Ignite Creation Date:
2024-10-26 @ 3:35 PM
Last Modification Date:
2024-10-26 @ 3:35 PM
Study NCT ID:
NCT06508398
Status:
COMPLETED
Last Update Posted:
None
First Post:
2024-07-14
Brief Title:
Healthcare-Associated Infections in Ukraine and the Activity of 4-Thiazolidinone Derivatives Against Related Pathogens
Sponsor:
None
Organization:
None
Study Overview
Official Title:
Species Spectrum and Biological Properties of Bacterial and Fungal Causative Agents of Health-care-associated Infections and in Vitro Study of Antimicrobial Activity Against Them Using 4-thiazolidinone Derivatives
Status:
COMPLETED
Status Verified Date:
2024-07
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
No
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
HAIsUA
Brief Summary:
The goal of this observational study is to evaluate the species spectrum and biological properties of bacterial and fungal pathogens causing healthcare-associated infections HAIs and to investigate the antimicrobial activity of new 4-thiazolidinone derivatives The main questions it aims to answer are
What are the common pathogens responsible for HAIs in ICU patients What is the antimicrobial and antifungal efficacy of 4-thiazolidinone derivatives against these pathogens
Participants will have their clinical samples collected and analyzed for pathogen identification and susceptibility testing The study will involve
Collecting clinical data and samples from ICU patients Conducting microbiological and biochemical tests Screening new antimicrobial compounds for efficacy The study does not involve a comparison group as it focuses on observational data and laboratory analysis
What are the common pathogens responsible for HAIs in ICU patients What is the antimicrobial and antifungal efficacy of 4-thiazolidinone derivatives against these pathogens
Participants will have their clinical samples collected and analyzed for pathogen identification and susceptibility testing The study will involve
Collecting clinical data and samples from ICU patients Conducting microbiological and biochemical tests Screening new antimicrobial compounds for efficacy The study does not involve a comparison group as it focuses on observational data and laboratory analysis
Detailed Description:
The study aims to characterize the structure and distribution of Healthcare-Associated Infections HAIs in Ukraine in recent years features of the species spectrum of pathogens and the spreading of antibiotic resistance clinical and microbiological characteristics of HAIs including those caused by rare pathogens of HAIs as well as a search synthesis screening of new chemical compounds with antimicrobial and antifungal activity in order to introduce new prototypes of antimicrobial drugs
According to the study design and analysis of the data of the CDC of Ukraine on the registration of HAIs cases in Ukraine during 2009-2020 was conducted As a result for the first time in Ukraine the registration of HAIs for the last 12 years was analyzed according to the results an average of 4759 710 cases of HAIs have been registered annually The analyzed materials give grounds to claim a significant underestimation of the incidence of HAIs in the country
According to the results of a comprehensive dynamic clinical and laboratory-instrumental examination of 250 patients of 4 local hospitals ICU departments and based on microbiological and epidemiological criteria the corresponding diagnosis was confirmed in 205 patients Among persons with HAIs 468 were men and 532 were women Among all cases of HAIs 249 were children including 88 newborns 649 - people aged 18-60 years older adults gt 60 years were 102 The most common nosologies were respiratory tract infections 366 and urinary tract infections 341 Most HAIs 586 occurred from the 5th to the 14th day of hospital stay
Three hundred eighty-nine biomaterials were taken from which 309 strains of microorganisms were isolated among which Gram-negative bacteria prevailed 515 the species spectrum of which included representatives of 27 different species Representatives of the genus Pseudomonas were the most isolated - 50 isolates 162 of the total number of pathogens Gram-positive microbiota is represented by 15 different species of pathogens the most - members of the genus Staphylococcus - 52 isolates which is 168 of the total number of pathogens Among the fungi 12 different species of pathogens were isolated most of them Candida non-albicans - 20 isolates which is 65 of the total number of pathogens
For the first time in Ukraine clinical cases caused by rare pathogens Raoultella Klebsiella terrigena and Vibrio metchikovii have been identified and described Our reported cases were compared with the clinical cases described in the literature It was shown that the isolate of R terrigena has film-forming properties more pronounced than the standard strain Raoutella terrigena ATCC 33257 and the rate of film formation exceeds the rate of film formation by staphylococci
Analyzing the clinical case caused by Vibrio metchikovii it should be noted that the most likely cause of infection is intraoperative microbial contamination of vascular prostheses
Species identification of pathogens was performed using biochemical test systems MIKRO-LA-TEST ErbaLachema Czech Republic using MALDI-TOF conducted at the Department of Microbiology of the College of Medicine in Bydgoszcz Poland and for individual strains - 16sRNA-ID The Identification score index of biochemical identification of cultures was gt 95 or gt 99 for 874 of isolates n270 508 of strains n157 had an atypicality index Tin of 025-049 ie these strains can be characterized as atypical MALDI ID-score 955 of isolates n295 was gt 20 ie showed good species identification other isolates had ID score 17-19 which indicates generic identification PCA analysis of Gram-negative rods of the genus Klebsiella allowed to divide them into 4 main clusters and showed significant similarity of isolates and together with RAPD analysis allowed to confirm the in-hospital transmission of pathogens According to the results of 16S rRNA analysis comparisons of Klebsiella pneumoniae isolates were performed which testified to the common origin of the infection Different identification methods established that a complete coincidence of results were recorded for 761 of strains n235 The highest identification accuracy is shown for 16sRNA analysis but the speed is for MALDI-TOF
The results of the antibiotic sensitivity showed that 628 n194 of isolates were MDR 74 n23 were EDR 288 n89 were not-MDR 1 n3 strains were attributed to PDR 2 - Pputida and 1 - Paeruginosa 338 n25 of the studied enterobacteria produced ESBL from another group of 47 studied isolates 839 produced OXA-48 among which all isolates were MDR The vast majority of fungal strains 829 were resistant to fluconazole which the most common choice of this drug can explain as empirical treatment of fungal infection
Cultures of Achromobacter xylosoxidans LMU-147 and Serratia marcescens LMU-48 were isolated for which their role in causing HAIs was proved The isolated strains are classified as class IV pathogenicity based on UA classification US CDC classification - Biosafety level 1 but they can penetrate internal organs more pronounced for serration Candida utilis LMU-127 is a low pathogenic strain that does not have invasive properties
Fifty-five new synthesized thiazole derivatives were used to search for and study new chemical compounds with antibiotic activity There was a pronounced antifungal effect in 3-5-1H-Indol-3-ylmethylene-4-oxo-2-thioxothiazolidin-3-yl-propanoic acid with a minimum inhibitory concentration against fungi of the genus Candida 25 μgmL and a selective antimicrobial effect against Escherichia coli in 2-5-1H-Indol-3-ylmethylene-4-oxo-2-thioxothiazolidin-3-yl-ethanesulfonic acid with a similar effect MIC25 μgmL The most active against Staphylococcus aureus group was 2-5-ylidene-4-oxo-2-thioxo-thiazolidin-3-yl-succinimides with a terminal fragment in the C5 position
For a 2-cyano-2- 5- ethoxymethylene -4-oxo-3-phenyl-thiazolidin-2-ylidene -N- o-tolyl acetamide derivative which does not contain a phenyleneamine or benzylidene moiety in the structure at position C5 position of the thiazolidone nucleus showed the highest activity against the multidrug-resistant clinical strain of Pseudomonas aeruginosa
A laboratory animal model studied the immunotoxicallergenicacute toxic effect of the 34leader compound34 with antimicrobial activity No immunotoxic and allergenic effects were found but there is a moderate anti-inflammatory effect Against the background of an increase in the absolute number of CD3 T-lymphocytes by 2146 a slight decrease in the quantitative level of CD22 B-lymphocytes by 198 was recorded Activation of the suppressor link caused some decrease in the immunoregulatory index indicator is unreliable
The effect of the test substance on the level of immunoglobulins and interleukins of laboratory animals showed a significant decrease in IgA by 214 p lt005 and an increase in IgG by 212 Thus there was an increase in the activity of the phagocytic system in terms of the growth of the phagocytic number and absorption properties of neutrophils The selectivity of such biological activity may be useful in the treatment of some immunopathological conditions
The identified effects accompanying antifungal activity indicate the prospects for further study of the 34drug-like molecule34 with polytargetative action
The analysis of the HAIs prevalence their registration the state of specific diagnostics comparison of modern methods of identification of microbial isolates from clinical material indicates the need to increase the level of microbiological research implementation of a standardized registration system and research of nosocomial infections with potentially adverse health effects
According to the thesis results and research of isolates39 biological properties the corresponding strains were deposited in the Depository of the Institute of Microbiology and Virology of the National Academy of Sciences of Ukraine
Based on the research 2 utility model patents were issued In addition molecular docking studies have shown that the 34leader compound34 7-34-Dimethoxyphenyl-5-methyl-3H-thiazolo45-bpyridin-2-one has shown good binding to selected protein targets compared to the reference N21 inhibitor and ciprofloxacin
Keywords Healthcare-Associated Infections HAIs nosocomial infections antimicrobial resistance antibiotic resistance device-associated pathogens antimicrobial activity antifungal activity 4-thiazolidinones thiazoles cellular immunity immunotropic action guinea pigs MALDI rare pathogens
Publications According to the thesis materials 10 articles were published including 8 articles indexed in the journals Web of Science andor Scopus article in the Ukrainian professional journal 1 article in a non-professional journal
The work results were presented at 17 conferences including in the form of an oral report at 3 international conferences outside Ukraine and 1 conference in Ukraine
Based on the work results 2 utility model patents and 3 certificates of initial deposition of the microorganism strain were published
According to the study design and analysis of the data of the CDC of Ukraine on the registration of HAIs cases in Ukraine during 2009-2020 was conducted As a result for the first time in Ukraine the registration of HAIs for the last 12 years was analyzed according to the results an average of 4759 710 cases of HAIs have been registered annually The analyzed materials give grounds to claim a significant underestimation of the incidence of HAIs in the country
According to the results of a comprehensive dynamic clinical and laboratory-instrumental examination of 250 patients of 4 local hospitals ICU departments and based on microbiological and epidemiological criteria the corresponding diagnosis was confirmed in 205 patients Among persons with HAIs 468 were men and 532 were women Among all cases of HAIs 249 were children including 88 newborns 649 - people aged 18-60 years older adults gt 60 years were 102 The most common nosologies were respiratory tract infections 366 and urinary tract infections 341 Most HAIs 586 occurred from the 5th to the 14th day of hospital stay
Three hundred eighty-nine biomaterials were taken from which 309 strains of microorganisms were isolated among which Gram-negative bacteria prevailed 515 the species spectrum of which included representatives of 27 different species Representatives of the genus Pseudomonas were the most isolated - 50 isolates 162 of the total number of pathogens Gram-positive microbiota is represented by 15 different species of pathogens the most - members of the genus Staphylococcus - 52 isolates which is 168 of the total number of pathogens Among the fungi 12 different species of pathogens were isolated most of them Candida non-albicans - 20 isolates which is 65 of the total number of pathogens
For the first time in Ukraine clinical cases caused by rare pathogens Raoultella Klebsiella terrigena and Vibrio metchikovii have been identified and described Our reported cases were compared with the clinical cases described in the literature It was shown that the isolate of R terrigena has film-forming properties more pronounced than the standard strain Raoutella terrigena ATCC 33257 and the rate of film formation exceeds the rate of film formation by staphylococci
Analyzing the clinical case caused by Vibrio metchikovii it should be noted that the most likely cause of infection is intraoperative microbial contamination of vascular prostheses
Species identification of pathogens was performed using biochemical test systems MIKRO-LA-TEST ErbaLachema Czech Republic using MALDI-TOF conducted at the Department of Microbiology of the College of Medicine in Bydgoszcz Poland and for individual strains - 16sRNA-ID The Identification score index of biochemical identification of cultures was gt 95 or gt 99 for 874 of isolates n270 508 of strains n157 had an atypicality index Tin of 025-049 ie these strains can be characterized as atypical MALDI ID-score 955 of isolates n295 was gt 20 ie showed good species identification other isolates had ID score 17-19 which indicates generic identification PCA analysis of Gram-negative rods of the genus Klebsiella allowed to divide them into 4 main clusters and showed significant similarity of isolates and together with RAPD analysis allowed to confirm the in-hospital transmission of pathogens According to the results of 16S rRNA analysis comparisons of Klebsiella pneumoniae isolates were performed which testified to the common origin of the infection Different identification methods established that a complete coincidence of results were recorded for 761 of strains n235 The highest identification accuracy is shown for 16sRNA analysis but the speed is for MALDI-TOF
The results of the antibiotic sensitivity showed that 628 n194 of isolates were MDR 74 n23 were EDR 288 n89 were not-MDR 1 n3 strains were attributed to PDR 2 - Pputida and 1 - Paeruginosa 338 n25 of the studied enterobacteria produced ESBL from another group of 47 studied isolates 839 produced OXA-48 among which all isolates were MDR The vast majority of fungal strains 829 were resistant to fluconazole which the most common choice of this drug can explain as empirical treatment of fungal infection
Cultures of Achromobacter xylosoxidans LMU-147 and Serratia marcescens LMU-48 were isolated for which their role in causing HAIs was proved The isolated strains are classified as class IV pathogenicity based on UA classification US CDC classification - Biosafety level 1 but they can penetrate internal organs more pronounced for serration Candida utilis LMU-127 is a low pathogenic strain that does not have invasive properties
Fifty-five new synthesized thiazole derivatives were used to search for and study new chemical compounds with antibiotic activity There was a pronounced antifungal effect in 3-5-1H-Indol-3-ylmethylene-4-oxo-2-thioxothiazolidin-3-yl-propanoic acid with a minimum inhibitory concentration against fungi of the genus Candida 25 μgmL and a selective antimicrobial effect against Escherichia coli in 2-5-1H-Indol-3-ylmethylene-4-oxo-2-thioxothiazolidin-3-yl-ethanesulfonic acid with a similar effect MIC25 μgmL The most active against Staphylococcus aureus group was 2-5-ylidene-4-oxo-2-thioxo-thiazolidin-3-yl-succinimides with a terminal fragment in the C5 position
For a 2-cyano-2- 5- ethoxymethylene -4-oxo-3-phenyl-thiazolidin-2-ylidene -N- o-tolyl acetamide derivative which does not contain a phenyleneamine or benzylidene moiety in the structure at position C5 position of the thiazolidone nucleus showed the highest activity against the multidrug-resistant clinical strain of Pseudomonas aeruginosa
A laboratory animal model studied the immunotoxicallergenicacute toxic effect of the 34leader compound34 with antimicrobial activity No immunotoxic and allergenic effects were found but there is a moderate anti-inflammatory effect Against the background of an increase in the absolute number of CD3 T-lymphocytes by 2146 a slight decrease in the quantitative level of CD22 B-lymphocytes by 198 was recorded Activation of the suppressor link caused some decrease in the immunoregulatory index indicator is unreliable
The effect of the test substance on the level of immunoglobulins and interleukins of laboratory animals showed a significant decrease in IgA by 214 p lt005 and an increase in IgG by 212 Thus there was an increase in the activity of the phagocytic system in terms of the growth of the phagocytic number and absorption properties of neutrophils The selectivity of such biological activity may be useful in the treatment of some immunopathological conditions
The identified effects accompanying antifungal activity indicate the prospects for further study of the 34drug-like molecule34 with polytargetative action
The analysis of the HAIs prevalence their registration the state of specific diagnostics comparison of modern methods of identification of microbial isolates from clinical material indicates the need to increase the level of microbiological research implementation of a standardized registration system and research of nosocomial infections with potentially adverse health effects
According to the thesis results and research of isolates39 biological properties the corresponding strains were deposited in the Depository of the Institute of Microbiology and Virology of the National Academy of Sciences of Ukraine
Based on the research 2 utility model patents were issued In addition molecular docking studies have shown that the 34leader compound34 7-34-Dimethoxyphenyl-5-methyl-3H-thiazolo45-bpyridin-2-one has shown good binding to selected protein targets compared to the reference N21 inhibitor and ciprofloxacin
Keywords Healthcare-Associated Infections HAIs nosocomial infections antimicrobial resistance antibiotic resistance device-associated pathogens antimicrobial activity antifungal activity 4-thiazolidinones thiazoles cellular immunity immunotropic action guinea pigs MALDI rare pathogens
Publications According to the thesis materials 10 articles were published including 8 articles indexed in the journals Web of Science andor Scopus article in the Ukrainian professional journal 1 article in a non-professional journal
The work results were presented at 17 conferences including in the form of an oral report at 3 international conferences outside Ukraine and 1 conference in Ukraine
Based on the work results 2 utility model patents and 3 certificates of initial deposition of the microorganism strain were published
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None