for Zemdri in Europe. Its R&D efforts will focus on developing C-Scape, an orally administered beta-lactam/beta-lactamase inhibitor combination, and new aminoglycoside antibiotics, both of which have stable funding.

Achaogen will cut spending on early-stage R&D , technical operations, and other expenses. It will lay off about 80 workers, or 28% of its workforce, including some top executives.

"The environment for novel antibacterials requires us to improve our cost structure and narrow our focus to position the company for long-term success," said Achaogen CEO Blake Wise, MBA. "I am saddened to announce a restructuring that broadly impacts the organization, including high caliber partners on the executive team."
Jul 26 Achaogen press  release


Small Chinese study analyzes optimal azithromycin in kids with LRTIs

A small study today in the Journal of Antimicrobial Chemotherapy shows the clinical benefits of early target attainment with azithromycin therapy in children with lower respiratory tract infections (LRTIs).

In the study, conducted at Beijing Children's Hospital from 2014 through 2017, 44 children with LRTIs were analyzed to assess and optimize antibiotic therapy. To evaluate target attainment, azithromycin trough levels were collected within the first 2 calendar days of hospitalization, and the relationship between trough concentrations during the first 24 to 48 hours and effectiveness and safety was explored.

The results showed that children with trough concentrations higher than 0.25 milligrams per liter (n= 8) had better antibacterial efficacy in terms of C-reactive protein (P = 0.006) and the percentage of neutrophils (P = 0.043) compared with children with trough concentrations lower than 0.25 mg/L (n = 36). No drug-related adverse events were associated with azithromycin therapy.

The authors say prospective trials in a large pediatric population are needed to confirm this observation.
Jul 27 J Antimicrob Chemother study


Carbapenem use identified as risk factor for colistin-resistant bacteria

Originally published by CIDRAP News Jul 26

In a paper today in Eurosurveillance, Swiss researchers report that prior exposure to carbapenems was the only risk factor for colonization or infection in patients with colistin-resistant E coli or Klebsiella pneumoniae.

In the retrospective matched case-control study, researchers at two university-affiliated hospitals in Basel, Switzerland, analyzed more than 10,000 E coli and K pneumoniae isolates collected over a 5-year period for susceptibility to colistin. Forty-two patients (33 with colistin-resistant E coli and 9 with colistin-resistant K pneumoniae) were identified, and they were matched with 126 control patients.

The results showed that baseline characteristics, prior comorbidities, prior exposure to antibiotics, and healthcare settings did not differ between cases and controls. Only two of the patients had previous exposure to colistin. Prior exposure to carbapenems, along with a stay abroad and hospitalization, was found to be associated with colistin resistance. In multivariable analysis, however, only prior exposure to carbapenems remained as a risk factor for colonization with colistin-resistant E coli or K pneumoniae (odds ratio, 5.00).

The authors of the study conclude that the associations between prior carbapenem exposure, as well as the concomitant resistance to quinolones, fosfomycin, and tobramycin identified in the colistin-resistant isolates, suggests that low-grade dissemination of colistin-resistant Enterobacteriaceae in human is mainly fueled by selection pressure occurring in patients exposed to different antimicrobials.

"Our findings suggest that sources of colistin-resistant Enterobacteriaceae may be present in the absence of widespread colistin use in human medicine and that selection pressure constitutes an important driver for the occurrence of colistin-resistant strains in clinical isolates," they write.
Jul 26 Eurosurveill research article


Study finds decline in antifungal use at US hospitals

Originally published by CIDRAP News Jul 26

Researchers with the US Centers for Disease Control and Prevention yesterday reported a small but statistically significant decrease in antifungal use among inpatients at US acute care hospitals.

The study, published in the Journal of Antimicrobial Chemotherapy, looked at data from a nationwide hospital drug database from 2006 through 2012. Over the 7-year period, 2.7% of all inpatients and 7.7% of all intensive care unit (ICU) patients received an antifungal. The overall antifungal days of therapy (DOT) for all study years combined was 35 per 1,000 patient-days, with antifungal DOT in ICUs more than twice as high compared with non-ICUs (73.7 vs. 31.0 DOT/1,000 patient-days). Azoles, primarily fluconazole, were the most frequently used antifungal class, followed by echinocandins.

Multivariable trend analysis showed an 18.2% decrease in overall antifungal use during 2006 through 2012 as measured by DOT, with azole use decreasing by 21% and polyene use decreasing by 47%; echinocandin use rose by 11% from 2006 to 2010, but then declined afterward. Unspecified septicemia, HIV, and antineoplastic therapy were among the top primary diagnosis codes for patients who received antifungal therapy.

The authors of the study say the declines in antifungal use do not necessarily mean that antifungals are being used appropriately, since they were not able to assess appropriateness in the study. Nor does it mean that antifungal stewardship efforts are not needed. They conclude that further monitoring and studies of antifungal use are needed to determine where antifungal stewardship efforts could have the most impact.
Jul 25 J Antimicrob Chemother abstract


Post-hurricane floodwaters found to harbor pathogens, resistance genes

Originally published by CIDRAP News Jul 26

An analysis of floodwaters in the months after Hurricane Harvey hit Texas last summer has found elevated levels of E coli and other pathogens and a higher abundance of antibiotic resistance genes, according to a new study in Environmental Science and Technology Letters.

In the study, researchers from Rice University and Virginia Tech surveyed microbial communities in bayou water, floodwater inside and outside residences, and residual bayou sediment collected post-flood. In two of Houston's major bayous, they found that levels of E coli 3 days post-flood were significantly higher than historic levels, and that immediate post-flood levels of E coli were significantly higher than those measured in samples collected over 2 months after the hurricane.

Six-month monitoring of one of the bayous showed that the relative abundances of two antibiotic resistance genes, sul1 and intI1, were highest immediately after the flood. This likely resulted from the discharge of untreated or partially treated sewage from wastewater treatment plants.

The researchers also found that the abundances of fecal indicator bacteria (E coli and enterococcus) and other pathogenic bacteria (Aeromonas, Klebsiella, Legionella, and Salmonella) were significantly higher in stagnant indoor water (from homes that were closed off more than 1 week) than in street water, bayou water, and open indoor water, while sul1 and intI1 genes in closed indoor waters were more abundant than in street water or bayou water. In addition, pathogenic gene markers were more abundant in floodwater sediment deposited in residential areas and public parks than in deep soil cores, and the pathogen profiles were different from those found in floodwaters and bayou waters.

The authors conclude, "Overall, the epic flooding caused by Harvey temporarily shifted the local microbial landscape, increasing the levels of gene markers for pathogenic bacteria, multiantibiotic resistance, and its extent of dissemination in the flooded areas."
Jul 23 Environ Sci Technol Lett abstract


Study finds very low levels of antibiotics in leeches lead to resistance

Originally published by CIDRAP News Jul 25

Very low levels of antibiotics in the gut of leeches used in medicine are enough to promote antibiotic-resistant bacteria—and exposure to the leeches led to resistant infections in plastic surgery patients—an international group of researchers reported yesterday in mBio.

In 2011, plastic surgeons began reporting patients who had infections with Aeromonas bacteria resistant to the key antibiotic ciprofloxacin (Cipro). And at about the same time, University of Connecticut (UConn) microbiologist Joerg Graf, PhD, the senior author of the study, found that a strain of Aeromonas that usually thrives in leeches was not surviving well in their gut.

Graf and his team analyzed the medicinal leeches, which are used to reduce swelling in plastic surgery patients. They found, according to Graf, "Without ever having been in a hospital, without having seen a patient, these leeches contained Cipro-resistant bacteria." But the amount of antibiotic present in the leeches was extremely low, about 0.01 micrograms (mcg) per milliliter (mL), 400 times less than the concentration a bacteria must survive in order to be considered "resistant," according to a UConn news release.

The researchers traced the presence of the antibiotic to poultry blood on which the leeches had fed.

To determine whether such low levels of ciprofloxacin were truly causing antibiotic resistance, the scientists sequenced the genomes of Aeromonas from leeches contaminated with antibiotics. They found that they contained the three bits of DNA necessary for resistance to ciprofloxacin.

In addition, when the ciprofloxacin-resistant Aeromonas were grown alongside a test strain of Aeromonas in a clean lab medium or inside a leech, the test strain grew all over them. But if there was even a tiny bit of antibiotic added into the mix, as low as 0.01 mcg/mL, the ciprofloxacin-resistant strain dominated.
Jul 24 mBio study
Jul 24 UConn news release


CDC reports uptick in Candida auris cases

Originally published by CIDRAP News Jul 25

The United States now has 340 confirmed cases of Candida auris, according to an updated case count from the Centers for Disease Control and Prevention (CDC). While the total case count remains fairly low, it's risen by 29 since May and nearly doubled since November 2017.

As of Jun 30, infections by the multidrug-resistant fungus have been identified in healthcare facilities in 11 states, with most cases reported in New York (196), New Jersey (79), and Illinois (46). Cases have also been reported in Massachusetts (7), Florida (3), Maryland (3), Oklahoma (2), California (1), Connecticut (1), Indiana (1), and Texas (1). All cases represent laboratory-confirmed C auris infections, with an additional 29 cases are listed as probable, 22 of them in New Jersey.

The CDC also said that 643 patients have been found to be colonized with C auris, detected through targeted screening in four states reporting clinical cases. The screening is being conducted as part of an effort to control the spread of the pathogen, which can persist on surfaces in healthcare facilities and spread between patients.

In patients with compromised immune systems, C auris can cause serious invasive infections affecting the bloodstream, heart, brain, ear, and bones. More than 1 in 3 patients with invasive C auris infections die. The fungus, which was originally reported in Japan in 2009, has shown resistance to the three major classes of antifungal drugs used to treat Candida infections.

C auris cases have been reported in 30 countries.
Jul 23 CDC case count update


Study: Italian hospital surfaces harbor MCR-1 genes

Originally published by CIDRAP News Jul 25

A new study shows that 8.3% of tested surfaces in eight Italian hospitals harbor the MCR-1 gene, which confers resistance to colistin, an antibiotic of last resort. The research is published in Emerging Infectious Diseases. 

Researchers conducted the study in an effort to establish the diffusion of the MCR-1 gene in healthcare settings. They collected 300 surface samples from the hospitals in 2016 and 2017, from the floor, bed footboard, and sink. A total of 25 (8.3%) of the samples had pathogens containing the MCR-1 gene.

"Identification results indicated that different species harbored the mcr-1 gene, including [Klebsiella] pneumoniaeK. oxytoca[Escherichia] coliAcinetobacter IwoffiiEnterobacter cloacaeE.agglomeransCitrobacter freundiiPseudomonas aeruginosa, and P. putida. These results suggest that this gene is silently spreading to many gram-negative bacteria responsible for infections in the clinical settings," the authors said.

MCR-1-associated colistin resistance was first reported in Italy in 2015, in an Escherichia coli strain. The gene is found in approximately 10% of animal isolates and in 0.1% to 2% of human isolates globally, the authors wrote.

This study suggests hospital surfaces represent a possible reservoir of serious antibiotic-resistant nosocomial pathogens.
Jul 23 Emerg Infect Dis study  


Report: US seeking weaker global guidelines for antibiotic use in livestock

Originally published by CIDRAP News Jul 24

The Trump administration is working behind the scenes to weaken global recommendations on antibiotic use in food-producing animals, according to a story yesterday in Bloomberg.

Bloomberg reports that US officials are helping to shape the recommendations through the Codex Alimentarius Commission, an agency that develops food standards and guidelines for international trade. The US is leading a working group to update guidelines for antibiotic use along the food chain.

According to a draft document obtained by Bloomberg, the recommendations from the group are weaker than those put forth in a report by the World Health Organization (WHO) in November 2017. While the WHO called for an end to the use of medically important antibiotics for growth promotion and disease prevention in healthy food-producing animals, the draft document suggests medically important antibiotics could still be used for disease prevention. In addition, the draft contains a loophole that would allow antibiotics to be used for growth promotion, a practice that's banned in the United States and other countries.

The US Department of Agriculture has criticized the WHO report, arguing that the recommendations are not supported by sound science. 
Jul 23 Bloomberg story
Nov 7, 2017, CIDRAP News story, "WHO calls for an end to antibiotic use in healthy animals"


Open-access database of forgotten antibiotics launches

Originally published by CIDRAP News Jul 24

Today UK researchers launched AntibioticDB, a free, open-access database of forgotten antibiotics in hopes of generating new leads in the fight against antimicrobial-resistant pathogens.

The searchable database brings together many once-promising leads from the past 50 years that have for various reasons stalled or been dropped, according to a news release from the John Innes Centre (JIC). The team behind AntibioticDB, led by Prof Laura Piddock of the University of Birmingham, argue that discontinued agents are an untapped resource that has been overlooked for drug development.

The researchers used a range of sources to identify compounds of interest, including leaders in the pharmaceutical industry and other key scientists. They obtained information on each compound or drug using online searches, literature archives, and interviews with experts. They include other data, as well, such as reasons for the lack of development.

Piddock said, "It can take up to 15 years and cost up to $5 billion from the discovery of a compound to progress through pre-clinical and clinical development before a medicine can be licensed and then marketed. There is no doubt that the antibiotic pipeline needs revitalization; however, the answer may be not only the development of new drugs, but also re-investigating compounds previously discontinued."

The team detailed its efforts last month in the Journal of Antimicrobial Chemotherapy.
Jul 24 JIC news release
Jun 11 J Antimicrob Chemother report

AntibioticDB website


Study notes highest rate of ESBL colonization in travelers to North Africa

Originally published by CIDRAP News Jul 24

A systematic review of three studies involving data on extended-spectrum beta-lactamase-producing Enterobacteriaceae (ESBL-PE) among travelers from Europe to Africa found that the ESBL-PE colonization rate was highest in North Africa, according to a study yesterday in BMC Infectious Diseases.

The studies were conducted from 2009 through 2013 and involved 396 Finnish and Dutch travelers. The researchers also compared the data to two recent large investigations reporting data by subregion and country in Africa.

The ESBL-PE colonization rate was highest in North Africa, followed by middle and eastern Africa, and lowest in southern and western Africa. Of individual countries with more than 15 visitors, the highest rates were seen for Egypt (12/17, 70.6%), Ghana (6/23, 26.1%), and Tanzania (14/81, 17.3%). The rate among travelers to Egypt is comparable to those reported in South and Southeast Asia, the authors write.

They conclude, "Even in areas with relatively low risk of colonization, antimicrobials clearly predispose to colonization with ESBL-PE. Travellers to Africa should be cautioned against unnecessary use of antibiotics."
Jul 23 BMC Infect Dis study 


Study: Intervention improves intraoperative antibiotic redosing

Originally published by CIDRAP News Jul 23

A multipronged project to improve intraoperative antibiotic redosing led to dramatic and sustained improvements in antibiotic redosing rates at an Iowa hospital, according to a new study in the American Journal of Infection Control.

The quality improvement project at University of Iowa Hospitals and Clinics began in 2015 with the introduction of a guideline-based intraoperative Antibiotic Administration Guide that listed recommendations for antibiotic choice by surgical category on one side and redosing recommendations on the other. The guide was distributed to anesthesia providers, and multiple education sessions were held for anesthesia providers, surgeons, nurses, and pharmacists who work regularly in the operating room. In addition, an automated redosing reminder was included in anesthesia electronic health records (EHRs). The department of anesthesia reported antibiotic redosing rates monthly to hospital leadership to encourage peer accountability and feedback.

In the retrospective observational study, a total of 13,695 surgical procedures performed from 2013 through 2017 were assessed using an interrupted time-series model. The compliance rate with intraoperative antibiotic redosing criteria for all surgeries lasting more than 4 hours was the primary outcome. Although the interrupted time-series model showed there was an already improving trend prior to the multifaceted intervention (incidence rate ratio [IRR], 1.004 per week), a 15% increase in appropriate antibiotic redosing rates (IRR, 1.158) was observed at the end of the intervention, with no compromise in the baseline improvement trend.

"Our experience demonstrates that combining EHR-based interventions with education and incentive models may help further improve compliance rates," the authors of the study conclude. They note that further studies to determine whether the intervention had an effect on clinically meaningful outcomes, such as surgical-site infections, are ongoing.
Jul 20 Am J Infect Control study


Antibiotic-resistant E coli increasing in Swiss nursing homes

Originally published by CIDRAP News Jul 23

An analysis of 10 years of resistance data from nursing homes in Switzerland found increasing levels of extended-spectrum cephalosporin-resistant (ESC-R) E coli, but with declining levels of methicillin-resistant S aureus (MRSA).

The study covers data from isolates sent to the Swiss Centre for Antibiotic Resistance from January 2007 to October 2017. Researchers from Switzerland published their findings in a Jul 20 online edition of Antimicrobial Resistance and Infection Control.

To explore carbapenem-resistance patterns in nursing homes among gram-negative bacteria, which included ESC-R E coli and K pneumonia, MRSA, and glycopeptide-resistant enterococci (GRE), the group looked at 16,804 samples from 9,040 patients, mostly from urinary sources. Most patients were from the French/Italian speaking part of Switzerland in the west and south.

ESC-R E coli increased from 5% in 2007 to 22% in 2017, while MRSA levels declined from 34% to 26% over the same period. Nitrofurantoin and fosfomysin retained high susceptibility rates against E coli, even for ESC-R isolates.

The researchers said a significant increase of ESC-R among E coli and K pneumonia mirrors an increase seen in the antibiotic resistance database for hospitals and outpatient clinics. The team also noted that the proportion of MRSA among S aureus isolates is also declining in hospitals.

The authors said the generalizability of their data is hampered by overrepresentation of the French/Italian speaking part of the country, but the prevalence of ESC-R E coli and K pneumoniaamong Swiss nursing homes has clearly been rising over the past decade. Also, they noted that more efforts should be taken to increase the number of nursing home samples from German-speaking parts of Switzerland to the resistance database.
Jul 20 Antimicrob Resist Infect Control abstract


PAHPA reauthorization moves forward, without new antibiotic incentive

Originally published by CIDRAP News Jul 23

A reauthorization of a pandemic preparedness bill approved last week by the US House Energy and Commerce Committee will not include an incentive aimed at spurring development of new antibiotics.

According to reporting by Stat, proponents of the incentive, the language of which was originally included in a bill titled the Re-Valuing Anti-microbial Products (REVAMP) Act of 2018, had hoped to have it inserted as an amendment to the reauthorization of the Pandemic and All-Hazards Preparedness Act (PAHPA), but that effort stalled. PAHPA, originally passed in 2006, now heads for a vote in the full US House of Representatives.

The proposed incentive would award drug companies that develop a priority antimicrobial product an extra 12 months of market exclusivity that could be used for another drug product. Companies could also extend market exclusivity for several drugs for less than a year. In return, drug makers would have to track resistance data, develop guidelines and procedures for appropriate use, and assess stewardship of the new antibiotic.

Backers of the idea view it as an important "pull" incentive that could spur antibiotic development. But as Stat reports, a coalition of physicians, hospitals, insurers, and pharmacy benefit managers, concerned that the incentive would delay patient access to cheaper generic drugs, urged Congress not to include the proposal in the PAHPA reauthorization.
Jul 18 Stat story
Jun 29 CIDRAP News story "Bipartisan bill proposes new 'pull' incentives for priority antibiotics"

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