ASP Scan (Weekly) for Oct 05, 2018

MRSA de-colonization of therapy dogs
Multiple Candida auris introductions
Early stewardship interventions
Bacteriophage clinical trial
Improper antibiotic prescribing in China
Point-of-care flu tests and antibiotics
New tetracycline approved
Combo antibiotic for CRE
Telemedicine and antibiotic prescribing
FDA approves new antibiotic
Linezolid resistance in food animals
Water consumption and UTIs

De-colonization of therapy dogs lessens risk of MRSA spread, study finds

A pilot study conducted by researchers at Johns Hopkins has found that using a special antiseptic shampoo and wipes to decolonize therapy dogs before and between visits with young cancer patients can reduce the transmission of methicillin-resistant Staphylococcus aureus (MRSA). The findings were presented today at IDWeek 2018.

In the study, the investigators sampled 45 cancer patients and four therapy dogs at Johns Hopkins Bloomberg Children's Hospital for the presence of MRSA before and after 13 therapy dog visits. Seven of those visits were control visits, in which the dogs were not decolonized; in the six intervention visits, the dogs were bathed with a chlorhexidine-based shampoo prior to visiting patients and were cleaned with chlorhexidine wipes between patient visits.

The hypothesis was that the dogs could be a vector for transmitting MRSA between patients. MRSA carriage in cancer patients is a concern because their weakened immune systems put them at greater risk of infection.

The investigators found that 4 of the 45 patients became MRSA carriers after the control visits, as did three of the dogs. Patients who interacted more closely with the dogs were six times more likely to be colonized with MRSA than those who didn't interact closely.

But during the six interventions visits, only one of the patients and two of the dogs became colonized, and the risk for MRSA transmission among patients who interacted closely with the dogs was significantly reduced. Overall, regardless of the level of interaction, the intervention reduced the risk of MRSA colonization in patients by 90%.

"While there was still a risk of children for children being involved in these therapy visits, because of their direct contact with other patients or other environments, it essentially removed the dog from the equation, which overall increased the safety of the visit," lead study author Kathryn Dalton, VDM, MPH, of Johns Hopkins Bloomberg School of Public Health, said at a press conference.

Dalton said they also observed many patient benefits from therapy-dog visits, including decreased stress levels and fewer reports of anxiety and pain. Because of the positive results, Dalton and her colleagues have received additional funding for a larger study involving multiple hospitals.
IDWeek 2018 abstract #160


Gene study supports multiple Candida auris introductions into US

Whole-genome sequencing of Candida auris isolates from patients in 10 US states suggests that the fungal strain came from four different global regions, reflecting multiple introductions into the country. A team led by researchers from the US Centers for Disease Control and Prevention's mycotic diseases branch reported its findings yesterday in The Lancet Infectious Diseases.

The group examined isolates collected from May 2013 through August 2017 from 133 cases, 73 of them clinical specimens and 60 screening samples. Of the clinical isolates, sequencing found that 90% were related to South Asian, 7% to South American, 1% to African, and 1% to East Asian isolates. Most isolates were from New York and New Jersey, and though they were related to South Asian C auris strains, most were genetically distinct.

Genetic comparison suggested that only 5 clinical case-patients (7%) likely contracted the fungus during healthcare exposure abroad. Genetic diversity within a patient was similar to that seen in facilities during outbreaks.

The investigators concluded that the findings shed light on fungus introduction and how it can occur following travel. They added that the genetic diversity among isolates from patients, states, and facilities adds evidence of local and ongoing transmission.

In a commentary in the same issue, Jacques Meis, MD, PhD, a mycologist from the Netherlands, and Anuradha Chawdhary, MD, PhD, a mycologist from India, wrote that the findings confirm earlier work that the global C auris population consists of four different clades that harbor nearly identical strains within each clade. They said the US cases don't represent a fifth clade but instead represent several introductions into the US healthcare system. They note that the travel-related cases identified in the study weren't the outbreak index cases, suggesting previous unrecognized presence and transmission of the fungus.

A major unanswered question is the reservoir for C auris outside hospitals, they note. Though the drivers of the spread are elusive, the two wrote that demographics, extensive fluconazole use in intensive care units, poor infection control, international travel, and medical tourism likely play a role in ongoing outbreaks.

"The stringent recognition of the problem and simultaneous implementation of precautions to prevent the spread of C auris among patients should be taken as seriously as in bacterial pathogens," they wrote.
Oct 4 Lancet Infect Dis abstract
Oct 4 Lancet Infect Dis commentary


Study finds stewardship intervention early in hospital stay may pay off

A single-center study in Japan determined that an intervention from an antimicrobial stewardship team earlier in a hospital stay was associated with significantly fewer antibiotics prescribed, a lower incidence of antimicrobial resistance, and reduced costs, according to a study yesterday in the International Journal of Infectious Diseases.

The retrospective study was conducted at Fukuoka University Hospital from April 2013 through March 2016. The researchers compared data among three study periods (SPs): SP1 (patients receiving antibiotics against MRSA and carbapenems for 14 or more days), SP2 (patients receiving specific antimicrobials for 14 or days), and SP3 (patients receiving specific antimicrobials regardless of the duration of treatment). The average timing of stewardship interventions ranged from 15.5 days after hospital admission in SP1 to 4.2 days in SP3.

The investigators determined that the antimicrobial use density of carbapenems and piperacillin-tazobactam decreased significantly (SP2 vs. SP3, P < 0.05), and the costs of specific antimicrobials decreased (SP1, $1,080,000; SP2, $944,000; SP3, $763,000). The rates of carbapenem resistance among Pseudomonas aeruginosa isolates showed a significant reduction from 16.2% in SP2 to 8.7% in SP3 (P < 0.05). The mortality rate and length of stay did not change during the study period.
Oct 4 Int J Infect Dis abstract


Topical phage treatment shows potential, weaknesses, in small clinical trial

Originally published by CIDRAP News Oct 4

The results of a small clinical trial in France show that a topical treatment containing a cocktail of bacteriophages successfully reduced bacterial burden in patients with infected burn wounds, but at a significantly slower rate than standard of care. The findings appeared yesterday in The Lancet Infectious Diseases.

In the randomized phase 1/2 PhagoBurn trial—the first randomized controlled trial to investigate phage therapy—25 patients with a confirmed burn wound that was clinically infected with Pseudomonas aeruginosa were recruited from nine hospitals in France and Belgium. The participants were randomly assigned 1:1 to receive topical treatment for 7 days with a cocktail of 12 natural lytic anti-P aeruginosa bacteriophages collected from hospital sewer water (PP1131) or standard of care (1% sulfadiazine silver emulsion cream). The primary end point was median time to sustained reduction in bacterial burden in two quadrants via a four-quadrant method, assessed by use of daily swabs in all participants.

Of the patients—recruited from Jul 22, 2015, to Jan 2, 2017—13 received  phage therapy and 12 received standard of care. The primary end point was reached in a median of 144 hours in the PP1131 group versus a median of 47 hours in the standard-of-care group (hazard ratio, 0.29; 95% confidence interval, 0.10 to 0.79; P = 0.018). In the PP1131 group, 6 of the 12 analyzable participants (50%) had a maximal bacterial burden versus 2 of 13 (15%) in the standard-of-care group. Adverse events were higher in the standard-of-care group (7/13, 54%) than in the PP1131 group (3/13, 23%). A follow-up study of bacteria isolated from patients whose PP1131 treatment failed showed resistance to low-phage doses.

Recruitment was stopped on Jan 2, 2017, because of concerns about patient exposure to insufficient phage concentration. On Mar 20, 2017, a data and safety monitoring board recommended stopping the trial because of the insufficient efficacy of PP1131.

The researchers say, however, that the clinically relevant reduction in bacterial burden observed in the group treated with the phage cocktail, and the smaller number of adverse events compared with standard of care, illustrate the potential of phage therapy.

"Although the effect was slower than in the control group, we found that our phage cocktail reduced bacterial burden in the infected wounds of patients with burns, one of the most difficult populations to treat, and something that, to our knowledge, has never been achieved in a human trial before," they write.
Oct 3 Lancet Infect Dis abstract


Study highlights high levels of inappropriate antibiotic prescribing in China

Originally published by CIDRAP News Oct 4

Chinese researchers employed actors pretending to be patients with one of three conditions that didn't require antibiotics and found that in 42% of 526 rural primary care encounters, physicians inappropriately prescribed the drugs anyway, according to a study today in the Journal of Antimicrobial Chemotherapy.

The study took place in village clinics and township health centers, the two lower tiers of China's three-tiered rural health system, in three geographically dispersed regions. The "patients" recruited for the study were trained to present cases of pulmonary tuberculosis, viral gastroenteritis, or unstable angina. The investigators also provided primary care providers with clinical vignettes to assess antibiotic prescribing habits.

The researchers found that providers inappropriately prescribed antibiotics in 221 of 526 patient visits, or 42% of the time. And compared with patient interactions, prescription rates were 29% lower in matching clinical vignettes (42% vs. 30%), suggesting practices don't always follow theoretical knowledge. Compared with vignettes assessing diagnostic and therapeutic knowledge jointly, prescribing rates were 67% lower in vignettes with the diagnosis revealed.

The authors conclude, "While a large proportion of overprescription may be due to factors such as financial incentives tied to drug sales and perceived patient demand, our findings suggest that deficits in diagnostic knowledge are a major driver of unnecessary antibiotic prescriptions."
Oct 4 J Antimicrob Chemother abstract


Point-of-care flu tests don't lower antibiotic prescribing, study finds

Originally published by CIDRAP News Oct 4

A meta-analysis today in Clinical Infectious Diseases of 13 studies involving point-of-care tests (POCTs) for influenza finds that they had no effect on admissions, return visits, or antibiotic prescribing but were associated with increased antiviral prescribing.

UK experts included in their review seven randomized and six non-randomized studies that involved more than 9,000 patients total. Most evidence came from pediatric emergency departments.

In randomized trials, POCTs had no effect on admissions, returning for care, or antibiotic prescribing, but they were tied to an increase in prescribing antivirals. In addition, further testing was reduced for full blood counts, blood cultures, and chest x-ray but not for urinalysis. Time in the emergency department was not changed. Fewer non-randomized studies reported these outcomes, with some findings reversed or lessened.

The researchers conclude, "Point-of-care testing for influenza influences prescribing and testing decisions, particularly for children in emergency departments."
Oct 4 Clin Infect Dis abstract


FDA approves new antibiotic for bacterial pneumonia, skin infections

Originally published by CIDRAP News Oct 3

The US Food and Drug Administration (FDA) yesterday approved Nuzyra (omadacycline) for the treatment of adults with community-acquired bacterial pneumonia (CABP) and acute bacterial skin and skin-structure infections (ABSSSIs), according to a press release yesterday from drug maker Paratek Pharmaceuticals.

Nuzyra is a "modernized" tetracycline that's designed to overcome tetracycline resistance and exhibits activity against gram-positive and gram-negative bacteria, atypicals, and drug-resistant strains. It comes in both intravenous and oral formulations.

"In the face of ever-increasing antibiotic resistance, the FDA approved Nuzyra with a label having full approval for both CABP and ABSSSI," Paratek president and chief medical officer Evan Loh, MD, said in the press release. "We are excited to bring to physicians an effective, well-tolerated monotherapy option for patients."

The approval was based on multiple clinical trials in which Nuzyra was found to be efficacious, safe, and well-tolerated in nearly 2,000 patients. Paratek plans to make the drug available in the first quarter of 2019.
Oct 2 Paratek Pharmaceuticals press release


Combo antibiotic for CRE infections performs well in phase 3 trial

Originally published by CIDRAP News Oct 2

The results of a phase 3 randomized, controlled clinical trial show that monotherapy with the antibiotic/beta-lacatamase inhibitor combination Vabomere (meropenem-vaborbactam) in patients with carbapenem-resistant Enterobacteriaceae (CRE) infections was associated with increased clinical cure, decreased mortality, and reduced kidney toxicity compared with the best available therapy (BAT). The results were published yesterday in Infectious Diseases and Therapy.

In the Targeting Antibiotic Non-susceptible Gram-negative Organisms (TANGO) II trial, 77 patients with confirmed CRE infection from 27 hospitals in eight countries were randomized 2:1 to receive meropenem-vaborbactam alone for 7 to 14 days or BAT (mono/combination therapy with polymyxins, aminoglycosides, tigecycline; or ceftazidime-avibactam alone). Forty-seven patients with confirmed CRE infection formed the primary analysis population. Efficacy end points included clinical cure, day-28 all-cause mortality, microbiologic cure, and overall success (clinical cure plus microbiologic eradication). The most common infection types were bacteremia and complicated urinary tract infections (cUTIs).

In the primary analysis population, cure rates were 65.6% (21/32) for patients receiving meropenem-vaborbactam and 33.3% (5/15) for BAT patients at end of treatment and 59.4% (19/32) and 26.7% (4/15) at test of cure. Day-28 all-cause mortality was 15.6% (5/32) and 33.3% (5/15) for meropenem-vaborbactam versus BAT, respectively. In the safety population, meropenem-vaborbactam was associated with fewer drug-related adverse events (24% [12/50] vs. 44% [11/25]), fewer serious adverse events (34% [17/50] vs. 44% [11/25]), and fewer kidney-related adverse events (4% [2/50] vs. 24% [6/25]) than BAT was.

Exploratory risk-benefit analyses of composite clinical failure or nephrotoxicity also favored meropenem-vaborbactam over BAT, 31.3% (10/32) to 80% (12/15).

The authors of the study conclude that the results indicate that meropenem-vaborbactam, which was approved by the US Food and Drug Administration in 2017 for use in cUTI patients based on results from the TANGO I trial, "will be a valuable addition to the antimicrobial armamentarium against CRE pathogens."
Oct 1 Infect Dis Ther study 


Telemedicine study finds antibiotic Rx linked with shorter encounters

Originally published by CIDRAP News Oct 1

Researchers from the Cleveland Clinic have observed that telemedicine encounters in which antibiotics were prescribed for a respiratory tract infection (RTI) were shorter than encounters where a non-antibiotic or nothing were prescribed.

In a study today in the Annals of Internal Medicine, the researchers reviewed 13,438 US telemedicine encounters from January 2013 through August 2016 to assess the association between prescription outcome and length of encounters for patients diagnosed as having RTIs, including sinusitis, pharyngitis, and bronchitis. Encounter length was defined as the time the patient was connected to and interacted with the physician. The adjusted difference in encounter length was determined using a mixed-effects linear regression model that controlled for patient characteristics, physician characteristics, and geographic concordance between patient and physician.

Physicians prescribed antibiotics in 67% of encounters, non-antibiotics in 13%, and nothing in 20%. The mean unadjusted encounter length was 6.6 minutes when antibiotics were prescribed, 8 minutes when non-antibiotics were prescribed, and 7.5 minutes when nothing was prescribed. In the adjusted model, encounters that resulted in nothing being prescribed were 33 seconds longer than those resulting in antibiotic prescriptions; those resulting in prescription of a non-antibiotic were 1.12 minutes longer than those in which an antibiotic was prescribed.

In addition, encounters for sinusitis and pharyngitis were found to be shorter than those for bronchitis and other RTIs, encounters with older patients were longer than those with younger patients, and encounters with physicians in the West took longer than those with physicians in the Northeast. The researchers were not able to determine the appropriateness of antibiotic prescribing.

The authors suggest the findings are noteworthy because prescribing non-antibiotics has been suggested as a way to improve patient satisfaction while avoiding unnecessary antibiotics. But the longer time needed to explain why an antibiotic isn't necessary could be an impediment, especially with telemedicine. They conclude, "Because telemedicine encounters are short and physicians are often reimbursed by encounter volume, antibiotic stewardship efforts that lengthen visits even slightly may be challenging to implement."
Oct 2 Ann Intern Med abstract


FDA approves new antibiotic under limited population pathway

Originally published by CIDRAP News Oct 1

The FDA has approved a new antibiotic for the treatment of lung disease caused by Mycobacterium avium complex (MAC), a nontuberculosis mycobacterium commonly found in water and soil.

The agency approved Arikayce (amikacin liposome inhalation suspension) for use in a limited population of patients who don't respond to conventional treatment. It's the first drug to be approved under the Limited Population Pathway for Antibacterial and Antifungal Drugs (LPAD), which was established by Congress as part of the 21st Century Cures Act to streamline development and approval of drugs to treat serious or life-threatening infections in a small population of patients who have no other treatment options.

"This pathway, advanced by Congress, aims to spur development of drugs targeting infections that lack effective therapies," FDA Commissioner Scott Gottlieb, MD, said in an FDA news release. "We're seeing a lot of early interest among sponsors in using this new pathway, and it's our hope that it'll spur more development and approval of antibacterial drugs for treating serious or life-threatening infections in limited populations of patients with unmet medical needs."

The safety and efficacy of Arikayce were demonstrated in a randomized, controlled clinical trial where one group of patients received the drug plus a background multidrug antibacterial regimen, and a second group received the multidrug antibacterial regimen alone. By the sixth month of treatment, 29% of patients who received Arikayce had no growth of mycobacteria in their sputum cultures for 3 consecutive months, compared with 9% of the patients who were not treated with Arikayce.

As required for drugs approved under LPAD, labeling for Arikayce will include statements conveying that the drug has been shown to be safe and effective for use only in a limited population of patients. 
Sep 28 FDA news release


Linezolid resistance genes found in cattle, swine enterococci

Originally published by CIDRAP News Oct 1

A study today by FDA and US Department of Agriculture (USDA) researchers is reporting the first known identification of linezolid resistance in bacteria from food-producing animals in the United States. The findings appear in the Journal of Antimicrobial Chemotherapy.

In an analysis of 500 bacterial isolates from food-animal cecal samples collected by the National Antimicrobial Resistance Monitoring System (NARMS) from 2013 through 2016, the researchers identified three isolates that were non-susceptible to linezolid, an oxazolidinone antibiotic that's used to treat vancomycin-resistant enterococci(VRE) infections in humans but is not used in animals. Two of the isolates were from cattle, including one each of Enterococcus faecium and E faecalis, and one E faecalis isolate was from a swine sample.

Whole-genome sequencing to determine the mechanisms underlying the resistant phenotypes revealed that all three isolates carried the linezolid resistance gene optrA, with one also carrying the cfr resistance gene. The genes were present on plasmids in all three isolates, and the E faecium isolate that possessed both optrA and cfr had them both on the same plasmid. In addition, the plasmid in the E faecium isolate also contained genes conferring resistance to aminoglycosides, macrolides, and phenicols.

The researchers note that while only three linezolid-resistant isolates were identified, the fact that they came from different sources and were genetically diverse suggests that linezolid-resistance plasmids are not limited to a distinct lineage of Enterococcus, and that resistant strains could independently emerge from different environments, including the food-animal environment. If these strains spread into humans, that could potentially threaten a critical antibiotic in human medicine.

"Although the presence of linezolid-resistant strains in food animals may not directly increase the risk of limiting the efficacy oxazolidinones in human therapy, people may become exposed to these bacteria through animal contact or contamination of food," the authors of the study write. "Now that we have identified linezolid resistance genes on plasmids that also carry other resistance genes, it remains to be seen whether these genes spread further through co-selection, clonal expansion, or other mechanisms."

The authors say investigators will continue to use NARMS to perform surveillance of linezolid resistance among enterococci from food animals and foods to identify any notable trends.
Oct 1 J Antimicrob Chemother abstract


Study: Drinking more water might prevent urinary tract infections

Originally published by CIDRAP News Oct 1

Women who drank more water were less likely to get urinary tract infections (UTIs) than controls and may be a way to reduce antibiotics, according to a study today in JAMA Internal Medicine.

The study involved 140 women who reported three or more UTIs in the previous year. Half of the women were encouraged to drink 1.5 liters of water daily for 12 months in addition to their normal beverages, and half were not. The women who drank more water saw a 50% reduction in UTIs. 

The mean number of cystitis (UTI) episodes was 1.7 (95% confidence interval [CI], 1.5-1.8) in the water group, compared with 3.2 (95% CI, 3.0-3.4) in the control group, with a difference in means of 1.5 (95% CI, 1.2-1.8; P < .001), the authors said. Overall, there were 327 cystitis episodes, 111 in the water group and 216 in the control group. The authors concluded by saying that increased water consumption is a useful tool for UTI prevention that limits antibiotic use.

In an accompanying editorial, JAMA editor Deborah Grady, MD, PhD, notes that the study was not blinded, and the results were self-reported. She also emphasized that the study was sponsored by Danone, a company that supplied bottled water to study participants.

Despite those caveats, Grady said, "The research question is important and the intervention was safe, easy, and effective (and it would be impossible to blind a trial in which drinking water is the intervention)."
Oct 1 JAMA Intern Med study
Oct 1 JAMA Intern Med editorial

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