presentation on beta-lactamasecreditseminar.pptx

The global burden of extended spectrum beta-lactamase: a public health crisis

1. FACULTY OF VETERINARY SCIENCE AND ANIMAL HUSBANDRY, SHUHAMA, SKUAST-KASHMIR THE GLOBAL BURDEN OF EXTENDED SPECTRUM BETA-LACTAMASE : A PUBLIC HEALTH CRISIS MASTER SEMINAR (VMC-690) Presented by: Kipa Yari MSV-2023-580 MVSc Scholar Division of Veterinary Microbiology And Immunology

2. INTRODUCTION What are ESBLs? ESBLs are hydrolyzing enzymes secreted by certain bacteria capable of hydroly zing Extended- spectrum cephalosporin . Global health Concern Impact on public health The global antibiotic resistance crisis ESBLs are produced most commonly by the nosocomial pathogens. E.g., E.coli, K lebsiella pneumoniae ESBLs encoding genes are highly diverse in nature, posses a unique character ( Rupp et al) Most prevalent genes currently such as bla TEM , bla SHV and bla CTX -M But susceptible to cephmycin and carbapenems .

3. WHY ARE ESBLS A GROWING CONCERN?? Prolonged Stays and Healthcare cost Increased Morbidity and Mortality Limited Treatment Options Community spread and Outbreaks RAPID GLOBAL SPREAD

4. HISTORY AND EVOLUTION 1940s Discovery of Beta- Lactamase Enzymes by Edward Abraham and Ernst chain from E.coli after the introduction of Penicillin TEM-1 and SHV-1, 1 st plasmid-mediated beta lactamase Resistance to penicillin and early Cephalosporin 1960s: TEM-1 ,the 1 st plasmid -mediated beta-lactamase ,isolated from the blood culture of E.coli , a patient named Temoniera in Greece. ( Bradfort , Esbl in 21 st century, 2001 ) 1970s-1980s Development of ESBLs Mutation of the beta- lactamase Genes Capable of hydrolyzing 3 rd Gen cephalosporin. 1960s

5. 1980s-1990s GLOBAL DISSEMINATION Different variants of ESBL spread globally , primarily in healthcare settings New variants , CTX-M Enzyme emerged 2000s: CTX-M-Types ESBLs domination Epidemiological Shift M ost prevalent, surpassing TEM and SHV type e.g CTX-M-15 2010s-present Ongoing evolution causing significant challenges due to emergence of more new ESBL variants. G lobal pooled prevalence escalated from 2.6% in 2003-2005 to 21.1% in 2015-2018. ( pubmed . Ncbi.nlm.nih.gov ) Rapid spread and Diversification

6. CLASSIFICATION OF ESBLS ESBls are structurally and functionally mutated version of beta-lactamases Evolution of non-ESBL to ESBL via specific amino acid substitutions make them more capable of hydrolyzing O xymino – Cephalosporin.

7. MAJOR FAMILIES OF ESBL TEM-3, TEM-10, TEM-52- widespread in Europe and Asia There are total of 243 different TEM variants found across the globe till 2021. 2 . SHV beta-lactamase ( sulfyhydryl variable) Naturally Originated as chromosomally encoded penicillinase enzymes found in k. pneumonia(SHV-1). (Livermore DM, 1995) Originally function as narrow spectrum beta- lactamases (SHV-1 ) Selective pressure from antibiotic use Mutation The 1 st SHV-type ESBL ,SHV-2, was identified in Germany in the 1980 s capable of hydrolyzing penicillins but had a low activity against cephalosporins 228 SHV variants have been identified though not all exhibit the ESBL phenotype.

8. CTX-M ( C efotaximase -Munich) ESBLs Emerging Variants CTX-M variants CTX-M-27- prevalence in E.coli, (Asia and Europe ) CTX-M-65- detected in K. pneumonia and E.coli In Latin America and china OXA -Type ESBLs Increasing in carbapenem -resistant isolates OXA-48-l ike Enzymes found in k. pneumonia OXA-181 and OXA-232, spreading rapidly in India, Middle East, and Africa GES-Type ESBLs GES-5 and GES-20 , found in P. aeruginosae Exhibiting both ESBL and carbapenemase activity GES-5 and GES-20 , found in P. aeruginosae Oxacillinases VEB-1-Type and PER-Type 1 st CTX-M-type ESBL was identified in 1990s in Munich, Germany, hydrolyze c efotaxime . 6 major types – CTX-M-1, CTX-M-2, CTX-M-8, CTX-M-9, CTX-M-25 and KLUC, on the basis of > or = 10% variance in amino acid sequence. CTM-M-15 , Most prevalent Globally. Over 170 CTX-M identified. The ESBL enzymes encoded bla genes originally found from the chromosome of Kluyvera species ( non-pathogenic E nterobacteriaceae )

9. BETA -LACTAM ANTIBIOTICS P enicillin Cephalosporins Carbapenems Monobactams Beta- lactam Ring

10. MECHANISM OF BETA- LACTAMASES B ased On Their Distinct Amino Acid Residue Zn+2 ions activates water molecules increasing its nucleophilicity Attack the amide bond of the ring Beta- lactam Ring opening Beta -Lactam binds to the active site of the enzyme 4. Hydrolysis and release of the inactivated antibiotic Beta- lactam Ring opening Metallo - Beta lactamase Serine beta-lactamase(SBL) 1. Substrate binding 2.Nucleophilic attack The active site attacks the amide bond of the ring 3. Ring opening

11. Expected Annual Rise of AMR by 5-10% annually by ICMR Annual Report 2021, due to abusive use of Broad- spectrum beta Lactamase. Indian Population is the Highest consumer of antibiotics in the World. AMR has been reported as highest causes of Death , survey conducted in 204 countries which is higher than HIV/Malaria/ AIDS. More than 70% of all AMR related deaths are due to Beta- Lactam and fluoroquinolone resistance. Resistance to Imipenems in the case of E.coli has rise from 28.4% in 2016 to 42.6% in 2021. ANTIMICROBIAL RESISTANCE

12. ESBL AND ITS CONTRIBUTIONS IN DEVELOPMENT OF MDR Mechanism of drug resistance Resistance to multiple classes of antibiotics ESBL production is not limited to Beta-lactam resistance carry additional genes Fluoroquinolones Aminoglycoside C arbapenem Sulfonamide and Trimethoprim Common MDR Pathogen: ESKAPE, CRE, VRE, MDR-TB

13. Antibiotics Clinical and therapeutic use Livestock medicine use Byproducts Pet animals and food animals contaminated by ARBs and ARGs Human waste contains ARBs and ARGs Human waste hospital contamination Transmission of ARGs between different bacteria through HGT Environment Transmission of ESBLs genes among humans, animals and t he environment Biofilm formation in the environment by producing Extra cellular polymeric substance Enhances bacterial resistance Disinfectants peracetic acid and H2O2 h ighly effective against k. pneumonia Control spread

14. GLOBAL PREVALENCE OF ESBL INFECTIONS Healthcare settings : A 2021 study analyzing 73,318 samples found 21.1% of inpatients carried ESBL-producing E.coli. (pmc.ncbi.nlm.nih.gov.) Community settings: Also reported a 17.6% intestinal carriage rate among healthy individuals worldwide . Regional variations: South-East Asia: highest community carriage was observed at 35.5%. Eastern M editeranean : highest carriage rate at 45.6% in healthcare settings. USA : In 2017, approx . 197,400 cases of ESBL-E infections were reported among hospitalized patients, resulting in an estimated 9,100 deaths . (CDC.gov.)

15. A multi- centric study reported ESBL prevalence rate as high as 87% in major tertiary care hospital across India. The SENTRY surveillance study indicated that ESBL prevalence in E.coli and Klebsiella species range from 62% to 100% i n various Indian Hospitals In Eastern India , 43% of community acquired UTI were predominantly caused by E.coli a nd K. pneumoniae Overall mortality rate among patients with infections caused by MDR pathogen was 13.1% in India

16. Global Prevalence In Livestock Sector Prevalence of ESBL- E. coli  isolates according to their sample source: ( a ) cattle, ( b ) pig, ( c ) sheep, and ( d ) chicken. Contrasting prevalence of ESBL- E. coli  by phenotypic and genotypic methods in 72 studies worldwide during the period from 2018 to 2023 . Species country percentage (%) prevalence Poultry India, Pakistan, Malaysia, Indonesia Tanzania Germany , UK, Italy 60.35% 63.3% 31. 4% Cattle ( Varying in prevalence Rate ) South Korea and Pakistan (CTX-M-15, CTX-M-1, CTX-M-9) 90.5% ( sheep) Sheep ( limited studies) Nigeria Southern Portugal 56.0% 90.5% ( sheep) Pig Thailand Tanzania Europe 98.0% (2019- highest) 63.3%( 2021) 18.8% ( swine feacal sample)

17. Global distribution of ESBL enzymes frequently detected in E. coli isolates from food-producing animals. Distributions of ESBL In E.coli in Livestock

18. Prevalence In India A systemic and Meta- analysis from 2019 found that overall prevalence of ESBL- producing bacteria among animals in India was 9%. Regional prevalence rate in animals Central zones 8% South 6% East 11% North 26%

19. ESBL TEST Increased length of patient hospital stay Increase mortality rate Increased multidrug resistance Complicated and rapidly spreading infections DIAGNOSTIC APPROACHES Indicated Phenotypic Molecular

20. Phenotypic 1. Disk Diffusion method Potential ESBL producers if the Zone of inhibition Cefazidime (<_22mm ) Cefotaxime (<_27mm ) Cefepime (<_24mm ) Aztreonam (<_27mm ) Cefpodoxime (<_17mm ) most recommended by CLSI . (Thompsons KS et al 1997) if isolates meets screening criteria screening Confirmatory phenotypic method 1.Combination Disk Test( CDT ) 2.Double Disk Synergy Test (DDST) 3. ESBL-E test ( Epsilon Test) Ellipse shaped inhibition zone Detects synergy between cephalosporin and clavulanic acid

21. MOLECULAR METHOD Multiplex PCR Detects genes such as bla -TEM, bla -SHV, bla -CTX - M Faster Detection of Multiple ESBL genes Chromogenic Agar detection Cephalosporin + chromogenic agar Hydrolyze Cephalosporin Only Resistant strains grow Bacterial strains shows varying colour enabling easy visualization Rapid identification( 18-24hr) Direct differentiation Chromogen media – CHROMagar ESBL ( E. coli ; pink or dark rose colonies) Brilliance ESBL agar

22. CHALLENGES IN ESBL DETECTION Lack of Standardized screening False Negative Results Co-existence of Multiple Resistance Mechanisms Variability in ESBL Genes Interference by Beta-lactamase inhibitors Delayed Result In Clinical settings Limited Availability Of Molecular Testing Impact on Therapy Choices

23. CURRENT THERAPIES For ESBL Based On CSLI guidelines Severe infection Carbapenems (Gold Standard ) Meropenem , Imipenem Ertapenem Mild to Moderate Combination of Beta- Lactam / beta lactam inhibitors Piperacillin – Tazobactam Ceftazidime -Avibactam Ceftolozane-tazobactam Therapy for UTIs only : Fosfomycin and Nitrofurantoin Last Resort Options Polymixins ( colistin , Polymixin B) Tigecyline – use for complicated intra-abdominal infection. Aminoglycosides ( Amikacin,Gentamicin , Tobramycin) Used for carbapenem resitance

24. WHO AND CDC RESPONSE TO ESBL THREAT Categorized 24 Antibiotic- resistance bacteria into Critical, High and Medium 2 . Global Antimicrobial Resistance surveillance 1. One Health approach 3 . Global Action Plans on AMR 4 . The 2024 WHO Bacterial Pathogen Priority List (BPPL

25. KEY INITIATIVES UNDERTAKEN BY CDC Surveillance and Data Collection: Emerging Infections Program (EIP) . Multi-Site Gram-negative surveillance Initiatives ( MuGSI ) National Healthcare Safety Network (NHSN) : CDC tracks ESBL trends in hospitals and communities Infection Prevention and Control: Guidelines and Resources Enhanced Barrier Precautions Research And Development; Epidemiological Studies Antibiotic stewardship programs to reduce unnecessary antibiotic use. Public Health And Healthcare professional Education: Awareness campaigns Training programs to healthcare proffessionals on responsible antibiotic use

26. Development Of New Antibiotics Alternative Treatment Strategies Strengthening Antibiotic Stewardship Quick Diagnostic Technology Using AI Vaccination strategies Investment In Research And Development Global Policy And Regulatory Measures Public Awareness And Education

27. Thank you