Biology subjects

Frimodt-Moller, N.

Publications and source records attributed to Frimodt-Moller, N..

4 recordsLinked to original sources

bioRxiv2023

Apramycin efficacy in the treatment of carbapenem-resistant Enterobacterales in murine blood stream infection models

BackgroundThe aminoglycoside apramycin has been proposed as a drug candidate for the treatment of critical Gram-negative systemic infections. However, its potential in the treatment of drug-resistant bloodstream infections (BSIs) has yet to be assessed. MethodsThe resistance gene annotations of 26 493 blood culture isolates were analyzed. In vitro profiling of apramycin comprised cell-free translation assays, broth microdilution, and frequency of resistance determination. The efficacy of apramycin was studied in a mouse peritonitis model for nine E. coli and K. pneumoniae isolates. ResultsGenotypic aminoglycoside resistance was identified in 87.8% of all 6973 carbapenem-resistant Enterobacterales blood-culture isolates, in comparison to 46.4% of colistin and 2.1% of apramycin resistance. Apramycin activity against methylated ribosomes was > 100-fold higher than other aminoglycosides. Frequencies of resistance were < 10-9 at 8 x MIC. Tentative epidemiological cutoffs (ECOFFs) were determined as 8 g/mL for E. coli and 4 g/mL for K. pneumoniae. A single dose of 5 to 13 mg/kg resulted in a 1-log CFU reduction in the blood and peritoneum. Two doses of 80 mg/kg, resulting in an exposure that resembles the AUC observed for a single 30 mg/kg dose in humans, resulted in complete eradication of carbapenem- and aminoglycoside-resistant bacteremias. ConclusionEncouraging coverage and potent in-vivo efficacy against a selection of highly drug-resistant Enterobacterales isolates in the mouse peritonitis model warrants further consideration of apramycin as a drug candidate for the treatment and prophylaxis of BSI.

microbiology↗

bioRxiv2021

An amphipathic and cationic antimicrobial peptide kills colistin resistant Gram-negative pathogens in vivo

New antibiotics are needed against multidrug resistant Gram-negative pathogens that have compromised global health systems. Antimicrobial peptides are generally considered promising lead candidates for the next generation of antibiotics but have not fulfilled this expectation. Here we demonstrate activity of a cationic amphipathic undecapeptide (ChIP; Charge change Independent Peptide) against a wide panel of multidrug resistant Gram-negative pathogens. Importantly, the antimicrobial activity of ChIP is independent of the surface charge changes that confer colistin resistance through modification of Lipid A, while decreased activity of ChIP correlates with GlcN1 tri-acylation of Lipid A. In an in vivo peritonitis mouse model ChIP displays excellent activity against both colistin sensitive and resistant Escherichia coli and Acinetobacter baumannii strains. Author SummaryAntimicrobial peptides hold promise as novel treatment options for diseases caused by multidrug resistant bacteria. Here we present evidence that the ChIP peptide, comprised of 11 D-amino acids, is active against a variety of Gram-negative bacteria that ranks high on the WHO list of critically important pathogens. ChIP initially interacts with the Gram-negative outer membrane, independent of its surface charge, followed by entry into the periplasm and permeabilization of the inner membrane, leading to bacterial cell death. Detailed analyses of the outer membrane indicate that the acylation pattern of lipopolysaccharides plays an important role for ChIP activity. In a mouse infection model, ChIP display excellent activity in reducing bacterial numbers for both Escherichia coli and Acinetobacter baumannii. Importantly, ChIP is highly efficient against bacteria resistant to colistin, an antibiotic normally considered as a last resort treatment of infections caused by multidrug resistant Gram-negative bacteria.

microbiology↗

bioRxiv2018

Comparative activity of Ceftriaxone, Ciprofloxacin and Gentamicin as a function of bacterial growth rate probed by Escherichia coli chromosome replication in the mouse peritonitis model

Commonly used antibiotics exert their effect predominantly on rapidly growing bacterial cells, yet growth dynamics taking place during infection in a complex host environment remain largely unknown. Hence, means to measure in situ bacterial growth rate is essential to predict the outcome of antibacterial treatment. We have recently validated chromosome replication as readout for in situ bacterial growth rate during Escherichia coli infection in the mouse peritonitis model. By the use of two complementary methods (qPCR and fluorescence microscopy) for differential genome origin and terminus copy number quantification, we demonstrated the ability to track bacterial growth rate, both on a population average and on a single-cell level; from one single biological specimen. Here, we asked whether the in situ growth rate could predict antibiotic treatment effect during infection in the same model. Parallel in vitro growth experiments were conducted as proof-of-concept. Our data demonstrate that the activity of commonly used antibiotics Ceftriaxone and Gentamicin correlated with pre-treatment bacterial growth rate; both drugs performing better during rapid growth than during slow growth. Conversely, Ciprofloxacin was less sensitive to bacterial growth rate, both in a homogenous in vitro bacterial population and in a more heterogeneous in vivo bacterial population. The method serves as a platform to test any antibiotics dependency upon active in situ bacterial growth. Improved insight into this relationship in vivo could ultimately prove helpful in evaluating future antibacterial strategies.\n\nImportanceMost antibiotics in clinical use exert their effect predominantly on rapidly growing bacterial cells, yet there is a lack of insight into bacterial growth dynamics taking place during infection in vivo. We have applied inexpensive and easily accessible methods for extraction of in situ bacterial growth rate from bacterial chromosome replication during experimental murine infection. This approach not only allows for a better understanding of bacterial growth dynamics taking place during the course of infection, but also serves as a platform to test the activity of different antibiotics as a function of pre-treatment in situ growth rate. The method has the advantage that bacterial growth rate can be probed from a single biological sample, with the potential for extension into clinical use in pre-treatment infected biological specimens. A better understanding of commonly used antibiotics level of dependency upon bacterial growth, combined with measurements of in situ bacterial growth rate in infected clinical specimens, could prove helpful in evaluating future antibacterial treatment regimens.

microbiology↗

bioRxiv2018

Dogs as reservoirs of Escherichia coli strains causing urinary tract infection in their owners

It is known that humans and pets living together can share the same Escherichia coli strain. In this study we assessed the role played by household pets as reservoirs of E. coli strains causing urinary tract infection (UTI) in their owners. Fecal swabs from 15 dogs and six cats living with 19 patients with community-acquired E. coli UTI were screened by antimicrobial selective plating to detect E. coli displaying the same susceptibility profile of the UTI-causing strain. Pet/patient pairs sharing strains with indistinguishable susceptibility and pulsed-field gel electrophoresis (PFGE) profiles were quantitatively screened for fecal carriage of the UTI-causing strain approximately 10 months later using bacterial counts on selective agar supplemented with the relevant antibiotics. Isolates from both time points were characterized by whole-genome single nucleotide polymorphism (SNP) analysis. PFGE revealed indistinguishable E. coli within two (11%) pet/patient pairs. In pair A, the UTI-causing strain was detected 10 months later in both the patient (108 CFU/g) and her dog (104 CFU/g). In pair B, only the dog was colonized with the UTI-causing strain upon re-sampling (105 CFU/g), indicating dog-to-man transmission. For both pairs, less than 70 SNPs distinguished any isolate from the first and second sampling. The study shows regular co-carriership of UTI-causing E. coli strains between humans and their pets, and indicates that dogs can be a source of human infection. Although final evidence for transmission is lacking, hygiene precautions should be considered by people fraternizing pets. This may be particularly relevant for persons with a compromised immune system.

microbiology↗