ASP Scan (Weekly) for Feb 08, 2019

Inadequate TB drug-susceptibility testing
New UK guidance on antibiotics for acute cough
FDA to review new Merck antibiotics
CARB-X novel antibiotic funding
Antibiotic prescribing intervention in China
Candida auris fungemia
Microbiology test use in Norway
CRP-guided therapy
Formulary restriction policy
New CARB-X funding

Study: Inadequate drug-susceptibility tests linked to poor TB treatment

The accuracy of tuberculosis (TB) drug-susceptibility testing in high-burden countries was inadequate, and inaccurate test results led to inadequate treatment that contributed to higher mortality in patients with drug-resistant forms of the disease, an international team of researchers reported yesterday in The Lancet Infectious Diseases.

In a multicenter cohort study conducted in seven high-burden countries (Cote d'Ivoire, Democratic Republic of the Congo, Kenya, Nigeria, South Africa, Peru, and Thailand), researchers collected tuberculosis isolates from patients aged 16 years and older and compared the results of drug-susceptibility testing done locally with results from gold-standard phenotypic drug-susceptibility testing conducted in a Swiss reference laboratory. They then examined mortality in patients who had concordant and discordant test results.

Drug-susceptibility tests of isolates from 634 patients at the reference lab found that 394 isolates (62%) were pan-susceptible, 45 (7%) were resistant to one drug, 163 (26%) were multidrug-resistant (MDR), and 30 (5%) were pre-extensively or extensively drug-resistant (pre-XDR or XDR). A comparison of the results from the local and reference laboratories showed that they were concordant for 513 (81%) of 634 patients and discordant for 121 (19%) of 634, resulting in an overall sensitivity of 90.8% (95% confidence interval [CI], 86.5 to 94.2) and specificity of 84.3% (95% CI, 80.3 to 87.7).

Mortality ranged from 6% (20 of 336) in patients with pan-susceptible strains and concordant test results who were treated according to World Health Organization (WHO) guidelines to 57% (8 of 14) in patients with resistant strains who were under-treated. More than half the people with misdiagnosed drug-resistant tuberculosis who received inadequate therapy died. In logistic regression models, compared with concordant drug-susceptibility test results, the adjusted odds ratio of death was 7.33 (95% CI, 2.70 to 19.95) for patients with discordant results who were under-treated.

The authors of the study say the results support the idea that rapid molecular drug-susceptibility testing at treatment initiation, preferably using whole-genome sequencing, is required to improve outcomes in patients with MDR and pre-XDR/XDR TB, though they acknowledge that much work is required to make that approach feasible and affordable in lower-income countries.

They conclude, "In the meantime, the capacity for the phenotypic and molecular drug-susceptibility testing recommended by WHO should be increased to ensure the most adequate treatment of drug-resistant tuberculosis in these settings."
Feb 7 Lancet Infect Dis study


UK releases new guidance on antibiotic prescribing for acute cough

The UK National Institute for Health and Care Excellence (NICE) yesterday issued new clinical guidance aimed at reducing antibiotic prescribing for adults and children with acute cough.

The guidance advises against offering antibiotics to treat patients with acute cough associated with either an upper respiratory tract infection or with acute bronchitis who are not systematically unwell. Clinicians are also advised to explain to patients why an antibiotic is not necessary, how long acute coughs lasts, how to manage symptoms with self-care (honey, herbal remedies, and over-the-counter cough medicine), and when to seek further medical help.

For patients who appear systematically unwell at a face-to-face examination, the guidance recommends an antibiotic be offered immediately. For patients with a higher risk of complications, the guidance suggests clinicians consider offering an antibiotic.

The guidance recommends doxycycline as the first-choice antibiotic for adult patients, and amoxicillin as the first-choice agent in children under the age of 18. 
Feb 7 UK NICE acute cough guidance


FDA to review new treatments for urinary tract infections, pneumonia

Originally published by CIDRAP News Feb 6

Merck announced yesterday that the US Food and Drug Administration has accepted for priority review a New Drug Application (NDA) for the combination of relebactam and imipenem/cilastatin and a supplemental NDA for Zerbaxa (ceftolozane and tazobactam).

Merck is seeking approval for the combination of relebactam, an investigational beta-lactamase inhibitor, with imipenem/cilastatin to treat complicated urinary tract infections (cUTIs) and complicated intra-abdominal infections caused by certain susceptible gram-negative bacteria in adults with limited or no alternative therapies available. The supplemental NDA for Zerbaxa, which is already approved for patients with cUTIs, is to treat adults with nosocomial pneumonia, including ventilator-associated pneumonia, caused by certain susceptible gram-negative organisms.

"There is a major unmet need for new treatment options to address the growing danger of serious and potentially life-threatening infections caused by gram-negative bacteria," Nicholas Kartsonis, MD, senior vice president and head of clinical research for infectious diseases and vaccines at Merck, said in a press release. "In a space where there are currently very few treatment options, these filings underscore Merck's ongoing commitment to delivering new antibacterial agents to healthcare practitioners and patients."

Corresponding applications for both medicines have been filed with the European Medicines Agency.
Feb 5 Merck press release


CARB-X grant focuses on gram-negative superbugs

Originally published by CIDRAP News Feb 6

Today the Combating Antibiotic Resistant Bacteria Biopharmaceutical Accelerator, also known as CARB-X, announced an award of $4.4 million to Recida Therapeutics of Menlo Park, Calif., to develop a novel antibiotic targeting gram-negative superbugs.

"The world urgently needs new classes of antibiotics and other life-saving products to prevent, diagnose, and treat deadly infections," said Kevin Outterson, JD, executive director of CARB-X and a Boston University law professor, in a press release. "Recida's lead program inhibits LpxC, and would represent a new drug class against gram-negative superbugs, if approved by the FDA. The projects in the Powered by CARB-X portfolio are in early development, but if successful, they offer tremendous hope in the global fight against drug-resistant bacteria."

The money will help Recida prepare their drug, RC-01, for an Investigational New Drug (IND) application submitted to the US Food and Drug Administration (FDA). In preclinical testing, RC-01 inhibited LpxC, a key enzyme in the outer membrane of gram-negative bacteria, including Enterobacteriaceae and Pseudomonas aeruginosa.

Recida's RC-01 is 1 of 12 new antibiotics in CARB-X's portfolio. Established in 2016, CARB-X will invest $500 million in antibacterial research and development over a 5-year span.
Feb 6 CARB-X press release 


Educational intervention in China cuts prescribing for kids' respiratory infections

Originally published by CIDRAP News Feb 6

Chinese, Canadian, and British researchers report that an educational intervention to reduce antibiotic prescribing in children with upper respiratory tract infections (URTIs) significantly cut the prescribing rate in rural Chinese primary care facilities. The study appeared yesterday in PLOS Medicine.

The study was a long-term follow-up to an unblinded cluster-randomized controlled trial of 25 primary care facilities in two counties in rural China. That study found that the intervention, which included clinical guidelines, monthly prescriber-review meetings, doctor-patient communication skills training, and educational materials for caregivers, reduced the antibiotic prescribing rate among children aged 2 to 14 with URTIs by 29 percentage points from the baseline within 6 months.

In the long-term follow-up, the researchers looked at trial outcomes in the 14 facilities (7 intervention facilities and 7 control facilities) in one county at 18 months after the start of the intervention (12 months after the trial ended) and conducted interviews to understand how the interventions were sustained. After adjusting for patient and prescriber covariates, they found that, compared to the non-intervention facilities, the antibiotic prescribing rate in the intervention facilities was 36 percentage points lower than it was at baseline.

Providers at two of the intervention facilities reported better clinical knowledge in appropriate use of antibiotics, enhanced communication skills with patients and caregivers, and increased confidence in not prescribing antibiotics for common URTIs, even when requested. In addition, better-performing facilities reported more frequent peer-review meetings. 

Though the authors say they would not expect the improvement in antibiotic prescribing to be sustained for longer time periods without refresher training sessions and regular supervision and monitoring, they believe this type of intervention could be successful in other low- and middle-income countries, where roughly 80% of URTIs are treated with antibiotics.
Feb 5 PLOS Med study


Report describes Candida auris fungemia cases in Brooklyn hospital

Originally published by CIDRAP News Feb 5

In a paper published yesterday in Emerging Infectious Diseases, a team of clinicians, infection control specialists, and pharmacists at a community hospital in Brooklyn described the management of patients with Candida auris bloodstream infections (fungemia).

Of the nine cases of C auris fungemia reported at the hospital since 2016, most involved patients in the their 70s who had come from nursing homes and had multiple concurrent conditions. Half of the patients had invasive devices. In addition, each patient had a recent history of broad-spectrum antimicrobial use, and many had concomitant antibiotic-resistant organisms—including Pseudomonas aeruginosa and Klebsiella pneumoniae—isolated during the treatment for C auris.

All patients were given micafungin as first-line therapy for an average duration of 22 days, and two of the patients received liposomal amphotericin B after failing micafungin therapy. Average hospitalization was 65 days. Two of the patients died, and 3 of the 7 discharged patients were sent to palliative care.

Although antifungal susceptibility results were not available at the time of treatment, analysis of test results showed that all isolates were markedly resistant to fluconazole, and 40% were resistant to liposomal amphotericin B. The authors of the paper recommend that physicians treating invasive C auris infections consider combination therapy with micafungin plus liposomal amphotericin B in patients who fail monotherapy with micafungin.

Since its identification in Japan in 2009, C auris has caused outbreaks in healthcare facilities in more than 20 countries. The fungus, which has shown resistance to the three major classes of antifungal drugs, can cause serious invasive infections in patients who have compromised immune systems, with an estimated mortality of between 30% and 60%.

Of the 551 invasive C auris infections reported to the Centers for Disease Control in Prevention since 2016, 280 have been in New York. 
Feb 4 Emerg Infect Dis research letter


Norwegian hospital study finds suboptimal use of microbiology tests

Originally published by CIDRAP News Feb 5

A multicenter study by Norwegian researchers has found that despite large numbers of microbiology test orders, few tests are used to inform antibiotic prescribing. The results appeared yesterday in Antimicrobial Resistance and Infection Control.

The study, conducted over a 5-month period in 2014 at three hospitals in western Norway, analyzed data on patients who had been prescribed antibiotics for sepsis, urinary tract infections (UTIs), skin and soft tissue infections, lower respiratory tract infections (LRTIs), or acute exacerbations of chronic obstructive pulmonary disease (COPD). The primary outcome measures were the degree of microbiology test ordering, compliance with microbiology testing recommendation in the national antibiotic guideline, and the proportion of test results used to inform antibiotic prescribing.

Of the 1,731 patient admissions analyzed, mean compliance with microbiology testing recommendations in the antibiotic guideline was 89%, ranging from 81% in patients with acute exacerbations of COPD to 95% in patients with sepsis. Substantial additional testing was performed beyond the recommendations, however, with 49% of LRTI patients having urine cultures and 22% of UTI patients having respiratory tests. Microbiology test results from one of the hospitals showed that 18% (120/672) of patient admissions had applicable test results, but only half of them were used for therapy guidance, resulting in 9% (63/672) of patient admissions having         test results that informed antibiotic prescribing. 

The authors of the study say the findings indicate that current use of microbiology lab services in Norway is suboptimal, with diagnostic uncertainty and clinicians' insufficient knowledge of microbiology contributing to excessive testing, and long turnaround times reducing the usefulness of certain tests.

"There is a need both for tests with better performance characteristics and improved test ordering practices," they write. "Furthermore, use of microbiology test results to inform antibiotic decision-making needs to be optimized in order to ensure adequate patient treatment and more targeted therapy."
Feb 4 Antimicrob Resist Infect Control study


CRP-guided treatment may help in kids' respiratory infections

Originally published by CIDRAP News Feb 4

A trial by researchers from Switzerland and Tanzania demonstrated that use of an electronic decision algorithm that incorporated C-reactive protein (CRP) levels helped improve clinical outcomes in children with respiratory infections and reduce antibiotic prescribing. The study was published in Clinical Infectious Diseases.

In the randomized, controlled, noninferiority trial, which was conducted at nine primary care centers in Dar es Salaam, Tanzania, from December 2014 to February 2016, children aged 2 to 59 months with fever and cough received an antibiotic based on a CRP-informed strategy (a combination of CRP level of 80 milligrams per liter or higher plus age/temperature-corrected tachypnea and/or chest indrawing) or the current WHO standard (respiratory rate of 50 or higher). The primary outcome of the study was clinical failure by day 7, and the secondary outcomes were antibiotic prescription at diagnosis, secondary hospitalization, or death by day 30.

Altogether, 1,726 children were included in the trial, with 868 in the CRP group and 858 in the control group; 0.4% were lost to follow-up. The proportion of clinical failure by day 7 was 2.9% (25/865) in the CRP arm versus 4.8% (41/854) in the control arm (risk difference -1.9%, -3.7% to -0.1%; risk ratio [RR], 0.60; 95% confidence interval [CI], 0.37 to 0.98). In the CRP group, 2.3% (20/865) of children received antibiotics, compared with 40.4% (345/854) of children in the control arm (RR, 0.06; 95% CI, 0.04 to 0.09). There were also fewer secondary hospitalizations and deaths in the CRP group: 0.5% (4/865) versus 1.5% (13/854) (RR, 0.30; 95% CI, 0.10 to 0.93).

The authors of the study conclude, "CRP testing using a high cut-off, combined with two respiratory signs into an electronic decision algorithm, was able to improve clinical outcome in children with respiratory infections while substantially reducing antibiotic prescription."
Feb 2 Clin Infect Dis abstract


Study: Formulary restriction policy effective in cutting restricted antibiotics

Originally published by CIDRAP News Feb 4

A formulary restriction and preauthorization (FRPA) program at an academic medical center was associated with declines in the use of restricted antibiotics in medical and pediatric units, according to a new study in the American Journal of Infection Control.

In the study, researchers with Virginia Commonwealth University (VCU) School of Medicine analyzed the longitudinal effectiveness of the FRPA program at VCU Health System by calculating the days of therapy for restricted and non-restricted drugs in the medical, surgical, and pediatric units over a 5-year period and then applying regression analysis to identify statistically significant time trends. Under FRPA, physicians must obtain approval from antibiotic stewardship program (ASP) staff before administering a restricted or non-formulary drug.

The results revealed a statistically significant downward trend in antibiotic use in 2 of 7 medical units, 0 of 4 surgical units, and 1 of 4 pediatric units, with 1 surgical unit showing a significant upward trend. In addition, no corresponding increase in prescribing of non-restricted antibiotics was found in the 2 medical units that saw declines in use of restricted antibiotics.

Though they note that their findings could be confounded by parallel ASP interventions, the authors of the study say the results show that that the FRPA program has been effective at limiting the use of restricted agents, especially in medical units, and that their unique methodology provides a simple, comprehensive review of FRPA performance.
Feb 2 Am J Infect Control study


CARB-X to fund Polyphor's novel class of gram-negative antibiotics

Originally published by CIDRAP News Feb 4

CARB-X announced today that it will award up to $2.6 million in funding to Swiss biopharmaceutical company Polyphor to develop a novel class of antibiotics to treat infections caused by gram-negative ESKAPE pathogens (Escherichia coli, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species).

The funding will help support preclinical development of Polyphor's new class of outer membrane protein–targeting antibiotics (OMPTA), which have demonstrated in vitro and in vivo activity against ESKAPE pathogens, including multidrug-resistant and colistin-resistant isolates, with a favorable safety profile in animals. Polyphor could receive up to $3 million more if certain project milestones are met.

"We are delighted to have the support of CARB-X, which will enable us to accelerate and further advance our preclinical candidate targeting resistant gram-negative bacteria," Polyphor CEO Giacomo Di Nepi, MBA, MSC, said in a CARB-X press release.

Since it was established in 2016, CARB-X has awarded more than $103 million for the development of new antibiotics, diagnostics, and alternative therapies for drug-resistant infections. The OMPTA antibiotics are among the 11 novel classes of antibiotics in the CARB-X portfolio.
Feb 4 CARB-X press release

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