ISSN: 0973-7510
E-ISSN: 2581-690X
, Priyamvadha Ramadorai2, Priyadarshini Shanmugam2 and Lavanya Mohanam2Integrons are the special group of mobile genetic elements which can acquire, shuffle and spread antimicrobial resistance genes. They mediate drug resistance among Enterobacteriaceae and Non-fermenters. The present study investigation was undertaken to envisage the presence of Class I integrase gene among multidrug resistant Gram-negative bacteria. In this prospective study, 60 bacterial isolates from various clinical specimens were subjected to routine identification and susceptibility testing by conventional methods. Later the isolates were subjected for detection of intI1 gene by conventional PCR. The overall prevalence of intI1 gene among the clinical isolates was 60% (36/60) in our study. Class I integrase gene distribution among multidrug resistant bacteria was 80% (24/30) in comparison to non-multidrug resistant bacteria 43.34% (13/30). Antibiotics that were linked to Class I Integrons and shown to be statistically significant (p = 0.05) included ampicillin, aztreonam, ciprofloxacin, cefazolin, cefepime and tobramycin all showed high levels of resistance. Prevalence of intI1 gene was high among Enterobacteriaceae than Non-fermenters. There is a significant association between intI1 gene and multidrug resistance among these pathogens. Klebsiella species are highly multidrug resistant in comparison to other isolates and all of them harboured intI1 gene. Integrons can be a platform for the discovery of certain new metabolic pathways which can bring revolution in the field of antibiotic drug resistance. The information on the Integrons will aid us in prompt utilization of antimicrobial agents for the treatment.
Class I Integrons, Enterobacteriaceae, Gram-negative Bacteria, Multidrug-resistance, and Non-fermenters
Bacteria are present universally, infections caused by them have great impact on the public health. Bacterial infections are less severe in comparison to viral and parasitic infections. However, resistance to antimicrobial agents have made bacterial infections a leading cause of illness in the health care setup.1
Antimicrobial resistance has emerged to be the global threat of 21st century. It is estimated to cause 70,000 deaths worldwide and predicted to kill 10 million individuals by 2050.2
Gram-negative Bacteria (GNB) develop multiple drug resistance, hence assume greater importance among high-risk groups. Enterobacteriaceae and Non-fermenting Gram-negative bacilli (NFGNB) are the two groups of organisms that comprise common pathogens causing hospital associated infection, which cause life-threatening infections.3
Bacteria develop resistance to antibiotics by various processes, which can be either by intrinsic or acquired in nature. Horizontal gene transfer techniques play a vital role in acquired drug resistance.4 There are several methods involved in horizontal gene transferring such as transformation, transduction and conjugation.4 Mobile genetic elements mediate the exchange of genetic material in the horizontal gene transfer process.5 They promote the acquisition of genes and result in the spread of antibiotic resistance.5,6 Integrons are a special group of mobile genetic elements which can acquire, shuffle and disseminate antimicrobial resistance genes.7 To date five classes of integrons have been identified, among them Class I is most predominantly identified in clinical isolates. The organisms harbouring these genes are resistant to various classes of antimicrobial agents.8 The rise of multidrug-resistance (MDR) in Gram-negative bacteria has dramatically raised in association with Class I integrons and has become a particularly serious problem for healthcare professionals.9,10
The significance of antibiotic resistance associated integrons in clinical setup has primarily been reflected in their global epidemiological observation, monitoring, prevalence, and evolution. Although there are studies demonstrating the significance of integrase gene carriage and multidrug-resistance among the GNB, there is a lacuna in the epidemiology of antibiotic resistance associated integrons among the bacterial isolates. The following study was undertaken with the objectives of firstly to identify the multidrug resistant isolates of Enterobacteriaceae and non-fermenter, secondly to assess the prevalence of Class I integrase gene (intI1) in these isolates and lastly to assess the distribution of Class I integrons among MDR and non-multidrug resistant isolates.
The present study was undertaken in the Microbiology department of tertiary care hospital. Sixty bacterial isolates were included in this study, of which 30 were members of the family Enterobacterales (previously Enterobacteriaceae) and 30 were non-fermenters. These were isolated from various clinical specimens collected from patients, both inpatients and outpatients, belonging to all age groups attending our hospital. These isolates were collected between May 2022 to August 2022. Isolates were identified by conventional method followed by susceptibility testing and detection of IntI1 gene by molecular technique.
Identification and susceptibility
The isolates thus obtained were subjected for conventional identification which includes culture and staining characteristics (Gram stain) and standard identification techniques by biochemical reactions. Susceptibility testing by Kirby Bauer Disc diffusion test as per CLSI M100 Ed 32.
The antimicrobial susceptibility testing was carried out by disk diffusion method (Kirby Bauer) according to CLSI guidelines for all the isolates.11 The following antibiotics which were procured from HiMedia Labs Mumbai, India were used: amikacin (30 µg), aztreonam (30 µg), cefazolin (30 µg), cefepime (30 µg), cefuroxime (30 µg), cefotaxime (30 µg), ceftazidime (30 µg), ciprofloxacin (5 µg), tobramycin (10 µg), gentamicin (10 µg), ofloxacin (5 µg), imipenem (10 µg), meropenem (10 µg) and piperacillin/tazobactam (100 µg/10 µg). Standard culture suspension of the isolates were prepared and turbidity was matched with 0.5 Mc Farland standard. Culture inoculum was spread on the surface of Mueller Hinton agar (MHA) using the sterile swab. After allowing the plates to dry for 5 minutes antibiotic discs were placed and incubated at 37°C. The sensitivity zone was measured comparing with standard zone size according to CLSI guidelines (2022). The quality control was set up using P. aeruginosa (ATCC 27853) and E. coli (ATCC 25922) strains. Microbroth dilution method was performed for determining the MIC for colistin (Hi-Media Labs Mumbai, India).
Molecular Method
DNA Extraction12
The extraction of DNA was done by boiling lysis method. Fresh culture of the organism was centrifuged for 10 minutes at 10,000 rpm. Later the supernatant was separated and 300 µl of nuclease free water was added. The culture was boiled for 10 minutes at 100°C. After boiling, the culture was immediately cooled to -20°C and was maintained at same temperature for 6 hours. The culture was then centrifuged for 10 min at 10,000 rpm. Later 2 µl supernatant was separated and stored at -20°C and was used as DNA template.
PCR Amplification
The PCR reaction mixture was 25 µl. It contained 200 µM of dNTPs, 1X PCR buffer (Tris HCl [10 mM]; KCl [50 mM]; MgCl2 [1.5 mM] and 0.1 Units Taq DNA polymerase, primers (10 pmol each) and 5 ng of template DNA. Amplification was done using Master cycler. The primers used were according to Goldstein et al., the primers sequence mentioned in the Table 1.13
Analysis of PCR products
PCR products was analysed by electrophoresis method with 2% agarose gel in 1X Tris acetic acid EDTA (TAE) buffer. The products of PCR reaction was visualised by gel electrophoresis after the gel was stained with ethidium bromide (EtBr) (Figure).
Figure. PCR amplification gel documentation picture
Statistical analysis
Data were entered in Microsoft Excel and analyzed using SPSS (version 27.0; SPSS Inc., Chicago, IL, USA). The categorical variables were expressed in proportion and numbers. The statistical significance was tested using Chi2 test for the categorical variables. The p-value less than 0.05 was considered to be significant statistically.
In the following study, the extracted Deoxyribonucleic acid (DNA) from 60 bacterial isolates were subjected to detection of intI1 gene by polymerase chain reaction (PCR) using the specific primers (Table 1). Of total 60 bacterial isolates, 36 were identified as being positive for intI1 gene. All the products obtained showed the same melting point as that of positive control in each assay run. The prevalence of intI1 gene among the isolates was 60% in our study. These 60 isolates were further evaluated on the basis of antimicrobial sensitivity. The presence of intI1 gene among Enterobacteriaceae and Non-fermenters were 80% (24/30) and 40% (12/30) respectively. The presence of intI1 gene among MDR pathogens was 80% (24/30) in comparison to non-multidrug resistant pathogens 43.34% (13/30) (Table 2).
Table (1):
List of primers used for the detection of Class I integron gene
| Target genes | Primer sequences 5’ to 3 ’ | Expected Amplicon Size | ||
|---|---|---|---|---|
| Class I integron gene (Int I) | F:CCTCCCGCACGATGAT R:TCCACGCATCGTCAGGC |
280bp | ||
| PCR Conditions | ||||
| 1 Cycle | 30 cycles | 1 Cycle | ||
| Initial denaturation | Denaturation | Annealing | Extension | Final extension |
| 94°C for 5 minutes | 94°C for 45 seconds | 52°C for 45
seconds |
72°C for 1 minute | 72°C for 7 minutes |
| Hold at 4°C | ||||
Table (2):
Total number of clinical isolates positive for Class I Integron
| Clinical isolates (N) | Class I Integron N (%) | |
|---|---|---|
| Present | Absent | |
| Bacterial Isolates (60) | 36 (60) | 24 (40) |
| Enterobacteriaceae (30) | 24 (80) | 6 (20) |
| Non fermenters (30) | 12 (40) | 18 (60) |
| Multidrug resistant isolates (30) | 24 (80) | 7 (23.34) |
| Non Multidrug resistant isolates (30) | 13 (43.34) | 17 (56.67) |
Highest distribution of intI1 gene was observed among Klebsiella species 100% (13/13), followed by Escherichia coli 68.75% and Non-fermenters. Table 3 Shows distribution of intI1 gene among various clinical isolates. The distribution of intI1 gene among exudate samples were 61% (n = 16/26), urine samples were 62.5% (n = 15/24) and respiratory isolates were 50% (n = 5/10).
Table (3):
Shows distribution of Class I integron among various clinical isolates
No. |
Clinical isolate |
No of isolates (N) |
Class I Integron (N) |
Percentage (%) |
|---|---|---|---|---|
1. |
Acinetobacter species |
14 |
4 |
28.5 |
2. |
Citrobacter freundii |
01 |
0 |
0.0 |
3. |
E.coli |
16 |
11 |
68.8 |
4. |
Klebsiella species |
13 |
13 |
100.0 |
5. |
Pseudomonas species |
16 |
8 |
50.0 |
The cases were distributed between the two to 82 years of age group. The highest incidence was seen among the age group above 61 years, comprising 28.3% of cases, followed by others. It was observed that among the 60 cases, there were 38 males and 22 females. The incidence was high among males with male to female ratio 1.7:1.
The sensitivity pattern was observed for 19 antibiotics. The resistance was high among the intI1 gene positive bacteria. It was statistically significant with ciprofloxacin, gentamicin, imipenem, meropenem, cotrimoxazole, tobramycin, and ofloxacin (p < 0.05) (Table 4).
Table (4):
Comparison of Antibiotic Resistance pattern among the Class I Integron positive and negative isolates
| Antibiotics | Total (N=60) | Class I Integron positive (N = 36) | Class I Integron negative (N = 24) | p value | |||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| R | I | S | R | I | S | R | I | S | |||
| AK | 30 | 2 | 26 | 23 | 1 | 12 | 7 | 1 | 14 | 0.06 | |
| AM | 44 | 0 | 0 | 28 | 0 | 0 | 16 | 0 | 0 | – | |
| CZ | 44 | 0 | 0 | 28 | 0 | 0 | 16 | 0 | 0 | – | |
| CPM | 46 | 1 | 10 | 31 | 0 | 4 | 15 | 1 | 6 | 0.12 | |
| CTX | 38 | 2 | 5 | 26 | 1 | 2 | 12 | 1 | 3 | 0.41 | |
| CXM | 42 | 0 | 2 | 27 | 0 | 1 | 15 | 0 | 1 | 0.68 | |
| CIP | 43 | 0 | 16 | 29 | 0 | 6 | 14 | 0 | 10 | 0.03 | |
| CL | 0 | 30 | 0 | 0 | 23 | 0 | 0 | 7 | 0 | – | |
| FOS | 1 | 0 | 12 | 0 | 0 | 9 | 1 | 0 | 3 | 0.11 | |
| GN | 34 | 0 | 26 | 26 | 0 | 10 | 8 | 0 | 16 | 0.003 | |
| IMI | 31 | 0 | 29 | 23 | 0 | 13 | 8 | 0 | 16 | 0.02 | |
| MEM | 30 | 1 | 29 | 23 | 0 | 13 | 7 | 1 | 16 | 0.02 | |
| NIT | 4 | 0 | 11 | 2 | 0 | 8 | 2 | 0 | 3 | 0.40 | |
| PTZ | 33 | 0 | 25 | 24 | 0 | 12 | 9 | 0 | 13 | 0.05 | |
| COT | 30 | 0 | 12 | 24 | 0 | 2 | 6 | 0 | 10 | 0.000 | |
| TB | 25 | 1 | 19 | 20 | 0 | 6 | 5 | 1 | 13 | 0.003 | |
| AZT | 6 | 1 | 9 | 5 | 0 | 3 | 1 | 1 | 6 | 0.09 | |
| CAZ | 15 | 0 | 0 | 8 | 0 | 0 | 7 | 0 | 0 | – | |
| OF | 8 | 0 | 7 | 7 | 0 | 1 | 1 | 0 | 6 | 0.005 | |
Abbreviations: R, resistant; I, intermediate resistant; S, Susceptible; AK, Amikacin; AM, Ampicillin; CZ, Cefazolin; CPM, Cefepime; CTX, Cefotaxime; CXM, Cefuroxime; CIP, Ciprofloxacin; CL, Colistin; FOS, Fosfomycin; GN, Gentamicin; IMI, Imipenem; MEM, Meropenem; NIT, Nitrofurantoin; PTZ, Piperacillin-Tazobactam; COT, Cotrimoxazole; TB, Tobramycin; AZT, Aztreonam; CAZ, Ceftazidime; OF, Ofloxacin
Table (5):
The comparison of antibiotic resistance among the MDR and Non-MDR Isolates
| Antibiotics | MDR Isolates (N = 30) | Non-MDR Isolates (N =30) | p value | ||||
|---|---|---|---|---|---|---|---|
| R | I | S | R | I | S | ||
| AK | 28 | 0 | 1 | 2 | 1 | 26 | 0.000 |
| AM | 23 | 0 | 0 | 21 | 0 | 0 | – |
| CZ | 23 | 0 | 0 | 21 | 0 | 0 | – |
| CPM | 30 | 0 | 0 | 16 | 1 | 10 | 0.001 |
| CTX | 23 | 0 | 0 | 16 | 2 | 5 | 0.01 |
| CXM | 23 | 0 | 0 | 19 | 0 | 2 | 0.13 |
| CIP | 30 | 0 | 0 | 12 | 0 | 16 | 0.000 |
| CL | 0 | 30 | 0 | 0 | 0 | – | – |
| FOS | 0 | 0 | 1 | 1 | 0 | 11 | 0.76 |
| GN | 28 | 0 | 2 | 6 | 0 | 24 | 0.000 |
| IMI | 30 | 0 | 0 | 1 | 0 | 29 | 0.000 |
| MEM | 30 | 0 | 0 | 0 | 1 | 29 | 0.000 |
| NIT | 0 | 0 | 1 | 4 | 0 | 10 | 0.53 |
| PTZ | 30 | 0 | 0 | 3 | 0 | 25 | 0.000 |
| COT | 21 | 0 | 1 | 9 | 0 | 10 | 0.000 |
| TB | 24 | 0 | 1 | 1 | 1 | 18 | 0.000 |
| AZT | 6 | 0 | 1 | 0 | 1 | 8 | 0.002 |
| CAZ | 7 | 0 | 0 | 8 | 0 | 0 | – |
| OF | 7 | 0 | 0 | 1 | 0 | 7 | 0.001 |
Abbreviations: R, resistant; I, intermediate resistant; S, Susceptible; AK, Amikacin; AM, Ampicillin; CZ, Cefazolin; CPM, Cefepime; CTX, Cefotaxime; CXM, Cefuroxime; CIP, Ciprofloxacin; CL, Colistin; FOS, Fosfomycin; GN, Gentamicin; IMI, Imipenem; MEM, Meropenem; NF, Nitrofurantoin; PTZ, Piperacillin-Tazobactam; COT, Cotrimoxazole; TB, Tobramycin; AZT, Aztreonam; CAZ, Ceftazidime; OF, Ofloxacin
The antibiotic resistance pattern of the MDR and Non-MDR isolates were compared for all 19 antibiotics. The resistance was statistically significant with amikacin, cefepime, cefotaxime, ciprofloxacin, gentamicin, imipenem, meropenem, piperacillin-tazobactam, cotrimoxazole, tobramycin, aztreonam and ofloxacin (p < 0.05) (Table 5).
Integrons are the mobile genetic elements which are usually located on transposons and have the ability to incorporate and disseminate antimicrobial resistance gene cassettes amongst the microorganisms.14 The general structure of integron comprises of a conserved sequence with variable region which contains inserted genes cassettes. The Class I integron comprises of three important components firstly an intl gene encodes an enzyme integrase which mediates insertion, excision and shuffling of gene cassettes; secondly an attl recombination site for gene cassette insertion and thirdly a Pc promoter region responsible for gene cassette expression.15 They play a vital role in disseminating MDR genes among Gram-negative bacteria.16 In developing countries including India, Gram-negative organisms are the predominant pathogens causing infectious diseases and are responsible for high mortality and morbidity among them.17 There are rising concerns about the integrons associated MDR clinical isolates.
The overall distribution of intI1 gene among Enterobacteriaceae and Non-fermenters in our study was 60% and the prevalence of intI1 gene among MDR was 80% (24/30) in comparison to Non-MDR strains 43.34% (13/30). There is an high prevalence of intI1 gene in our study which is supported by other studies. An Indian study by Kaushik et al. in the year 2012 showed Class I and Class II integron to be associated with 66.10% (39/59) of Gram-negative bacteria and 32 among them were MDR and E. coli was the predominant isolate.18 Lavanya et al. in their study on Pseudomonas observed that all the carbapenem resistant isolates were harbouring intI1 gene.19
Kargar et al. in his work on E. coli observed 42% of isolates to be MDR and 78.26% were associated with Class I integrons.20 Another study by Mohadeseh zarei-yazdeli on various clinical isolates showed 82.6% of isolates were associated with intI1 gene, among them 59.7% were MDR and 22.9% were sensitive and intermediate strains.21 Kor et al. investigated 147 multidrug-resistant Enterobacteriaceae and Pseudomonas isolates from patients admitted to Malaysian hospitals and revealed prevalence of intI1 gene to be 45.6%.22 Maurine et al. in his study also showed high connection between MDR and the integron gene in Enterobacteriaceae.10 Nikibakhsh et al. in their work, all the Acinetobacter strains were MDR and 58.8% of them were associated with intI1 gene.23 In our study gentamicin, imipenem, meropenem, ciprofloxacin, cotrimoxazole, ofloxacin and tobramycin are the drugs predominantly associated with intI1 gene and are statistically significant. MDR isolates were resistant to the antimicrobials such as cotrimoxazole, gentamicin, imipenem, meropenem, tobramycin, amikacin, cefepime, ciprofloxacin, ampicillin, piperacillin/tazobactam, aztreonam, ofloxacin and cefuroxime. Maurine et al. in a study also showed MDR to be associated with resistance to the antimicrobials such as Cotrimoxazole, gentamicin, tobramycin, amikacin, ciprofloxacin, ampicillin, piperacillin/tazobactam, cefuroxime.10 Mohadeseh et al. observed highest resistance for piperacillin (90.03%), ciprofloxacin (87.54%) and cotrimoxazole (81.13%).21 All these studies support the fact that the resistance rate is high among the isolates which were associated with intI1 gene. In our study, the prevalence of Class I integrons and MDR were high among Enterobacteriaceae in comparison to
Non-fermenters.
The predominant isolates in our study were Klebsiella species, E. coli and Pseudomonas: among them, the distribution of intI1 gene was 100%, 68.8% and 50% respectively. Farzaneh et al. also observed all the Klebsiella species (100%) harbour intI1 gene in his research.24 But in a study by Kuihai et al. in China, Acinetobacter spp. was the predominant isolate to harbour intI1 gene which was followed by K. pneumoniae (72.5%) and E. coli are other isolates.25
We had clinical isolates from all the age group ranging from two years to 82 years. However, we did not observe age playing any role in the prevalence of MDR of the isolates. Male predominance was observed in our study. With respect to intI1 gene or MDR we did not observe any preference for a particular gender. Wound swab/pus samples as predominant clinical samples followed by urine and respiratory. The ability of the integrons to spread the drug resistance, pathogenicity and virulence has a great impact on the healthcare system. Integrons can be a platform for the discovery of certain new metabolic pathways which can bring revolution in the field of antibiotic drug resistance. The information on the integrons will aid us in the prompt utilization of antimicrobial agents for the treatment.
Antimicrobial resistance is of major health concern. Integrons are unique mobile genetic elements which mediate resistance among bacteria, especially gram-negative bacteria. We analysed the distribution of intI1 gene among Gram-negative bacteria in the various clinical samples and their association with multidrug resistance. A significant correlation between the intI1 gene and multidrug-resistance was observed. Detection of intI1 gene was high among Enterobacteriaceae in comparison to non-fermenters. The majority of Klebsiella species were multidrug-resistant, and all of them carried the intI1 gene. The Knowledge on the integron mediated antimicrobial resistance will aid us in prompt utilization of antimicrobial agents for the treatment.
ACKNOWLEDGMENTS
The authors would like to thank their colleagues and technologists in the Department for their support.
CONFLICT OF INTEREST
The authors declare that there is no conflict of interest.
AUTHORS’ CONTRIBUTION
KP and PS designed the study. KP, PR and LM performed data collection. KP, PR, PS and LM performed experiments. KP, PR, PS and LM performed result analysis. KP, PR, PS and LM wrote, reviewed, edited and approved the manuscript for publication.
FUNDING
None.
DATA AVAILABILITY
All datasets generated or analyzed during this study are included in the manuscript.
ETHICS STATEMENT
This study was approved by the Institutional Ethical Committee, with reference number is IHEC-II/0012/21.
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