Carl Erik Nord’s research while affiliated with Karolinska Institutet and other places

Clostridioides difficile infection represents a growing clinical challenge. The new compound omadacycline is a potential treatment alternative, as many antibiotics have limited activity or are rarely used due to costs and side effects. The activity of omadacycline and five comparators was assessed with agar dilution on a 2015-to-2018 collection of 65 C. difficile isolates from Sweden. Omadacycline demonstrated in vitro activity against the contemporary ribotypes of C. difficile, and further clinical investigation is needed. IMPORTANCE Evaluating the activity of novel antimicrobials like omadacycline is of great interest, as a reliable and efficient antimicrobial treatment for Clostridioides difficile infections is in demand.

Background Between 2015 and 2017, 21,850 Enterobacterales isolates and 6,156 Pseudomonas aeruginosa isolates were collected by 77 centers in 18 European countries as part of the INFORM study (which was included into the Antimicrobial Testing Leadership and Surveillance [ATLAS] study in 2018). Methods A central reference laboratory performed antimicrobial susceptibility testing using broth microdilution panels according to CLSI guidelines. The presence of β-lactamases was confirmed using multiplex PCR assays. Results Among Enterobacterales isolates, highest rates of susceptibility were to ceftazidime-avibactam (99.0%; MIC90 0.5 mg/L), meropenem (96.3%), amikacin (95.2%%), and imipenem (92.8%). All Enterobacterales organisms were highly susceptible to colistin (≥94.6%), apart from Proteus mirabilis, which is intrinsically resistant to colistin. Susceptibility rates among ceftazidime-resistant isolates were 95.7% for ceftazidime-avibactam and 87.9% for colistin, and 78.5% and 71.1% respectively among carbapenemase-positive isolates. Colistin was the only agent with activity against metallo-β-lactamases (100% susceptibility) among Enterobacterales and P. aeruginosa isolates. Overall susceptibility rates among P. aeruginosa were highest to colistin (99.5%) and ceftazidime-avibactam (92.3%), and were similar to ceftazidime-resistant isolates for colistin (98.9%) and reduced to 66.2% for ceftazidime-avibactam. Susceptibility rates among multidrug-resistant P. aeruginosa isolates were 98.9% to colistin, and 71.7% to ceftazidime-avibactam. Conclusions Clinical isolates of Enterobacterales and P. aeruginosa collected from Europe, between 2015 and 2017, were highly susceptible to ceftazidime-avibactam, suggesting it is a useful alternative agent for patients whose treatment options may be limited. Persistent antimicrobial resistance requires continued surveillance and monitoring.

Background The purpose of the current study was to determine the final content validation, psychometric characteristics, clinically meaningful improvement, and responder thresholds of the Clostridium difficile infection (CDI)–Daily Symptoms (CDI-DaySyms™) patient-reported outcome (PRO) questionnaire. Methods This validation study was part of two phase III studies (NCT01987895 and NCT01983683) conducted in patients with mild-to-moderate or severe CDI who completed the CDI-DaySyms™ daily throughout the treatment period. The questionnaire was evaluated in three stages: final PRO item content validation (Stage I); psychometric evaluation of reliability and construct validity (Stage II); and determination of clinically meaningful improvement and responder thresholds using distribution-based methods (Stage III). Results The analysis included 168 patients. Most patients were female and Caucasian with mild-to-moderate CDI. The mean age was 57.1 years. Initial item analysis supported by confirmatory factor analysis demonstrated the relevance of 10 items grouped into three distinct domains (Diarrhea Symptoms, Abdominal Symptoms, and Systemic/Other Symptoms). Domain scores demonstrated acceptable internal consistency and test-retest reliability, were sensitive to change, and correlated in expected directions with other relevant symptom and disease-severity measures. Responder thresholds were defined as score changes of − 1.00, − 0.80, and − 0.70 in the Diarrhea Symptoms, Abdominal Symptoms, and Systemic/Other Symptoms domains, respectively. Conclusions The CDI-DaySyms™ is a valid measure of patient-reported CDI symptoms, with good measurement properties, which supports its utility as an endpoint in clinical studies. Further studies confirming responder thresholds based on anchor-based methods are required. Trial registration NCT01987895, registered November 20, 2013; NCT01983683, registered November 14, 2013.

Background: Cadazolid is a novel quinoxolidinone antibiotic developed for treating Clostridium difficile infection. We aimed to investigate the safety and efficacy of cadazolid compared with vancomycin in patients with C difficile infection. Methods: IMPACT 1 and IMPACT 2 were identically designed, multicentre, double-blind, placebo-controlled, non-inferiority, randomised phase 3 trials. IMPACT 1 was done in Australia, Brazil, Canada, France, Germany, Italy, the Netherlands, Peru, Poland, Romania, Spain, and the USA, and IMPACT 2 was done in Argentina, Belgium, Brazil, Canada, Chile, Croatia, Czech Republic, Greece, Hungary, Israel, Romania, Slovakia, South Korea, the UK, and the USA. Patients (aged 18 years or older) with mild-to-moderate or severe C difficile infection (diarrhoea with positive glutamate dehydrogenase and toxin A or B enzyme immunoassays) were randomly assigned (1:1) with a randomisation list stratified by centre and C difficile infection episode type (block size of four), and allocation was masked to investigators and participants. Patients received either oral cadazolid 250 mg twice daily with vancomycin-matching placebo capsule four times daily or oral vancomycin 125 mg four times a day with cadazolid-matching placebo suspension twice daily for 10 days, with 30 days of follow-up. The primary efficacy outcome was non-inferiority (margin -10%) of cadazolid versus vancomycin for clinical cure in the modified intention-to-treat and per-protocol populations. Clinical cure was defined as resolution of diarrhoea with no additional treatment for C difficile infection. These trials are registered with ClinicalTrials.gov, numbers NCT01987895 (IMPACT 1) and NCT01983683 (IMPACT 2). Findings: Between March 28, 2014, and March 24, 2017, for IMPACT 1, and Dec 13, 2013, and May 2, 2017, for IMPACT 2, 1263 participants were randomly assigned to receive cadazolid (306 in IMPACT 1 and 298 in IMPACT 2) or vancomycin (326 in IMPACT 1 and 311 in IMPACT 2). In the modified intention-to-treat population in IMPACT 1, 253 (84%) of 302 had clinical cure in the cadazolid group versus 271 (85%) of 318 in the vancomycin group. In IMPACT 2, 235 (81%) of 290 versus 258 (86%) of 301 had clinical cure. In the per-protocol population, 247 (88%) of 282 versus 264 (92%) of 288 had clinical cure in IMPACT 1 and 214 (87%) of 247 versus 237 (92%) of 259 in IMPACT 2. Non-inferiority for clinical cure to vancomycin was shown in IMPACT 1 but not in IMPACT 2 (IMPACT 1 treatment difference: -1·4 [95% CI -7·2 to 4·3] for modified intention to treat and -4·1 [-9·2 to 1·0] for per protocol; IMPACT 2: -4·7 [-10·7 to 1·3] for modified intention to treat and -4·9 [-10·4 to 0·6] for per protocol). The safety and tolerability profiles of the two antibiotics were similar. Interpretation: Cadazolid was safe and well tolerated but did not achieve its primary endpoint of non-inferiority to vancomycin for clinical cure in one of two phase 3 C difficile infection trials. Therefore, further commercial development of cadazolid for C difficile infection is unlikely. Funding: Actelion Pharmaceuticals.

This declaration, signed by an interdisciplinary task force of 234 experts from 83 different countries with different backgrounds, highlights the threat posed by antimicrobial resistance and the need for appropriate use of antibiotic agents and antifungal agents in hospitals worldwide especially focusing on surgical infections. As such, it is our intent to raise awareness among healthcare workers and improve antimicrobial prescribing. To facilitate its dissemination, the declaration was translated in different languages.

Objectives To develop a patient-reported outcome (PRO) questionnaire for symptoms of Clostridium difficile infection (CDI) following the US Food and Drug Administration PRO guidelines. Methods Patients’ experiences of CDI symptoms were elicited in open-ended discussions with patients and nurses at five US sites (stage 1). A draft PRO measure was developed after demonstration of concept saturation. Two rounds of cognitive interviews were conducted with patients at three US sites (stage 2), with revision of the draft measure after each round. All patients were 18 years or older, with confirmed CDI. The study was conducted with input from a panel of five CDI experts in Europe and North America. Results Stage 1 included interviews with 18 patients and supplementary interviews with 6 nurses; 16 additional patients were interviewed in stage 2. Patients were representative of the general CDI population and were diverse in age, sex, and disease severity. Concept saturation was reached in stage 1. Items were organized in a draft conceptual framework with five hypothesized domains: diarrhea, abdominal discomfort, tiredness, lightheadedness, and other symptoms. Stage 2 demonstrated initial content validity of the 13-item draft daily diary (CDI-DaySyms). Participants reported that the questions were clear, relevant, and comprehensive. They were able to use the instructions to complete the diary correctly and considered the 24-hour recall period appropriate. Conclusions The CDI-DaySyms captures symptoms relevant to patients undergoing CDI, demonstrating initial content validity. Final content and psychometric validity are being evaluated in a substudy comprising patients from two ongoing international clinical trials (ClinicalTrials.gov identifiers NCT01987895 and NCT01983683).

1. Surg Infect (Larchmt). 2017 Nov/Dec;18(8):846-853. doi: 10.1089/sur.2017.219. A Global Declaration on Appropriate Use of Antimicrobial Agents across the Surgical Pathway. [No authors listed] This declaration, signed by an interdisciplinary task force of 234 experts from 83 different countries with different backgrounds, highlights the threat posed by antimicrobial resistance and the need for appropriate use of antibiotic agents and antifungal agents in hospitals worldwide especially focusing on surgical infections. As such, it is our intent to raise awareness among healthcare workers and improve antimicrobial prescribing. To facilitate its dissemination, the declaration was translated in different languages. DOI: 10.1089/sur.2017.219 PMID: 29173054 [Indexed for MEDLINE]