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Dissertation Submitted in Partial Fulfillment of the Regulations IDENTIFICATION OF GENES CODING FOR CARBAPENEMASES IN CLINICAL ISOLATES OF CARBAPENEM RESISTANT KLEBSIELLA SPECIES IN A TERTIARY CARE HOSPITAL Dissertation submitted in Partial fulfillment of the Regulations required for the award of M.D. DEGREE In MICROBIOLOGY– BRANCH IV The Tamil Nadu DR. M.G.R. MEDICAL UNIVERSITY Chennai MAY 2020. UNIVERSITY REGISTRATION NO: 201714252 CERTIFICATE This is to certify that the enclosed work “Identification of Genes Coding for Carbapenemases in Clinical Isolates of Carbapenem Resistant Klebsiella Species in a Tertiary Care Hospital” submitted by Dr.S.Sharon Dorothy to The Tamilnadu Dr. MGR Medical University is based on bonafide cases studied and analysed by the candidate in the Department of Microbiology, Coimbatore Medical College Hospital during the period from July 2018 to June 2019 under the guidance and supervision of Dr. N.Mythily, MD., Professor & HOD, Department of Microbiology and the conclusion reached in this study are her own. Guide Dr. N.MYTHILY, MD., Professor & HOD, Department of Microbiology, Coimbatore Medical College, Coimbatore. Dr. B. ASOKAN. M.S., M.Ch., Dr., N.MYTHILY, MD., Dean, Professor & HOD, Coimbatore Medical College and Hospital, Department of Microbiology, Coimbatore – 14. Coimbatore Medical College, Coimbatore – 14. DECLARATION I, Dr.S.Sharon Dorothy solemnly declare that the dissertation entitled “Identification of Genes Coding for Carbapenemases in Clinical Isolates of Carbapenem Resistant Klebsiella Species in a Tertiary Care Hospital” was done by me at Coimbatore Medical College Hospital, during the period from July 2018 to June 2019 under the guidance and supervision of Dr. N. Mythily, M.D., Professor & HOD, Department of Microbiology, Coimbatore Medical College, Coimbatore. This dissertation is submitted to The Tamilnadu Dr. MGR Medical University towards the partial fulfilment of the requirement for the award of M.D. Degree (Branch – IV) in Microbiology. I have not submitted this dissertation on my previous occasion to any University for the award of any degree. Place: Date : Dr. S.Sharon Dorothy ACKNOWLEDGEMENT ACKNOWLEDGEMENT I express my deep debt of gratitude to our respectful Dean, Dr.B. Asokan, M.S., M.Ch., for permitting me to do this study. I wish to place my deep sense of gratitude and sincere thanks to Dr. N. Mythily MD., Professor and Head of the Department of Microbiology, for the constant encouragement, guidance and timely advice given to me during the course of my post-graduation. I sincerely place my thanks to Associate Professors Dr.P.Sankar,M.D., Dr.B.Padmini, M.D., for their support and encouragement. I express my sincere thanks to my Assistant Professors Dr.N.Bharathi Santhose M.D., Dr.C.Ashok Kumar MD., Dr.R.Radhika,MD., Dr.P.Malini, M.D., and Dr.S.Nirmala Devi, M.D., for their valuable suggestions. My special thanks to my post graduate colleagues Dr.C.Varsha, Dr.C.P.Shanthini and Dr.K.Soundarya and other post graduates in the Department of Microbiology for their co-operation in completing my study. I would grossly fail in my duty, if I do not mention here of my subjects who have undergone the pain and discomfort of the investigations during this study. I take this opportunity to thank all the technical staffs in the Department of Microbiology who gave me their kind co-operation throughout my study. I affectionately thank my family members who are giving their constant support throughout my entire post-graduation course without which this work would not have been successful. I am thankful to God, who have been with me all throughout my way to reach the destination. CERTIFICATE - II This is to certify that this dissertation work titled “Identification of Genes Coding for Carbapenemases in Clinical Isolates of Carbapenem Resistant Klebsiella Species in a Tertiary Care Hospital” of the candidate Dr.S.Sharon Dorothy with registration Number 201714252 for the award of Doctor of Medicine in the branch of Microbiology. I personally verified the urkund.com website for the purpose of plagiarism Check. I found that the uploaded thesis file contains from introduction to conclusion pages and result shows 5% (Five) percentage of plagiarism in the dissertation. Guide sign with Seal. CONTENTS CONTENTS S.NO CONTENTS PAGE NO 1. 01 INTRODUCTION 2. 07 AIMS & OBJECTIVES 3. 08 REVIEW OF LITERATURE 4. 30 MATERIALS & METHODS 5. 54 RESULTS 6. 64 DISCUSSION 7. 78 SUMMARY 8. 81 CONCLUSION 9. BIBLIOGRAPHY 10. ANNEXURE 11. MASTER CHART LIST OF TABLES S.NO TABLE 1. SAMPLE WISE DISTRIBUTION OF KLEBSIELLA INFECTIONS 2. TYPES OF KLEBSIELLA SPECIES ISOLATED FROM STUDY POPULATION 3. GENDER WISE DISTRIBUTION OF KLEBSIELLA ISOLATES 4. WARD WISE DISTRIBUTION OF CARBAPENEM RESISTANT KLEBSIELLA SPECIES 5. FACTORS INFLUENCING INCIDENCE OF RESISTANT INFECTIONS IN VARIOUS WARDS 6. AGE WISE DISTRIBUTION OF CARBAPENEM SENSITIVE AND CARBAPENEM RESISTANT ISOLATES OF KLEBSIELLA 7. RISK FACTORS ASSOCIATED WITH INFECTIONS OF KLEBSIELLA SPECIES 8. INVITRO ACTIVITY OF VARIOUS ANTIBIOTICS AGAINST KLEBSIELLA ISOLATES 9. DETECTION OF ESBL AND Amp C β LACTAMASE PRODUCTION BY VARIOUS METHODS 10. VARIOUS TYPES OF β LACTAMASE ENZYME PRODUCERS AMONG ANTIBIOTIC RESISTANT KLEBSIELLA ISOLATES 11. COMPARISON OF VARIOUS PHENOTYPIC METHODS IN THE DETECTION OF CARBAPENEMASES 12. DETECTION OF CARBAPENEMASES BY MOLECULAR METHODS LIST OF CHARTS S.NO CHART 1. SAMPLE WISE DISTRIBUTION OF KLEBSIELLA INFECTIONS 2. TYPES OF KLEBSIELLA SPECIES ISOLATED FROM STUDY POPULATION 3. GENDER WISE DISTRIBUTION OF KLEBSIELLA ISOLATES 4. WARD WISE DISTRIBUTION OF CARBAPENEM RESISTANT KLEBSIELLA SPECIES 5. AGE WISE DISTRIBUTION OF CARBAPENEM RESISTANT KLEBSIELLA INFECTIONS 6. RISK FACTORS ASSOCIATED WITH INFECTIONS OF CARBAPENEM RESISTANT KLEBSIELLA INFECTIONS 7. ANTIMICROBIAL RESISTANCE PATTERN OF KLEBSIELLA ISOLATES 8. DETECTION OF β LACTAMASES BY PHENOTYPIC METHODS 9. DETECTION OF CARBAPENEMASES BY VARIOUS PHENOTYPIC METHODS 10. ISOLATES PRODUCING VARIOUS TYPES OF β LACTAMASES DETECTED BY PHENOTYPIC METHODS 11. VARIOUS GENES CODING FOR CARBAPENEMASES DETECTED BY MOLECULAR METHODS LIST OF COLOUR PLATES S.NO COLOUR PLATE 1. NUTRIENT AGAR PLATE SHOWING COLONIES OF KLEBSIELLA 2. Mac Conkey AGAR PLATE SHOWING MUCOID LACTOSE FERMENTING COLONIES OF KLEBSIELLA 3. BIOCHEMICAL REACTIONS OF KLEBSIELLA PNEUMONIAE 4. BIOCHEMICAL REACTIONS OF KLEBSIELLA OXYTOCA 5. CARBOHYDRATE FERMENTATION TESTS OF KLEBSIELLA SPECIES 6. AMINO ACID DECARBOXYLATION TESTS OF KLEBSIELLA SPECIES 7. GRAM STAINING PICTURE OF KLEBSIELLA SHOWING SHORT GRAM NEGATIVE BACILLI 8. KLEBSIELLA ISOLATE RESISTANT TO MEROPENEM AND SENSITIVE TO COLISTIN AND TIGECYCLINE 9. E STRIP SHOWING KLEBSIELLA ISOLATE RESISTANT TO MEROPENEM (4 µg/ml) 10. E STRIP SHOWING KLEBSIELLA ISOLATE SENSITIVE TO COLISTIN ( 1 µg/ml) 11. DETECTION OF ESBL BY COMBINED DISC METHOD 12. DETECTION OF ESBL BY E STRIP 13. DETECTION OF Amp C BY COMBINED DISC METHOD 14. DETECTION OF CARBAPENEM RESISTANT ISOLATES BY DISC DIFFUSION METHOD 15.. DETECTION OF CARBAPENEMASES BY Carba NP TEST 16. DETECTION OF CARBAPENEMASE BY mCIM AND eCIM 17. DETECTION OF CARBAPENEMASES BY PCR 18. LOADING SAMPLES IN THERMOCYCLER 19. AGAROSE GEL ELECTROPHORESIS 20 MOLECULAR IMAGER (Gel Doc XR+,Biorad.,USA) 21 DISTRIBUTION OF NDM-1 GENES IN RESISTANT ISOLATES 22 DISTRIBUTION OF OXA -48 like GENES IN RESISTANT ISOLATES LIST OF ABBREVIATIONS CDC CENTER FOR DISEASE CONTROL CLSI CLINICAL AND LABORATORY STANDARDS INSTITUTE CRE CARBAPENEM RESISTNANT ENTEROBACTERIACEAE ESBL EXTENDED SPECTRUM β LACTAMASE PCR POLYMERASE CHAIN REACTION CRKP CARBAPENEM RESISTANT KLEBSIELLA PNEUMONIAE` DNA DEOXY RIBONUCLEIC ACID mCIM MODIFIED CARBAPENEM INACTIVATION METHOD eCIM EDTA MODIFIED CARBAPENEM INACTIVATION METHOD CDT COMBINED DISC TEST MBL METALLO β LACTAMASE NDM NEW DELHI METALLO β LACTAMASE OXA OXACILLINASES VIM VERONA INTEGRON METALLO β LACTAMASE IMP IMIPENEMASE KPC KLEBSIELLA PNEUMONIAE CARBAPENEMASE bla KPC GENE CODING FOR KLEBSIELLA PNEUMONIAE CARBAPENEMASE TBE TRIS- BORATE- EDT A bp BASE PAIR EtBr ETHIDIUM BROMIDE HAI HOSPITAL ACQUIRED NFECTION TSB TRYPTIC SOY BROTH SSI SURGICAL SITE INFECTION INTRODUCTION INTRODUCTION Klebsiella belongs to the family Enterobacteriaceae and tribe Klebsiellae. Klebsiella pneumoniae is considered to be one of the most common Gram negative bacteria. It was` initially named after the scientist Carl Friedlander as “Friedlander bacillus” and later came to be called as Klebsiella(1). The genus includes six species- Klebsiella pneumoniae, oxytoca, granulomatis, variicola, singaporensis and alba. Klebsiella pneumoniae is the type genus of this species. Klebsiella are widely distributed in the gastrointestinal tracts of humans and animals(2). Klebsiella pneumoniae is the most common species frequently recovered from clinical specimens. It causes a classic form of primary pneumonia. It is also found in the oropharynx of normal human beings (1-6%), however hospitalized patients possess a higher prevalence of about 20%(3). Patients with debilitating conditions such as Alcoholism, Diabetes mellitus and Chronic Obstructive Pulmonary Disease have more chances of developing severe lung diseases. Klebsiella species has evolved to be a frequent cause of nosocomial infections. It is an important cause of outbreaks in hospitals. The management of infections caused by these organisms is further complicated by the increased incidence of hypervirulent strains. K. pneumoniae is the causative agent of several different healthcare -associated infections, such as bloodstream infections, wound infections, 1 pneumonia, and meningitis.
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