Clinical trial NCT05048693: Use of New Antibiotics in Sweden
Official title: Use of New Antibiotics Against Multidrug-resistant Gram-negative Bacteria in Swedish University Hospitals
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Multi-antibiotic Resistance
Keywords: Multidrug-resistant Gram-negative bacteria
Antibiotic resistance
Cefiderocol
Ceftazidime-avibactam
Ceftolozane-tazobactam
Fosfomycin
Meropenem-vaborbactam
Imipenem-relebactam
Lead sponsor: Uppsala University
Sponsor class: OTHER
Collaborators: name: Karolinska University Hospital
name: Sahlgrenska University Hospital
name: University Hospital, Linkoeping
name: Skane University Hospital
name: University Hospital, Umeå
name: Örebro University, Sweden
First posted: 2021-09-17
Enrollment: 41
Sex: ALL
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: CASE_ONLY
Time perspective: PROSPECTIVE
Sampling method: PROBABILITY_SAMPLE
Study population: Patients in seven University Hospitals in Sweden treated with any of the following antibiotics; cefiderocol, ceftazidim-avibactam, ceftolozan-tazobactam, fosfomycin, meropenem-vaborbactam or imipepenem-relebactam against an acute infection.

Brief summary: Antibiotic resistance is a growing global health problem of great concern, especially multidrug-resistant Gram-negative bacteria. In recent years some new antibiotics targeting these bacteria have been developed. The aim of this study is to investigate how these new antibiotics are used in Sweden. Information will be collected on patients, types of infections, dosing strategies, treatment outcome and occurrence of antibiotic resistance during treatment. The overall goal is to increase the knowledge about how these antibiotics are prescribed and how to optimize the use of them in clinical practice.

Detailed description: Emergence and spread of antibiotic-resistant bacteria is one of the greatest threats facing human health today. Multi-resistant Gram-negative bacteria constitutes the biggest challenges and particularly carbapenem-resistant bacteria, against which available treatment options usually are very limited and the mortality is high (\>50%) in severly ill patients. In recent years some new antibiotics have been developed with in-vitro effect against those bacteria. Still, clinical data regarding those antibiotics are limited and resistance development has been reported. Combination therapy with two or more antibiotics are often used to treat multi-resistant Gram-negative bacteria and are sometimes applied also with the newer drugs. Combination therapy is supported mainly by in vitro studies rather than clinical evidence. More research is needed to investigate which antibiotic combinations has the biggest potential.

The main objective of this study is to assess current use of the following antibiotics in Swedish university hospitals: cefiderocol, ceftazidime-avibactam, ceftolozane-tazobactam, fosfomycin, meropenem-vaborbactam and imipenem-relebactam.

Following informed consent, all patients treated with any of the study drugs at one of the seven university hospitals in Sweden can be included in the study. Guardian approval is needed to include study participants \<15 years of age. Besides routine testing with biomarkers and cultures within clinical practice, bacterial cultures will be taken seven days after start of treatment with the study drug, from the sample site where the infecting pathogen was first identified (e.g., blood, wound, nasopharynx, urine), to assess microbiological cure. Screening for multidrug-resistant Gram-negative bacteria in feces will also be conducted with screening cultures seven days after initiated therapy with study drug to detect emergence of resistance in the intestinal microbiota. The cultures will be analyzed at the local clinical microbiology departments.

Information on patient characteristics (age, gender, comorbidity etc.), site of infection, infecting pathogen and associated resistance profile, severity of infection, choice of treatment (drug, dose, treatment duration and eventual antibiotic combination therapy) will be obtained from the electronical medical records. Further treatment outcome including mortality, treatment failure, increasing need of intensive care, duration of hospitalization, suspected side effects and occurrence of Clostridioides difficile enteritis will also be extracted. The follow-up period is 30 days.

Patient names and personal identification numbers will be replaced by a number. Personal data will be stored at the Department of infectious diseases, at respective hospital where the study participant has been included. Only the responsible researchers will have access to the code key and be able to link personal information to the individual participants. All information will be handled in accordance with the General Data Protection Regulation (GDPR) and all analyses and presentation of data will be performed using anonymous data.

To determine antibiotic resistance profiles of the infecting pathogens, bacterial isolates will be sent to the reference laboratory at Uppsala University. The strains will be characterized with phenotypical methods for minimum inhibitory concentration (MIC) determination (e.g., microdilution, agar dilution) as well as genetical testing with whole-genome sequencing determining the presence of resistance genes and genetic mutations (e.g., production of beta lactamases, porin loss and efflux). In case of repeated growth of the same bacterial species in clinical or screening samples seven days from start of treatment, the two strains (prior and post treatment start of study drug) will be compared by MIC determination and whole-genome sequencing to detect emergence of antibiotic resistance during treatment.

Finally, the isolates will undergo in-vitro testing at the reference laboratory at Uppsala University, where the efficacy of different antibiotic combinations will be investigated with multiple in vitro methods including automated time-lapse microscopy and bacterial time-kill experiments with static and dynamic antibiotic concentrations. Bacterial killing, bacterial growth and selection of resistant subpopulations will be determined.

Eligibility criteria: Inclusion Criteria:

* Treatment with any of the following antibiotics; cefiderocol, ceftazidim-avibactam, ceftolozan-tazobactam, fosfomycin, meropenem-vaborbactam or imipepenem-relebactam against an acute infection.

Exclusion Criteria:

* Ongoing treatment with any of the above mentioned antibiotics for more than seven days at the point of inclusion.

Primary outcomes:
measure: Clinical cure
timeFrame: 30 days from enrollment
measure: Microbiological cure
timeFrame: 30 days from enrollment
measure: All-cause mortality
timeFrame: 30 days from enrollment
Secondary outcomes:
measure: Severity of illness
timeFrame: 30 days from enrollment
measure: Indication for treatment
timeFrame: 30 days from enrollment
measure: Use of antibiotic combination therapy
timeFrame: 30 days from enrollment
measure: Microbiological results
timeFrame: 30 days from enrollment
measure: Treatment failure
timeFrame: 30 days from enrollment
measure: Colonization with multidrug-resistant Gram-negative bacteria in feces
timeFrame: 30 days from enrollment
measure: Mortality attributable to infection
timeFrame: 30 days from enrollment
measure: Readmissions within 30 days
timeFrame: 30 days from enrollment
measure: Documented side effects
timeFrame: 30 days from enrollment
measure: Occurrence of Clostridioides difficile infection
timeFrame: 30 days from enrollment
measure: Duration of hospitalization
timeFrame: 1 year from enrollment
measure: Use of study drug in relation to the approved indications
timeFrame: 1 year from enrollment
measure: Dosing of study drug in relation to recommendations
timeFrame: 1 year from enrollment
measure: Phenotypic characterization of isolated bacteria
timeFrame: 1 year from enrollment
measure: Genotypic characterization of isolated bacteria
timeFrame: 1 year from enrollment
measure: Emergence of antibiotic resistance
timeFrame: 2 years from enrollment
Other outcomes:
Locations:
city: Gothenburg
country: Sweden
facility: Sahlgrenska University Hospital
city: Linköping
country: Sweden
facility: Linköping University Hospital
city: Lund
country: Sweden
facility: Skåne University Hospital
city: Stockholm
country: Sweden
facility: Karolinska University Hospital
city: Umeå
country: Sweden
facility: Umeå University Hospital
city: Uppsala
country: Sweden
facility: Uppsala University Hospital
city: Örebro
country: Sweden
facility: Örebro University Hospital
Study officials:
affiliation: Uppsala University Hospital
name: Thomas Tängdén, MD, Phd
role: PRINCIPAL_INVESTIGATOR
References: