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ASP Scan (Weekly) for Jul 18, 2021

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

Multidrug-resistant organisms reduced in nursing home residents’ rooms

A multicomponent intervention implemented at nursing homes in Michigan significantly reduced the prevalence of multidrug-resistant organisms (MDROs) in residents’ rooms, according to the results of a randomized clinical trial reported today in JAMA Network Open.

Using a cluster-randomized trial design, researchers from the University of Michigan and the Veterans Affairs Ann Arbor Healthcare System compared the presence of MDROs in patients and their room environments at 3 nursing homes that implemented the intervention with the MDRO presence at 3 control nursing homes. The intervention included enhanced barrier precautions, chlorhexidine bathing, MDRO surveillance, environmental cleaning education and feedback, hand hygiene promotion, and healthcare workers’ education and feedback. Control nursing homes continued standard care practices.

Over 808 study visits, the researchers obtained 3,654 patient cultures and 5,606 environmental cultures. The intervention reduced the odds of MDRO prevalence in patients’ environments by 43% (adjusted odds ratio [aOR], 0.57; 95% confidence interval [CI], 0.35 to 0.94), but there was no statistically difference at the patient level before or after adjustment (aOR, 0.57; 95% CI, 0.29 to 1.14).

When adjusting for patient-level covariates, the intervention was not associated with significantly decreased time to new acquisition of methicillin-resistant Staphylococcus aureus (hazard ratio [HR], 0.20; 95% CI, 0.04 to 1.09), vancomycin-resistant Enterococci (HR, 0.84; 95% CI, 0.46 to 1.53), or resistant gram-negative bacilli (HR, 1.14; 95% CI, 0.73 to 1.78).

“By acknowledging that patients and their environments are dyads that readily transmit to one another, our results highlight how critical it is to study interventions that impact both patient colonization and environmental contamination,” the authors wrote. “Under this analysis, we can conclude that this intervention influences patients and their environment overall, thus reducing MDRO transmission potential within facilities.”
Jul 16 JAMA Netw Open

Shorter regimen for resistant TB found effective with lower linezolid dose

Originally published by CIDRAP News Jul 15.

New data presented today indicate that a shorter treatment regimen for highly drug-resistant forms of tuberculosis (TB) remains highly effective with reduced doses of one of its components.

The phase 3 ZeNix trial, conducted in Moldova, Georgia, Russia, and South Africa, assigned 181 patients with extensively drug-resistant (XDR)-TB, pre-XDR-TB, and failed or treatment-intolerant multidrug-resistant TB into four study arms. The patients were all treated with the BPaL (bedaquiline, pretomanid, and linezolid) regimen for 6 months, with each arm receiving a different dose of linezolid.

A previous trial, the Nix-TB trial, had found that treatment efficacy for the BPaL regimen was 89%, but with high rates of side effects, such as peripheral neuropathy and anemia, that were associated with linezolid.

Per the intent-to-treat analysis, the treatment success rate was 93% for patients who received the highest dose of linezolid (1,200 milligrams [mg] for 6 months), and was similarly high in the remaining arms—89% among patients receiving 1,200 mg for 2 months, 91% for those receiving 600 mg for 6 months, and 84% among those who treated with 600 mg for 2 months.

Reported side effects also declined with lower doses of linezolid. Peripheral neuropathy was reported in 38% of those receiving the highest dose, compared with 13% of those receiving the lowest dose. A similar downward trend in patients reporting anemia was observed.

“The results of the ZeNix trial support the observed high efficacy of the BPaL regimen as seen in the Nix trial,” principal trial investigator Francesca Conradie, MD, said at a press conference ahead of the International AIDS Society conference, where the results will be presented. “There appears to be a lower dose of adverse events of note, with a preservation of the high rate of efficacy of around 90%.”

The BPaL regimen was approved for use in patients with highly resistant TB in 2019. The 6-month, all-oral regimen is significantly shorter and more effective than previous treatment regimens, which lasted at least 18 months and had global success rates of only 43%.

“We now have evidence that the BPaL regimen can be optimized to make it even easier to use,” Mel Spigelman, MD, President and CEO of TB Alliance, which developed pretomanid for use in the regimen, said in a press release.
Jul 15 TB Alliance press release 

More research needed on heavy impact of antibiotic resistance, report says

Originally published by CIDRAP News Jul 14.

A Wellcome report yesterday says more research is needed on drug-resistant bacterial infections (DRIs), but current data indicate that DRIs can be more likely to occur—and have more serious ramifications—in people with health conditions like cancer or who have received extensive treatment such as surgery.

The authors did a rapid evidence assessment of studies related to DRIs and surgery (11), organ transplants (22), cancer (10), intensive care unit admission (11), diabetes (16), HIV (15), infants/children (8), immunodeficiency (7), liver and kidney disease (3), and physical trauma such as road accidents (5).

They found that DRIs, particularly antibiotic-resistant infections, are often more likely in those with health conditions, with some studies showing that certain conditions may increase likelihood of death or health complications. However, they note a lack of DRI-related research on not only the health conditions they included in the report but also many they wanted to include, such as strokes, asthma, and childbirth.

In a first-person anecdote by Lillian Sung, MD, PhD, of the Hospital for Sick Children in Toronto in the executive summary, she talked about how physicians have needed to use stronger treatments over the years, resulting in a cycle of increasing resistance and more side effects. And even with these mitigations, she writes, children can go from being fine to dying within 12 hours because of DRIs.

Another excerpt by Paul Turner, MBBS, PhD, director of the Cambodia Oxford Medical Research Unit, touches on concerns in lower- and middle-income countries: “If you lose the use of azithromycin in places like the US and UK, maybe it doesn’t seem like a big deal,” he writes. “Kids with an ear infection will be able to get another antibiotic. But if we lose azithromycin in places like Cambodia or Nepal or Pakistan because of drug resistance, there is no oral treatment left for typhoid. It’s the last one left.”

The Wellcome authors conclude, “The trends that were identified—of links between resistant infections and greater mortality risks, for example—were overwhelmingly negative, but urgent research is needed to understand the impact of [antimicrobial resistance] and to drive an immediate and ambitious policy response.”
Jul 13 Wellcome report

Study highlights limited access, financial challenges for new antibiotics

Originally published by CIDRAP News Jul 13.

Patients in several high-income countries still have limited access to most of the new antibacterials approved since 2010,
and as a result sales revenue for these drugs has been insufficient—findings that highlight the poor commercial prospects for new antibiotics, researchers reported yesterday in Clinical Infectious Diseases.

To better understand barriers to effective antibacterial therapy in high-income countries, the researchers examined patient access to new antibacterials in G7 countries (Canada, France, Germany, Italy, Japan, the United Kingdom, and the United States) and seven other high-income countries in Europe, looking at the commercial launch dates, the lag time between regulatory approval and commercial launch, and sales data. They included all new molecular entity antibiotics approved by either the US Food and Drug Administration, the European Medicines Agency (EMA), Health Canada, or the Japanese Pharmaceuticals and Medical Devices Agency from Jan 1, 2010, through Dec 31, 2019.

Of the 18 antibacterials identified (16 antibiotics and 2 products for Clostridioides difficile), the majority were accessible in only three countries (the United States, United Kingdom, and Sweden), and the remaining countries had access to less than half of them. Only 4 antibacterials were launched in the European countries studied, and only 2 were launched in all 14 countries. European marketing authorization did not lead to automatic European access, as only a few of the 14 antibacterials approved by the EMA were commercially launched. No significant difference in access between innovative and non-innovative products was observed.

Median annual sales in the first approval market (generally the United States) for all 18 drugs were $16.2 million. Sponsors of four of the antibacterials filed for bankruptcy following regulatory approval, and sponsors for three other drugs had market capitalizations less than $300 million.

“Mean sales of $16.2 million are insufficient to cover ongoing commercialization costs, including manufacturing, regulatory, medical affairs, and post-approval commitments, with no opportunity to recover sunk R&D [research and development] costs,” the study authors wrote. “This economic situation explains why sponsors for seven of the eighteen products suffered either bankruptcy or market capitalizations below the sunk cost of R&D, with the bulk of this economic damage coming since April 2019.”

The authors say the findings reinforce calls for new economic incentives that will delink profits for new antibiotics from unit sales.
Jul 12 Clin Infect Dis abstract

Point-prevalence study reveals high antibiotic use in Ghanaian hospitals

Originally published by CIDRAP News Jul 13.

Point-prevalence surveys conducted in antimicrobial resistance (AMR) surveillance sentinel hospitals in Ghana found high levels of antibiotic use and empiric prescribing, researchers reported yesterday in JAC-Antimicrobial Resistance.

Overall prevalence of antibiotic use across the sentinel sites from September through December 2019 was 54.9% (1,591 out of 2,897 patients), ranging from 48.7% to 67.2%. The highest prevalence of antibiotic use was observed in adult intensive care units (89.3%). The average number of antibiotics per patient was 1.7, with 66% administered via the parenteral route, and 53.9% of patients received at least one antibiotic on the day of the survey.

Most antibiotics (52.2%) were used to treat infections, while 26.1% were for surgical prophylaxis and 13.7% had no documented indication. Of the 1,367 antibiotic prescriptions for treatment of infections, approximately 96% were prescribed empirically. Only 48.2% of the antibiotic prescriptions had a documented reason in the notes.

There were 35 different antibiotics prescribed across all hospitals. The five most commonly used antibiotics were metronidazole (20.6%), cefuroxime (12.9%), ceftriaxone (11.8%), amoxicillin/clavulanic acid (8.8%), and ciprofloxacin (7.8%).

“Such high antibiotic prescription rates in hospitals are fuelled by factors such as inadequate diagnostic microbiology services and differences in the organizational structures of hospitals,” the study authors wrote. “Given the association between antimicrobial use and the selection of resistant pathogens, the high frequency of antimicrobial use in Ghana is a reflection of the AMR problem in the country.”

The authors say the findings could be used as benchmarks for improving antibiotic prescribing.
Jul 12 JAC-Antimicrob Resist study

Non-antibiotic drugs may be a risk for resistant bacteria

Originally published by CIDRAP News Jul 12.

A study of hospital patients in Israel found a link between multidrug-resistant gut bacteria and exposure to commonly used non-antimicrobial drugs (NAMDs), researchers reported last week at the European Congress of Clinical Microbiology and Infectious Diseases (ECCMID).

Out of 1,807 patients admitted to Tel Aviv Medical Center from Jan 1, 2017, to Apr 18, 2019, who had upper urinary tract infection, positive urine or blood culture growing Enterobacterales, and exposure to any of 19 NAMDs prior to admission, 994 patient samples (52.2%) contained drug resistant organisms and 431 (23.8%) had multidrug-resistant organisms (MDROs). Univariate analysis found that exposure to seven drug classes was associated with a resistant organism, and three drug classes—proton-pump inhibitors (PPIs), beta-blockers, and antimetabolites—were significantly associated with MDROs.

A multivariable logistics regression analysis that included previous antibiotic exposure and hospitalization found that exposure to beta-blockers, PPIs, and antimetabolites was significantly associated with resistance to third-generation cephalosporins, trimethoprim-sulfamethoxazole, and fluoroquinolones, with antimetabolites having the greatest impact on antibiotic resistance.

“Our findings highlight the importance of non-antimicrobial drug exposure as a risk factor for antibiotic resistance,” lead author Meital Elbaz, MD, of Tel Aviv Medical Center, said in a European Society of Clinical Microbiology and Infectious Diseases (ESCMID)press release. “We urgently need larger studies with more drug classes to confirm the discovery and to clarify the biological link between common prescription drugs and antibiotic resistance.”
Jul 9 ECCMID abstract
Jul 9 ESCMID press release

Resistant bacteria found in more than half of dog food samples

Originally published by CIDRAP News Jul 12.

In another study presented at ECCMID last week, researchers from Portugal reported that samples of commercially available dog food contained MDR Enterococci, including isolates that were genetically identical to bacteria isolated from hospital patients.

The researchers analyzed 55 samples of dog food (22 wet, 8 dry, 4 semi-wet, 7 treats, and 14 raw-frozen) and found that 30 samples (54%) contained Enterococci that expressed resistance to erythromycin (73%), tetracycline (63%), quinupristin-dalfopristin (60%), streptomycin (53%), chloramphenicol (50%), ampicillin or ciprofloxacin (47% each), gentamycin (40%), linezolid (23%), or vancomycin and teicplanin (2% each). MDR isolates were found in all the raw-frozen samples and three of the non-raw samples.

Genetic sequencing revealed that some of the MDR Enterococcus faecium isolates in the dog-food samples were identical to isolates found in hospital patients in the United Kingdom, Germany, and the Netherlands, as well as to isolates from livestock and wastewater in the United Kingdom.

The researchers also conducted experim
ents that showed resistance genes from the dog food could be transferred to other types of bacteria, which suggests the potential for spread to people.

“The close contact of humans with dogs and the commercialisation of the studied brands in different countries poses an international public health risk,” lead author Ana Freitas, PhD, of the University of Porto, said in an ESCMID press release. “Dog owners should always wash their hands with soap and water right after handling pet food and after picking up faeces.”
Jul 9 ECCMID abstract
Jul 10 ESCMID press release

Azithromycin doesn’t help mild-to-moderate COVID-19, study finds

Originally published by CIDRAP News Jul 12.

A randomized clinical trial conducted in the United Kingdom found that use of the antibiotic azithromycin in patients with mild-to-moderate COVID-19 did not reduce the risk of subsequent hospital admission or death. The results were presented last week at ECCMID and published simultaneously in The Lancet Respiratory Medicine.

In the open-label, randomized trial conducted at 19 UK hospitals from Jun 3, 2020, to Jan 29, 2021, adult COVID-19 patients considered suitable for initial ambulatory management were assigned to receive either standard care plus 500 milligrams of azithromycin once a day for 14 days or standard care alone. The primary outcome was hospital admission or death from any cause within 28 days of randomization.

A total of 298 patients were enrolled, and the primary outcome was assessed in 292. The mean age of patients 45.9 years. Fifteen of 145 patients (10%) randomly assigned to azithromycin were admitted to hospital or died, compared with 17 of 147 (12%) who received standard care alone, for an adjusted odds ratio of 0.91 (95% confidence interval [CI], 0.43 to 1.92). Unadjusted and fully adjusted analyses (further adjusted for age, chronic pulmonary disease, and presence of cancer) demonstrated no significant differences between treatment groups.

This is the latest clinical trial to find no benefit for azithromycin in treating COVID-19 patients, either alone or combined with the antimalaria drug hydroxychloroquine. The previous trials have mainly involved hospitalized patients with late-stage, severe disease, or patients in the early stages of disease with minimal symptoms, while this study focused on patients in the early stages of disease who were at high risk for deterioration. Another distinction of the study was that patients received a high dose of azithromycin for a long duration, so that antiviral, antibacterial, and anti-inflammatory benefits could be assessed.

“In conclusion, our findings in mild-to-moderate COVID-19 managed in ambulatory care, taken together with trials in early disease in primary care and from trials in patients admitted to hospital with severe disease, suggest that azithromycin does not reduce hospital admissions, respiratory failure, or death compared with standard care, and should not be used in the treatment of COVID-19,” the study authors wrote.
Jul 9 Lancet Respir Med study

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