ABSTRACT
BACKGROUND: Multidrug-resistant Gram-negative bacilli are responsible for more than 50% of healthcare-associated infections. Colonization dynamics, characteristics, and risk factor data for CR-GNB are scarce in children. AIM: To examine the molecular characteristics of, and risk factors for nosocomial colonization with, carbapenem-resistant Gram-negative bacilli (CR-GNB) in hospitalized paediatric patients in a tertiary university hospital's paediatric units in Turkey. METHODS: A prospective case-control study was performed at a university hospital in Istanbul, Turkey. FINDINGS: A total of 1840 rectal swab specimens were collected from all 762 hospitalized children between March 2013 and October 2013. Among them, 176 (23%) patients were colonized with CR-GNB. Of these, 72 (9%) patients were colonized with carbapenem-resistant Enterobacteriaceae, 138 (18%) with CR-non-fermenter Gram-negative bacilli (CR-NF) and 34 (4%) with both. The median CR-GNB colonization time was 10 days (range: 1-116). The median duration of rectal colonization with CR-GNB was 8 days (range: 1-160). NDM (31%) was the second most frequent carbapenemase identified in Acinetobacter baumannii isolates, and has not previously been detected in Turkey. All of the 17 patients colonized with NDM-producing A. baumannii were newborns in the neonatal intensive care unit. Independent risk factors for CR-GNB colonization were: age <1 year, nasogastric tube placement, presence of underlying chronic diseases, ampicillin usage, surgical intervention, and carbapenem use. CONCLUSION: This is the first description of NDM in A. baumannii in newborn units in Turkey. Carbapenem usage is a common independent risk factor for both CRE and CR-NF colonization, which underscores the importance of antibiotic stewardship programmes.
Subject(s)
Anti-Bacterial Agents/pharmacology , Carbapenems/pharmacology , Genotype , Gram-Negative Bacteria/isolation & purification , Gram-Negative Bacterial Infections/epidemiology , Gram-Negative Bacterial Infections/microbiology , beta-Lactam Resistance , Adolescent , Anti-Bacterial Agents/therapeutic use , Carbapenems/therapeutic use , Case-Control Studies , Child , Child, Preschool , Drug Utilization , Female , Gram-Negative Bacteria/classification , Gram-Negative Bacteria/drug effects , Gram-Negative Bacteria/genetics , Hospitals, University , Humans , Infant , Infant, Newborn , Intensive Care Units, Neonatal , Male , Prospective Studies , Risk Factors , Tertiary Care Centers , Turkey/epidemiologyABSTRACT
The resistance-nodulation-division (RND) family efflux pumps are important in the antibiotic resistance of Gram-negative bacteria. However, although a number of bacterial RND efflux pump inhibitors have been developed, there has been no clinically available RND efflux pump inhibitor to date. A set of BSN-coded 2-substituted benzothiazoles were tested alone and in combinations with ciprofloxacin (CIP) against the AcrAB-TolC overexpressor Escherichia coli AG102 clinical strain. The results indicated that the BSN compounds did not show intrinsic antimicrobial activity when tested alone. However, when used in combinations with CIP, a reversal in the antibacterial activity of CIP with up to 10-fold better MIC values was observed. In order to describe the binding site features of these BSN compounds with AcrB, docking studies were performed using the CDocker method. The performed docking poses and the calculated binding energy scores revealed that the tested compounds BSN-006, BSN-023, and BSN-004 showed significant binding interactions with the phenylalanine-rich region in the distal binding site of the AcrB binding monomer. Moreover, the tested compounds BSN-006 and BSN-023 possessed stronger binding energies than CIP, verifying that BSN compounds are acting as the putative substrates of AcrB.
Subject(s)
Anti-Bacterial Agents/pharmacology , Benzothiazoles/pharmacology , Ciprofloxacin/pharmacology , Escherichia coli Proteins/antagonists & inhibitors , Escherichia coli/drug effects , Anti-Bacterial Agents/chemistry , Benzothiazoles/chemistry , Binding Sites , Ciprofloxacin/chemistry , Drug Resistance, Bacterial , Escherichia coli/isolation & purification , Escherichia coli/metabolism , Escherichia coli Proteins/metabolism , Microbial Sensitivity Tests , Molecular Docking Simulation , Protein Binding , Quantitative Structure-Activity RelationshipABSTRACT
RND family efflux pumps are important for multidrug resistance in Gram-negative bacteria. To date no efflux pump inhibitors for clinical use have been found, so developing the specific inhibitors of this pump system will be beneficial for the treatment of infections caused by these multidrug-resistant pathogens. A set of BSN-coded 2-substituted benzothiazoles were tested alone and in combination with ciprofloxacin (CIP) against the RND family efflux pump AdeABC overexpressor Acinetobacter baumannii SbMox-2 strain. The results indicated that the BSN compounds did not have antimicrobial activity when tested alone. However, if they were applied in combination with CIP, it was observed that the antibiotic had antimicrobial activity against the tested pathogen, possessing a minimum inhibitory concentration value that could be utilized in clinical treatment. A 3D-common features pharmacophore model was applied by using the HipHop method and the generated pharmacophore hypothesis revealed that the hydrogen bond acceptor property of nitrogen in the thiazole ring and the oxygen of the amide substituted at the second position of the benzothiazole ring system were significant for binding to the target protein. Moreover, three hydrophobic aromatic features were found to be essential for inhibitory activity.