Improving the treatment of bacterial infections caused by multidrug-resistant bacteria through drug repositioning.

Drug repurposing (repositioning) is a dynamically-developing area in the search for effective therapy of infectious diseases. Repositioning existing drugs with a well-known pharmacological and toxicological profile is an attractive method for quickly discovering new therapeutic indications. The off-label use of drugs for infectious diseases requires much less capital and time, and can hasten progress in the development of new antimicrobial drugs, including antibiotics. The use of drug repositioning in searching for new therapeutic options has brought promising results for many viral infectious diseases, such as Ebola, ZIKA, Dengue, and HCV. This review describes the most favorable results for repositioned drugs for the treatment of bacterial infections. It comprises publications from various databases including PubMed and Web of Science published from 2015 to 2023. The following search keywords/strings were used: drug repositioning and/or repurposing and/or antibacterial activity and/or infectious diseases. Treatment options for infections caused by multidrug-resistant bacteria were taken into account, including methicillin-resistant staphylococci, multidrug-resistant Mycobacterium tuberculosis, or carbapenem-resistant bacteria from the Enterobacteriaceae family. It analyses the safety profiles of the included drugs and their synergistic combinations with antibiotics and discusses the potential of antibacterial drugs with antiparasitic, anticancer, antipsychotic effects, and those used in metabolic diseases. Drug repositioning may be an effective response to public health threats related to the spread of multidrug-resistant bacterial strains and the growing antibiotic resistance of microorganisms.

Decreased susceptibility to vancomycin and other mechanisms of resistance to antibiotics in Staphylococcus epidermidis as a therapeutic problem in hospital treatment.

Multidrug-resistant coagulase-negative staphylococci represent a real therapeutic challenge. The aim of the study was to emphasize the importance of heteroresistance to vancomycin presence in methicillin-resistant strains of S. epidermidis. The research comprised 65 strains of S. epidermidis. Heteroresistance to vancomycin was detected with the use of the agar screening method with Brain Heart Infusion and a population profile analysis (PAP test). In addition, types of cassettes and genes responsible for resistance to antibiotics for 22 multidrug resistant strains were determined. Our investigations showed that 56 of 65 S. epidermidis strains were phenotypically resistant to methicillin. The tested strains were mostly resistant to erythromycin, gentamicin, clindamycin, and ciprofloxacin. Six strains showed decreased susceptibility to vancomycin and their heterogeneous resistance profiles were confirmed with the PAP test. All tested multi-resistant strains exhibited the mecA gene. More than half of them possessed type IV cassettes. ant(4')-Ia and aac(6')/aph(2''), ermC and tetK genes were most commonly found. The described phenomenon of heteroresistance to vancomycin in multidrug resistant bacteria of the Staphylococcus genus effectively inhibits a therapeutic effect of treatment with this antibiotic. That is why it is so important to search for markers that will enable to identify heteroresistance to vancomycin strains under laboratory conditions.

Phenotypic and Genotypic Characterization of Antimicrobial Resistance in Streptococci Isolated from Human and Animal Clinical Specimens.

Recently, the phenomenon of infection of humans as hosts by animal pathogens has been increasing. Streptococcus is an example of a genus in which bacteria overcome the species barrier. Therefore, monitoring infections caused by new species of human pathogens is critical to their spread. Seventy-five isolates belonging to streptococcal species that have recently been reported as a cause of human infections with varying frequency, were tested. The aim of the study was to determine the drug resistance profiles of the tested strains, the occurrence of resistance genes and genes encoding the most important streptococcal virulence factors. All tested isolates retained sensitivity to ß-lactam antibiotics. Resistance to tetracyclines occurred in 56% of the tested strains. We have detected the MLSB type resistance (cross-resistance to macrolide, lincosamide, and streptogramin B) in 20% of the tested strains. 99% of the strains had tetracycline resistance genes. The erm class genes encoding MLSB resistance were present in 47% of strains. Among the strains with MLSB resistance, 92% had the streptokinase gene, 58% the streptolysin O gene and 33% the streptolysin S gene. The most extensive resistance concerned isolates that accumulated the most traits and genes, both resistance genes and virulence genes, increasing their pathogenic potential. Among the tested strains, the gene encoding streptokinase was the most common. The results of the prove that bacteria of the species S. uberis, S. dysgalactiae and S. gallolyticus are characterized by a high pathogenic potential and can pose a significant threat in case of infection of the human body.

Vancomycin heteroresistance among methicillin-resistant clinical isolates S. haemolyticus, S. hominis, S. simulans, and S. warneri.

Besides being an essential part of the skin microbiome, coagulase-negative staphylococci are the etiological factors of serious infections. The aim of the study was to evaluate the heteroresistance to vancomycin and the potential antimicrobial efficacy of teicoplanin and daptomycin against the multiresistant strains of S. haemolyticus, S. hominis, S. warneri, and S. simulans. The study covered 80 clinical coagulase-negative staphylococci. Teicoplanin, vancomycin, and daptomycin MICs for the tested strains were determined according to EUCAST recommendation. The vanA and vanB genes were searched. The brain heart infusion screen agar method detected vancomycin heteroresistance. The population analysis profile method and analysis of autolytic activity were applied for the strains growing on BHI containing 4 mg/L vancomycin. Seven S. haemolyticus, two S. hominis, and two S. warneri strains presented a heterogeneous resistance to vancomycin. Their subpopulations were able to grow on a medium containing 4-12 mg/L of vancomycin. Monitoring heteroresistance to peptide antibiotics, which are often the last resort in staphylococcal infections, is essential due to the severe crisis in antibiotic therapy and the lack of alternatives to treat infections with multiresistant strains. Our work highlights the selection of resistant strains and the need for more careful use of peptide antibiotics.

Pathogenic potential and antimicrobial resistance of Staphylococcus pseudintermedius isolated from human and animals.

Crossing of interspecies barriers by microorganisms is observed. In recent years, Staphylococcus pseudintermedius-a species formerly thought to be animal-has also been isolated from human clinical materials. Many virulence factors are responsible for the colonization, which is the first step an infection, of the new host organism. We analyzed the factors influencing this colonization as well as susceptibility to antibiotics in fourteen S. pseudintermedius strains isolated from clinical cases from humans and animals. The occurrence of genes responsible for binding elastin, fibronectin, and fibrinogen and some phenotypic features, although different between strains, is comparable in both groups. However, the animal isolates had more genes coding for virulence factors. All isolates tested had the exfoliating toxin gene and the leukotoxin determining genes, but only the human strains had enterotoxin genes. The assessment of antibiotic resistance of strains of both groups indicates their broad resistance to antibiotics commonly used in veterinary medicine. Antibiotic resistance was more common among animal isolates. The multilocus sequence typing analysis of the studied strains was performed. The results indicated a large diversity of the S. pseudintermedius population in both studied groups of strains. Equipped with important virulence factors, they showed the ability to infect animals and humans. The clonal differentiation of the methicillin-susceptible strains and the multidrug resistance of the strains of both studied groups should be emphasized. The considerable genetic diversity of strains from a limited geographical area indicates the processes of change taking place within this species. Thus, careful observation of the ongoing process of variation is necessary, as they may lead to the selection of S. pseudintermedius, which will pose a significant threat to humans.

Pathogenicity and drug resistance of animal streptococci responsible for human infections.

Bacteria of the genus Streptococcus, earlier considered typically animal, currently have also been causing infections in humans. It is necessary to make clinicians aware of the emergence of new species that may cause the development of human diseases. There is an increasing frequency of isolation of streptococci such as S. suis, S. dysgalactiae, S. iniae and S. equi from people. Isolation of Streptococcus bovis/Streptococcus equinus complex bacteria has also been reported. The streptococcal species described in this review are gaining new properties and virulence factors by which they can thrive in new environments. It shows the potential of these bacteria to changes in the genome and the settlement of new hosts. Information is presented on clinical cases that concern streptococcus species belonging to the groups Bovis, Pyogenic and Suis. We also present the antibiotic resistance profiles of these bacteria. The emerging resistance to ß-lactams has been reported. In this review, the classification, clinical characteristics and antibiotic resistance of groups and species of streptococci considered as animal pathogens are summarized.