Use of New Antibiotics in Sweden

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.

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.