ASP Scan (Weekly) for Feb 16, 2018

Carbapenem-resistant infections
Hospital stewardship savings
MCR-1 in Italy, Hong Kong
Fast track for ESBL inhibitor
MDR-TB drug combo
End-of-life antibiotics
ID physicians and stewardship
Contact precautions for MRSA, VRE
Farm antibiotic use

Our weekly wrap-up of antimicrobial stewardship & antimicrobial resistance scans

Trial finds no benefit of combo drugs for severe carbapenem-resistant infections

In patients hospitalized with serious infections from carbapenem-resistant gram-negative bacteria, a combination of colistin and meropenem wasn't associated with fewer clinical failures compared with colistin alone, researchers reported today in The Lancet Infectious Diseases.

The randomized controlled open-label trial was conducted from October 2013 through December 2016 and included 406 patients from six hospitals in Israel, Greece, and Italy who mainly had ventilator-associated pneumonia, hospital-acquired pneumonia, or bloodstream infections caused by carbapenem-resistant Acinetobacter baumannii.

Among the group, 156 were randomized to colistin alone and 152 received colistin plus meropenem. After evaluating the patients 14 days after treatment, the researchers found no significant difference in clinical failure between the two groups. They observed that combination therapy increased diarrhea incidence but decreased the incidence of mild renal failure.

The team concluded that the combination treatment wasn't superior in severe A baumannii infections and that the trial wasn't powered to assess the impact on other bacteria.

In a related commentary in the same issue, two experts from the Case VA Center for Antimicrobial Resistance and Epidemiology and Case Western Reserve University School of Medicine in Ohio wrote that the findings are consistent with other similar studies of colistin combination therapies.

They said the findings don't close the door on combination therapy for carbapenem-resistant A baumannii or other gram-negative bacteria, because certain genotypes or phenotypes may respond differently to combination therapy. The authors also said they are awaiting results of another trial that may be better powered to assess carbapenem-resistant Enterobacteriaceae or Pseudomonas aeruginosa.
Feb 16 Lancet Infect Dis abstract
Feb 16 Lancet Infect Dis commentary


Review: Stewardship could save millions of days of antibiotic therapy

Experts from the Centers for Disease Control and Prevention (CDC), in a letter yesterday in Infection Control and Hospital Epidemiology, estimated that antibiotic use could be cut 16%—resulting in saving 16 million days of therapy—if effective antimicrobial stewardship programs (ASPs) are implemented in adult acute-care hospitals the United States.

The team analyzed date from 13 studies that reported the effects of ASPs on total antibiotic use in adult US acute-care hospitals. They then applied the median and interquartile range (IQR) to the 2012 national estimate of adult antibiotic use in such hospitals obtained from a national database.

They determined a median decline of 15.8% in 2012 (IQR, 0 to 27.3%). This would save 18 million days of antibiotic therapy (IQR, 0 to 28 million).

"This number does not include other important improvements that could be made, such as narrowing the spectrum of therapy and shortening postdischarge efforts," they concluded. "Hospital stewardship programs should be supported in their efforts to protect patients from preventable harms caused by unnecessary antibiotic exposure."
Jan 15 Infect Control Hosp Epidemiol letter


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

Originally published by CIDRAP News Feb 14

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

Originally published by CIDRAP News Feb 14

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

Originally published by CIDRAP News Feb 14

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

Originally published by CIDRAP News Feb 14

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 (WHO) 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


Survey suggests end-of-life situations affect views on antibiotic use

Originally published by CIDRAP News Feb 12

The results of a survey of physicians published today in Infection Control and Hospital Epidemiology indicate that when treating patients at the end of life, physicians' decisions about continuing antimicrobial use are influenced by many factors.

The 51-item survey containing both closed and open-ended questions on end-of-life antimicrobial use—estimated by some studies to be as high as 87%—was administered to physicians affiliated with the University of Pennsylvania and Children's Hospital of Philadelphia from January through April 2017. The objective was to examine reasons why physicians continue or discontinue antibiotics at end of life, and whether they prefer to continue antibiotics use in certain situations.

Of the 637 physicians surveyed, 283 (44.4%) responded. Most physicians agreed that overuse of antibiotics contributes to antibiotic resistance (96.1%) and that medical practitioners have a responsibility to reduce the use of unnecessary antibiotics (99.3%), but less than half (49.8%) agreed that antibiotic use in end-of-life care contributes to resistance. In addition, 86.2% responded that it was important to respect a patient's request to continue antibiotic treatment for an infection at the end of life.

For every infection surveyed, a higher proportion of pediatricians said they would often or always continue antibiotic treatment for active infections, and 19.9% of pediatricians said they would often or always continue antibiotic therapy for patients in hospice care whose death was imminent, compared to 2.7% of adult physicians. Analysis of free-text answers by 73 respondents revealed three overarching answers for continuing antibiotic therapy at end of life: to avoid being seen as withholding treatment, to prolong life in the face of diagnostic uncertainty, and to reduce pain.

"In conclusion, many factors, including patient-centeredness, workplace culture, and clinical considerations, contribute to the decision framework that physicians utilize when prescribing antimicrobials at the end of life," the authors write. They suggest further research is needed to assess the attitudes and factors that shape decision-making in order to guide antibiotic recommendations at the end of life.
Feb 12 Infect Control Hosp Epidemiol study


Paper explains why ID physicians should lead ASPs

Originally published by CIDRAP News Feb 12

A new white paper by members of the Infectious Diseases Society of America, the Society for Healthcare Epidemiology of America, and the Pediatric Infectious Diseases Society makes the case that infectious disease (ID) physicians are best-suited to lead ASPs.

The paper, published today in Clinical Infectious Diseases, argues that ID physicians possess unique experience and skills by virtue of their training that make them a natural choice for leading ASPs and maximizing the potential of members of multidisciplinary ASP teams. Among their skills  are expertise in monitoring and managing patients with infections across all healthcare settings, comprehensive knowledge of antimicrobial use and adverse consequences, knowledge of microbiologic principles that inform rational prescribing, and the ability to drive quality improvement. And because ID physicians also frequently serve in both formal and informal leadership roles in quality improvement and patient safety initiatives, they are accustomed to managing multidisciplinary teams and recognizing opportunities for change and improvement.

"ASP ID physicians can influence antimicrobial prescribing patterns by raising awareness of harms associated with unnecessary antimicrobial use and by drawing on their experience as leaders of multidisciplinary teams to build trust and consensus," the authors write.

The paper goes on to cite several examples of robust results achieved by ID physician-led ASPs, including significant reductions in broad-spectrum antibiotic use, antimicrobial days of therapy, antimicrobial costs, and Clostridium difficile rates. It also provides suggestions for arrangements that can extend the reach of ID physicians to facilities with limited resources, such as telemedicine programs and contractual agreements that permit ID physicians to combine off-site leadership with limited in-person visits.

The authors add that ASP teams should also include ID pharmacists, nurses, microbiologists, and infection preventionists, and that team members should be provided with appropriate resources.
Feb 12 Clin Infect Dis paper


Commentary supports use of gloves and gowns for MRSA, VRE

Originally published by CIDRAP News Feb 12

A commentary today in the Journal of the American Medical Association (JAMA) argues that despite the lack of a strong clinical evidence base and concerns about costs and impact on patients, contact precautions remain an important strategy for infection prevention, particularly for endemic methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococci (VRE).

In recent years, large clinical trials have failed to clarify whether the use of gloves and gowns is an effective strategy for preventing transmission of all types of drug-resistant pathogens, and as a result, there have been some calls for more selective use of contact precautions in settings of endemic MRSA and VRE. But the authors of the paper argue that contact precautions have an important role in clinical care and infection control. In particular, they cite a decline in healthcare-associated MRSA infections in the United States and Europe over the past 10-12 years that has coincided with the implementation of infection-control practices that include contact precautions, along with hand hygiene and active surveillance.

The authors say part of the problem is estimating the effectiveness of contact precautions is hard. That's because contact precautions are rarely used as the sole infection-prevention intervention in healthcare settings, so it's difficult to isolate their impact in observational studies. But they argue there are rational reasons to believe they play an important role in preventing pathogen transmission. Among them is the fact without the use of gloves and gowns, multidrug-resistant pathogens like MRSA would end up on healthcare workers' clothing and hands, and some proportion of those organisms would get transmitted to patients given the lackluster adherence to hand hygiene.

They also contend that while contact precautions may be burdensome to healthcare workers and may affect patient flow, studies have shown that use of contact precautions does not cause more adverse events or increase anxiety or depression among patients.

"Current evidence suggests that more rigorous evaluation of infection-prevention practices is needed before easing the use of CP in settings of endemic MRSA and VRE," the authors write. "Facilities should increase efforts to prevent the transmission of pathogens that can cause serious infections, not decrease them."
Feb 12 JAMA commentary


US farm antibiotic use 5 times higher than in UK, report says

Originally published by CIDRAP News Feb 12

US farmers use almost five times the amount of antibiotics their UK counterparts use, according to a new report from the Alliance to Save Our Antibiotics (ASOA).

ASOA experts based their calculations on species data published by the UK's Veterinary Medicines Directorate and the US Food and Drug Administration, supplemented by recent data published by British supermarkets. They found that antibiotic use in the United States is 9 to 16 times higher per beef steer, 3 times higher for chickens, almost twice as high for pigs, and 5.5 times higher for turkeys than it is in the United Kingdom.

For all food animals, the US/UK ratio was 4.9, or about five times higher.

"We should note that one reason for the fivefold difference in overall farm antibiotic use between the two countries is that the UK has many more sheep than the US, and sheep are low users of antibiotics," the authors of the report write. "Nevertheless, as we have seen in this document, large differences also exist in each animal species, particularly cattle."

"At present, the European Union has a ban on the importation of US beef, due to the use of growth hormones in the cattle in the US," the authors add. "However, post-Brexit, there exists the possibility that the UK will allow US beef to be imported as part of a trade deal with the US. The finding that antibiotic use in US cattle is 9 to 16 times higher than it is in British cattle, raises further concerns about the ways in which US beef is produced, and the potential dangers it may pose to consumers."

Kath Dalmeny of the Sustain food and health charity, said in an ASOA news release, "Cheap meat comes at a high price—often lower standards of cleanliness, animal welfare and high use of antibiotics. Any trade deals must aim to support high standards so that human and animal health and welfare are protected."
Feb 8 ASOA report
Feb 8 ASOA news release

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