International Journal of Current Research and Review
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IJCRR - 11(18), September, 2019

Pages: 06-11

Date of Publication: 28-Sep-2019

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Cephalosporins and Metronidazole as Risk Factors for ESBL-Producing Organisms

Author: Scherer JS, Carvalho OF, Silliprandi EM, Dos Santos RP

Category: Healthcare

Abstract:Prevalence of Extended-spectrum \?-lactamase (ESBL)-producing organisms is increasing in healthcare associated (HCA) institutions and community. We conducted a matched case-double control study to assess the risk factors for acquisition of these multi-drug resistant organisms (MDRO), in a cardiac center in Brazil. We studied two hundred and thirty-eight patients (58 cases). Two groups of comparison were included: control Group 1 (N=120), with patients without infection; and control Group 2 (N=70), with patients with infection by non-ESBL producers Klebsiella spp., E. coli or Proteus mirabilis. On multivariate analysis, risk factors for hospital acquisition of ESBL-producing organisms were as follows: previous use of second-generation cephalosporins (OR 5.73; 95% CI 1.30-25.31), fourth-generation cephalosporins (OR 3.62; 95% CI 1.24-10.53) and metronidazole (OR 11.68; 95% CI 1.20-114.00). Previous identification of MDRO (OR 8.98, 95% CI 1.61-50.18), number of days on antibiotic use (OR 1.12; 95% 1.04-1.20) was also independently associated with ESBL-producing organisms. Interestingly, the presence of other MDRO in ward (OR 0.30; 95% CI 0.13-0.71) was associated as a protector factor for ESBL identification. When there was a low consumption of third-generation cephalosporins and quinolones, the second- and fourth-generation cephalosporins and metronidazole were, associated with ESBL-producing bacteria. In addition, adherence to isolation precautions and infection control recommendations can help to prevent ESBL-resistance dissemination.

Keywords: ESBL, Multidrug resistance, Enterobactereaceae, Infection control

Full Text:


            Extended-spectrum β-lactamase (ESBL)-producing organisms pose a great challenge to epidemiologists, infection control practitioners and physicians1,2. The dissemination of these broad spectrum resistant bacteria is difficult to control and the therapeutic options for severe infections are limited1,3,4.

            The emergence of ESBL-producers bacteria is increasing in both hospitals and community5.  This resistant mechanism is most found in Klebsiella pneumoniae in hospital and Escherichia coli in community as well5,6.

            There are several reasons for the increasing prevalence of these organisms in hospitals4,7, such as, the selective pressure of antimicrobials overuse, the use of invasive devices, cross-transmission between patients, hospital cross-infection, and the increase in prevalence of community origin6,8,9,10.

Infection by these organisms is associated with higher mortality rates11,12. Carbapenems use is associated with lower mortality in patients with serious infections8,13.  Although   other   agents may be used in non-severe infected patients, this use must be viewed with caution14,15,16,17

            We conduct a case control-study in a cardiac center in Brazil to identify risk factors for ESBL-producing organisms identification.


            A matched case-double control study was conducted at Instituto de Cardiologia, a 250-bed hospital for cardiology patients in southern Brazil. Instituto de Cardiologia attends adult and pediatric, surgical and clinical cardiology patients. In addition, the hospital has a cardiac transplant service, and three intensive care units (ICUs), which account for 16% of institution’s beds.

            Adult (age ≥ 18 years) inpatients were selected from the entire hospital irrespective of unit. Case patients were those with identification of ESBL-producing bacteria at any site, after 48 hours of admission. For this analysis, we included two control groups: Group 1 was composed of patients from hospital units but not with ESBL-producing organisms; and patients with non ESBL-producing composed Group 2 Klebsiella spp., Escherichia coli, or Proteus mirabilis. Controls were matched in terms of age (± 3 years), date of sample identification (± 3 days), gender, and hospital ward. 

            From January 2008 to December 2009 all ESBL-producing organisms were included (patient cases). Controls were selected in a rate 1:2 (Group 1): 1 (Group 2).

            All samples were processed at the microbiology laboratory at Instituto de Cardiologia. Detection of ESBL-producing bacteria was made according to the National Committee for Clinical Laboratory and Standards guidelines18. The susceptibility to antibiotics used agar disc diffusion method tested. For detection ESBL-producing strains, Double-disc synergy test was used. Bacteria considered as multidrug resistant organism (MDRO) were as follows: methicillin resistant Staphylococcus aureus (MRSA), ESBL-producing Escherichia coli, Klebsiella spp., Proteus mirabilis, carbapenems resistant Acinetobacter baumanii and Pseudomonas aeruginosa, vancomycin resistant enterococci (VRE).

            We reviewed data from patients’ medical charts. Antibiotic use was measured for 24 months of study period, for the entire hospital. Data from prescribed drugs, such as, carbapenems, fluoroquinolones, cephalosporin’s, piperacillin/tazobactam, vancomycin, ampicillin+sulbactam and oxacillin, metronidazole, clindamycin, sulfametoxazole+trimetoprrim were reviewed. Patient comorbidities, invasive devices use and surgical procedures, ICU admission, previous MDRO identification in the previous 90 days, previous hospital stay during the last year, and other than ESBL-producing MDRO identified in patient ward were also reviewed.

            Previous antibiotic use was at least 48h of inpatient use in the current admission. Time-at-risk is defined as the duration of time between admission and the detection of the antibiotic-resistant organism on culture for cases; as the number of days between admission and detection of the susceptible organism on culture, for non-resistant enterobactereacea infected controls; and the time between admission and discharge for non-infected control patients. Antibiotic consumption counted a number of defined daily doses (DDD), expressed as DDD per 100 patient-days. Central venous catheter (CVC), urinary catheterization, and mechanical ventilation were considered as invasive devices.

            A descriptive analysis of the variables collected from each patient was performed. The chi-squared test or Fisher’s exact test were used for univariate analysis of selected categorical variables. All odds ratios on univariate analysis were controlled for time at risk exposure. Associations were considered statistically significant when P value was ≤.05. Multivariate analysis, along with 95% confidence intervals (CI) and Odds ratios were calculated using the Logistic regression model. We divided the analysis in three models. The first model included the risk factors other than specific antimicrobials that were statistically significant on univariate analysis; the second model included the antimicrobials with statistical significance on univariate analysis and days on antimicrobial use. The final model included the variables that were statistically significant in the first two models. All analysis was corrected for time at risk. All collected data was stored in Excel® 2000 version and analyzed using SPSS® 18.0 program.

                The research and ethics committee of Fundação Universitária de Cardiologia (Brasil) approved the study and waived the need for informed consent because of the nature of the study.


            Patient characteristics are shown in Table 1. Through the study period, we included fifty-eight case patients. Most of them infected with Klebsiella spp. (65.5%; N=38). The rest of patients were infected with Proteus spp. (25.9%; N=15) and E. coli (8.6%; N=5). Control

Group 2, were composed by 70 patients with identification of non ESBL-producing Klebsiella spp. (85.7%; N=60), Proteus spp. (10.0%; N=7), and  E. coli (4.3%; N=3). One hundred and twenty patients were included in control Group 1.

            Most patients were at general ward (55.2%; N=137); 26.6% (N=66) at post-surgical ward; 15.7% (N=39) at ICU; and 2.4% (N=6) were at emergency department. From case patients, most specimens were from urinary tract (39.6%; N=23), respiratory tract (32.8%; N=19), and surgical wound (12.1%; N=7). From control group 2 sites of specimen identification were as follows: respiratory tract (45.7%; N=32), urine (31.4%; N=22), blood culture (10.0%; N=7), and surgical wound (7.1%; N=5).

            From January 2008 to December 2009 the mean consumption of antibiotics (in DDD/100 patient-days) were as follows: fourth-generation cephalosporins (5.9), third-generation cephalosporins   (0.3), second-generation cephalosporins (2.0), first-generation cephalosporins (4.1), oxacillin (5.7), ampicillin+sulbactam (4.4), piperacillin+tazobactam (2.2), quinolones (2.1), vancomycin (1.4), and carbapenems (0.8).

            Table 2 shows the multivariate analysis of statistically significant variables on univariate model, for both control groups.

            Antimicrobials, associated with ESBL-producing organism, on univariate analysis of control Group 1, controlled for time at risk, were: piperacillin+tazobactam (OR 3.14, IC 95% 1.33-7.39; P<0.01), first-generation cephalosporins (OR 0.35, IC 95%, 0.16-0.73; P<0.01), second-generation cephalosporins (OR 4.99, IC 95% 1.44-17.27; P=0.01), fourth-generation cephalosporins (OR 3.71, IC 95%, 1.65-8.33; P<0.01), metronidazole (OR 11.14, IC 95%, 1.24-100.39; P=0.03). From the analysis of control group 2: second-generation of cephalosporins (OR 3.97, IC 95%, 1.00-15.46; P=0.05), and fourth-generation cephalosporins (OR 3.06; IC 95%, 1.24-7.55; P=0.01). Multivariate analysis of specific antimicrobial use is shown in Table 3.

            The table 4 illustrates the final multivariate model, where specific antimicrobial drugs, with statistical significance on previous multivariate model and length of antimicrobial use are tested with significant statistical variables related to patient severity, previous presence of MDRO, or MDRO in patient ward.



            To answer the question “What are the risk factors for acquiring ESBL-producers pathogen among hospitalized patients?” Our study concluded that the second-generation cephalosporins, metronidazole, days on antibiotic use and previous MDRO other than ESBL were independently associated with ESBL-producer. For the question “What are the risk factors for developing ESBL-producers pathogen among patients with non-ESBL Klebsiella spp. E. coli, and Proteus spp.?” The answer was the second- and fourth generation cephalosporins, previous identification of a MDRO other than ESBL, and, interestingly, the presence of other MDRO in ward were associated with protection form ESBL-producers identification.

            In our setting where there is a high consumption of cephalosporins, especially fourth-generation cephalosporins, but a low consumption of third-generation cephalosporin and quinolones, use of second- and fourth-generation cephalosporins were associated with ESBL production. Besides the use of piperacillin+tazobactam was not associated with ESBL production. The hospital antimicrobial stewardship program (ASP) recommends the use of fourth- and second- instead of the third-generation cephalosporins and quinolones, because the associated risk of resistance linked to these drugs19,20. Besides the use of penicilins and piperacillin+tazobactam are stimulated, the carbapenems are the drugs reserved for infection by ESBL-producers21,22.

            A variety of antimicrobial classes and antimicrobial drugs have been associated with ESBL-production in bacteria23,24. Cephalosporins, especially third-generation cephalosporins, fourth-generation cephalosporins, the quinolones, piperacillin+tazobactam, vancomycin, penicilins and beta-lactamase-inhibitors penicilins, and gentamicin all have been linked to ESBL-producing bugs25. Although a few studies have assessed important methodological principles like those that control group selection derived from appropriate sampling of the base population, time at risk and comorbid illnesses for studies on ESBL resistance.

            Behar et al, evaluated risk factors for ESBL resistance in Klebsiella pneumoniae in four different groups of comparisons, with two types of controls: non-resistant Klebsiella pneumoniae and patients without infection derived from the same source of cases26. They found the cephalosporins use as a consistent risk factor. Besides, time at risk and CVC use were also identified as risk factors.

            Furthermore, Odds ratios were slightly higher considering antimicrobial use in the comparison between case and control Group 2, as stated by others. Furthermore, the cephalosporins as risk factors confirms the risk associated with ESBL-producers, however, our study confirms that second- and fourth-generation cephalosporins can also be related to ESBL-resistance in a setting of low use of other cephalosporins. In addition, this is the first study to link metronidazole use to ESBL-producers. Interestingly, this association was only seen in control group 1.  We speculate that this might be related to the suppression of intestinal anaerobic flora and the rise of resistant enterobactereacea. The use of other antimicrobial with activity against anaerobes like meropenem, ampicillin+sulbactam, and piperacillin+tazobactam were not related to resistance probably because enterobactereacea suppression flora too20.

            A few institutions implemented the use of piperacillin+tazobactam intended to reduce ESBL-producers. Other independently factors associated with ESBL were: previous MDRO isolation and days on antibiotic use. Interestingly, the presence of any MDRO in case patient ward was a protector factor for identification of ESBL-resistance, a group from Baltimore suggests that patient-to-patient transmission is not an important cause of the acquisition of ESBL-producing27. Although, we have not studied the association between adherence to contact precautions and resistance, we suppose that with the identification of a   MDRO other than ESBL-producers in the ward, the implementation of contact precautions protected other patients from ESBL-producing bacteria. In our hospital, most general wards were composed of three to five patients dividing the same room.

            Control-group selection in antimicrobial resistant studies is of great importance26. As recommended, we choose to include controls selected from the same unit of cases patients that were in hospital in a period near to the case patient resistant bacteria identification. Besides, using two control groups we try to control for the selection bias that arises when only antimicrobial-susceptible organisms are used as control patients28. Although we could not include in the final analysis a severity score for our patients, the inclusion of comorbities that were statistically related to the outcome on univariate analysis and the adjustments for time-at-risk on multivariate analysis could reduce bias to this confounding. Patients admitted for longer periods are more likely to receive a greater number of antibiotics20. In addition, time-at-risk correlates with illness severity.


            Our study has some limitations: our patients are from a specific cardiac center, which caused difficult generalization of results. We could not study the mechanisms of resistance in our patients. Our patients’ selection was based on clinical specimens collected as decision from the attending physician. We did not systematically collected surveillance samples, this way we could not ascertain about previous colonization.

            In order to review our antimicrobial policy we aim to investigate which specific antimicrobial or other risk factor was associated with ESBL-producing bacteria. Although cefepime and cefuroxime have been used for preserving third-generation cephalosporins, they were also associated with ESBL-resistance29. The implementation of contact precautions and a strict adherence to this measure contributes to the control of resistance in our setting30.


            Authors acknowledge the immense help received from the scholars whose articles are cited and included in references of this manuscript. The authors are also grateful to authors/editors/publishers of all those articles, journals and books from where the literature for this article has been reviewed and discussed.


            This study was conducted without financial support, study resources came from the authors.


            The authors declare that they have no competing interests.


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A Study by Gupta R. et al. entitled "A Clinical Study of Paediatric Tracheostomy: Our Experience in a Tertiary Care Hospital in North India" is awarded Best Article for Vol 13 issue 16
A Study by Chandran Anand et al. entitled "A Prospective Study on Assessment of Quality of Life of Patients Receiving Sorafenib for Hepatocellular Carcinoma" is awarded Best article for Vol 13 issue 15
A Study by Rosa PS et al. entitled "Emotional State Due to the Covid – 19 Pandemic in People Residing in a Vulnerable Area in North Lima" is awarded Best Article for Vol 13 issue 14
A Study by Suvarna Sunder J et al. entitled "Endodontic Revascularization of Necrotic Permanent Anterior Tooth with Platelet Rich Fibrin, Platelet Rich Plasma, and Blood Clot - A Comparative Study" is awarded Best Article for Vol 13 issue 13
A Study by Mona Isam Eldin Osman et al. entitled "Psychological Impact and Risk Factors of Sexual Abuse on Sudanese Children in Khartoum State" is awarded Best Article for Vol 13 issue 12
A Study by Khaw Ming Sheng & Sathiapriya Ramiah entitled "Web Based Suicide Prevention Application for Patients Suffering from Depression" is awarded Best Article for Vol 13 issue 11
A Study by Purushottam S. G. et al. entitled "Development of Fenofibrate Solid Dispersions for the Plausible Aqueous Solubility Augmentation of this BCS Class-II Drug" is awarded Best article for Vol 13 issue 10
A Study by Kumar S. et al. entitled "A Study on Clinical Spectrum, Laboratory Profile, Complications and Outcome of Pediatric Scrub Typhus Patients Admitted to an Intensive Care Unit from a Tertiary Care Hospital from Eastern India" is awarded Best Article for Vol 13 issue 09
A Study by Mardhiah Kamaruddin et al. entitled "The Pattern of Creatinine Clearance in Gestational and Chronic Hypertension Women from the Third Trimester to 12 Weeks Postpartum" is awarded Best Article for Vol 13 issue 08
A Study by Sarmila G. B. et al. entitled "Study to Compare the Efficacy of Orally Administered Melatonin and Clonidine for Attenuation of Hemodynamic Response During Laryngoscopy and Endotracheal Intubation in Gastrointestinal Surgeries" is awarded Best Article for Vol 13 issue 07
A Study by M. Muthu Uma Maheswari et al. entitled "A Study on C-reactive Protein and Liver Function Tests in Laboratory RT-PCR Positive Covid-19 Patients in a Tertiary Care Centre – A Retrospective Study" is awarded Best Article of Vol 13 issue 06 Special issue Modern approaches for diagnosis of COVID-19 and current status of awareness
A Study by Gainneos PD et al. entitled "A Comparative Evaluation of the Levels of Salivary IgA in HIV Affected Children and the Children of the General Population within the Age Group of 9 – 12 Years – A Cross-Sectional Study" is awarded Best Article of Vol 13 issue 05 Special issue on Recent Advances in Dentistry for better Oral Health
A Study by Alkhansa Mahmoud et al. entitled "mRNA Expression of Somatostatin Receptors (1-5) in MCF7 and MDA-MB231 Breast Cancer Cells" is awarded Best Article of Vol 13 issue 06
A Study by Chen YY and Ghazali SRB entitled "Lifetime Trauma, posttraumatic stress disorder Symptoms and Early Adolescence Risk Factors for Poor Physical Health Outcome Among Malaysian Adolescents" is awarded Best Article of Vol 13 issue 04 Special issue on Current Updates in Plant Biology to Medicine to Healthcare Awareness in Malaysia
A Study by Kumari PM et al. entitled "Study to Evaluate the Adverse Drug Reactions in a Tertiary Care Teaching Hospital in Tamilnadu - A Cross-Sectional Study" is awarded Best Article for Vol 13 issue 05
A Study by Anu et al. entitled "Effectiveness of Cytological Scoring Systems for Evaluation of Breast Lesion Cytology with its Histopathological Correlation" is awarded Best Article of Vol 13 issue 04
A Study by Sharipov R. Kh. et al. entitled "Interaction of Correction of Lipid Peroxidation Disorders with Oxibral" is awarded Best Article of Vol 13 issue 03
A Study by Tarek Elwakil et al. entitled "Led Light Photobiomodulation Effect on Wound Healing Combined with Phenytoin in Mice Model" is awarded Best Article of Vol 13 issue 02
A Study by Mohita Ray et al. entitled "Accuracy of Intra-Operative Frozen Section Consultation of Gastrointestinal Biopsy Samples in Correlation with the Final Histopathological Diagnosis" is awarded Best Article for Vol 13 issue 01
A Study by Badritdinova MN et al. entitled "Peculiarities of a Pain in Patients with Ischemic Heart Disease in the Presence of Individual Combines of the Metabolic Syndrome" is awarded Best Article for Vol 12 issue 24
A Study by Sindhu Priya E S et al. entitled "Neuroprotective activity of Pyrazolone Derivatives Against Paraquat-induced Oxidative Stress and Locomotor Impairment in Drosophila melanogaster" is awarded Best Article for Vol 12 issue 23
A Study by Habiba Suhail et al. entitled "Effect of Majoon Murmakki in Dysmenorrhoea (Usre Tams): A Standard Controlled Clinical Study" is awarded Best Article for Vol 12 issue 22
A Study by Ghaffar UB et al. entitled "Correlation between Height and Foot Length in Saudi Population in Majmaah, Saudi Arabia" is awarded Best Article for Vol 12 issue 21
A Study by Siti Sarah Binti Maidin entitled "Sleep Well: Mobile Application to Address Sleeping Problems" is awarded Best Article for Vol 12 issue 20
A Study by Avijit Singh"Comparison of Post Operative Clinical Outcomes Between “Made in India” TTK Chitra Mechanical Heart Valve Versus St Jude Mechanical Heart Valve in Valve Replacement Surgery" is awarded Best Article for Vol 12 issue 19
A Study by Sonali Banerjee and Mary Mathews N. entitled "Exploring Quality of Life and Perceived Experiences Among Couples Undergoing Fertility Treatment in Western India: A Mixed Methodology" is awarded Best Article for Vol 12 issue 18
A Study by Jabbar Desai et al. entitled "Prevalence of Obstructive Airway Disease in Patients with Ischemic Heart Disease and Hypertension" is awarded Best Article for Vol 12 issue 17
A Study by Juna Byun et al. entitled "Study on Difference in Coronavirus-19 Related Anxiety between Face-to-face and Non-face-to-face Classes among University Students in South Korea" is awarded Best Article for Vol 12 issue 16
A Study by Sudha Ramachandra & Vinay Chavan entitled "Enhanced-Hybrid-Age Layered Population Structure (E-Hybrid-ALPS): A Genetic Algorithm with Adaptive Crossover for Molecular Docking Studies of Drug Discovery Process" is awarded Best article for Vol 12 issue 15
A Study by Varsha M. Shindhe et al. entitled "A Study on Effect of Smokeless Tobacco on Pulmonary Function Tests in Class IV Workers of USM-KLE (Universiti Sains Malaysia-Karnataka Lingayat Education Society) International Medical Programme, Belagavi" is awarded Best article of Vol 12 issue 14, July 2020
A study by Amruta Choudhary et al. entitled "Family Planning Knowledge, Attitude and Practice Among Women of Reproductive Age from Rural Area of Central India" is awarded Best Article for special issue "Modern Therapeutics Applications"
A study by Raunak Das entitled "Study of Cardiovascular Dysfunctions in Interstitial Lung Diseas epatients by Correlating the Levels of Serum NT PRO BNP and Microalbuminuria (Biomarkers of Cardiovascular Dysfunction) with Echocardiographic, Bronchoscopic and HighResolution Computed Tomography Findings of These ILD Patients" is awarded Best Article of Vol 12 issue 13 
A Study by Kannamani Ramasamy et al. entitled "COVID-19 Situation at Chennai City – Forecasting for the Better Pandemic Management" is awarded best article for  Vol 12 issue 12
A Study by Muhammet Lutfi SELCUK and Fatma entitled "Distinction of Gray and White Matter for Some Histological Staining Methods in New Zealand Rabbit's Brain" is awarded best article for  Vol 12 issue 11
A Study by Anamul Haq et al. entitled "Etiology of Abnormal Uterine Bleeding in Adolescents – Emphasis Upon Polycystic Ovarian Syndrome" is awarded best article for  Vol 12 issue 10
A Study by entitled "Estimation of Reference Interval of Serum Progesterone During Three Trimesters of Normal Pregnancy in a Tertiary Care Hospital of Kolkata" is awarded best article for  Vol 12 issue 09
A Study by Ilona Gracie De Souza & Pavan Kumar G. entitled "Effect of Releasing Myofascial Chain in Patients with Patellofemoral Pain Syndrome - A Randomized Clinical Trial" is awarded best article for  Vol 12 issue 08
A Study by Virendra Atam et. al. entitled "Clinical Profile and Short - Term Mortality Predictors in Acute Stroke with Emphasis on Stress Hyperglycemia and THRIVE Score : An Observational Study" is awarded best article for  Vol 12 issue 07
A Study by K. Krupashree et. al. entitled "Protective Effects of Picrorhizakurroa Against Fumonisin B1 Induced Hepatotoxicity in Mice" is awarded best article for issue Vol 10 issue 20
A study by Mithun K.P. et al "Larvicidal Activity of Crude Solanum Nigrum Leaf and Berries Extract Against Dengue Vector-Aedesaegypti" is awarded Best Article for Vol 10 issue 14 of IJCRR
A study by Asha Menon "Women in Child Care and Early Education: Truly Nontraditional Work" is awarded Best Article for Vol 10 issue 13
A study by Deep J. M. "Prevalence of Molar-Incisor Hypomineralization in 7-13 Years Old Children of Biratnagar, Nepal: A Cross Sectional Study" is awarded Best Article for Vol 10 issue 11 of IJCRR
A review by Chitra et al to analyse relation between Obesity and Type 2 diabetes is awarded 'Best Article' for Vol 10 issue 10 by IJCRR. 
A study by Karanpreet et al "Pregnancy Induced Hypertension: A Study on Its Multisystem Involvement" is given Best Paper Award for Vol 10 issue 09

List of Awardees

A Study by Ese Anibor et al. "Evaluation of Temporomandibular Joint Disorders Among Delta State University Students in Abraka, Nigeria" from Vol 13 issue 16 received Emerging Researcher Award

A Study by Alkhansa Mahmoud et al. entitled "mRNA Expression of Somatostatin Receptors (1-5) in MCF7 and MDA-MB231 Breast Cancer Cells" from Vol 13 issue 06 received Emerging Researcher Award

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Disclaimer: International Journal of Current Research and Review (IJCRR) provides platform for researchers to publish and discuss their original research and review work. IJCRR can not be held responsible for views, opinions and written statements of researchers published in this journal.


International Journal of Current Research and Review (IJCRR) provides platform for researchers to publish and discuss their original research and review work. IJCRR can not be held responsible for views, opinions and written statements of researchers published in this journal


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