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.