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Superbugs- What really is it?
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K. Karthik
Introduction
• A bacterium carrying resistance to more than one antibiotic is called as superbug or super bacteria.
• Presently- a pile of bacteria line up in this list• No ESKAPE from superbug1. Enterococcus faecium2. Staphylococcus aureus3. Klebsiella pneumoniae4. Acinetobacter baumanii,5. Pseudomonas aeruginosa, 6. Enterobacter species
Bugs web the world
Supe-R-evolution
• Basis of Darwin’s theory- survival of fittest
• Selection pressure
Antibiotics
Mechanism
• Spontaneous mutation
• Lateral gene transfer- conjugation, transformation, transduction
• Uptake of resistance gene form plasmid, transposons, integrons
• CRISPR(Clustered Regularly Interspaced Short Palindromic Repeats)- act against gene uptake
Mutation
• Change in the nucleotides at a single position can lead to mutation- resistance
• gyrA (DNA gyrase) –mutation in 83 and 87 nucleotide lead to change in aminoacids-resistance development - quinalonessimilarly for parC (topoisomerase IV )
Mutation
PBP
PBP
Thickened peptidoglycan-vancomycin trapped in peptidoglycan
Beta lactam
Beta lactamase Peptidoglycan
Vancomycin
Alter in peptidoglycanshape
Mutated mRNA
Protein
Normal DNA
Mutation and methylation of rRNA
Linezolid, quinupristin–dalfopristin, daptomycin,tigecycline
1
3
2
Resistance development
• Widespread use of antibiotics
• Antibiotics as growth promoters
• Irregular dosing and period of antibiotic usage
• Over the counter sale of antibiotics
• Direct use of higher generation antibiotics
MRSA
• 1981, USA- in i/v drug users
• Commonly referred as superbug in press
• Common strains EMRSA15 and EMRSA16 (Johnson et al., 2001)
• Types:
– Community-associated MRSA (CA-MRSA)
– Health care-associated MRSA (HA-MRSA)
Trend in S. aureus resistance development
CA/HA-MRSA
• CA-MRSA- seen in healthy people- usually skin infections
• RISK factors: Crowding, contact, compromised skin, contaminated surfaces, shared items and poor hygiene
• HA-MRSA- seen in hospitalized patience (Immunocompromised)
• Risk: hospitalization, surgery, dialysis, long-term care, indwelling devices, and history of previous MRSA infection
PVL-MRSA
• Panton Valentine Leukocidine +ve MRSA- CA MRSA type- highly virulent
• Targets white blood cells- depletion of WBC-low immunity
• Causes boils, abscess, tissue necrosis
• Extreme condition: septic arthritis, septicemia and lethal necrotizing pneumonia
USA300
• New strain of MRSA
• Do not have the capability to acquire genes from other MRSA
• They inherit from USA500 strain
• Bacterial toxin alpha haemolysin (Hla)- can serve as weapon against MRSA
• Immunization with Hla reduced skin infection
Human animal
• 1972- I report of MRSA in cattle
• Now reported in almost all livestock's
• Old thoughts: MRSA- human to animal through hands to nostrils
• New ideas: Bi-directional
• Healthy animals- reservoir (Klevens et al., 2007, Smith et al., 2009)
• Wild animals: USA300 strain isolated- elephants
Extended spectrum beta lactamase
• ESBL joins MRSA, VRSA, VISA and vancomycinresistant Enterococcus
• ESBL hydrolyses all penicillins, cephalosporinsand monobactams
• E. coli and Klebsiella are the important organism –ESBL
• Mortality rate : 25-75%
NDM-1
• New Delhi Metello betalactamase -1
• 2009, swedish patient- urinary tract infection-carbapenem-resistant K. pneumonia
• Resistant to all antibiotics except tigecyclineand colistin.
• Resistance gene located on plasmid
• E. coli and K. pneumonia commonly acquires this gene (blaNDM-1)
Genes carried by NDM-1 superbugs
• blaTEM-1, blaOXA-1, blaOXA-10 and blaCMY (various β-lactamases)
• qnrA6 and qnrB1 (quinolone resistance)
• armA, rmtA and rmtC (nearly all aminoglycoside antibiotics)
• arr-2 (rifampicin ribosyltransferase)
• sul-2(sulfonamide-resistant dihydopteroate synthase)
• cmlA (chloramphenicol acetyltransferase)
• ereC (macrolide resistance)
• A few plasmids carrying blaNDM-1 also encode other carbapenemases, including OXA-181- and VIM-types
Variants
• NDM-2• Acinetobacter baumannii from Germany- showed
sequence change NDM-1 gene by substitution of C to G at 82
• Leads to amino acid change- no plasmid in these strains
• First variant of NDM-1 in A. baumannii• NDM-3 and NDM-4 in Enterobacteriaceae from
Australia and India (Nordman et al., 2011)• Consequences -?
MDR-TB/ XDR-TB
• 440,000 MDR-TB cases as per WHO, 2008
• India & China- 50% global contribution
• Spontaneous mutation; no HGT
• Drug usage as monotherapy- leads to resistance
• India, Gujarat state: 2006 Survey – MDR-TB:216
– XDR in MDR: 7
– % XDR in MDR: 3·2% (1·2–6·6)
Resistance development- clinical threat
Incorrect treatmentMycobacterium
infection
Healthcare center
Clinical threats
• One resistant MRSA kills> people than AIDS, Parkinson's and homicide together
• MRSA can spread through sharing of clothing, personal items and sports equipment
• Surgical site infection (SSI)- crucial post operative complication.
• Spread of NDM-1 through endoscope camera-UK
• >29% of SSIs are complicated with MRSA
Threats..
• Flesh eating bugs- causes severe infection to human and treatment failure
• Spread by sneezing, coughing and contact
Organism/ resistance Resistance mechanism Future AntimicrobialAgents with Potential Clinical Use
Hospital-associated MRSA
Vancomycin (both VISAand VRSA)
Thickening of cell wall Linezolid, quinupristin–dalfopristin, daptomycin,tigecycline, ceftobiprole, ceftaroline,dalbavancin, telavancin, oritavancin,iclaprim
Daptomycin changes in cell wall and cellmembrane
Linezolid, quinupristin–dalfopristin, tigecycline,ceftobiprole, ceftaroline, dalbavancin,telavancin, oritavancin, iclaprim
Linezolid Mutations in the 23S ribosomal RNA genes
Daptomycin, quinupristin–dalfopristin, tigecycline,ceftobiprole, ceftaroline, dalbavancin,telavancin, oritavancin, iclaprim
Organism/ resistance Resistance mechanism Future AntimicrobialAgents with Potential Clinical Use
Vancomycin-resistant Enterococcus faecium
Ampicillin Mutation and overexpression of pbp5
Linezolid, quinupristin–dalfopristin, daptomycin,tigecycline
High-level resistance toaminoglycosides
Acquisition of aminoglycoside-modifying enzymes;ribosomal mutations
No alternative for a reliable bactericidal effectalone or in combination
Linezolid Mutations in the 23S ribosomal RNA genes
Quinupristin–dalfopristin, daptomycin, tigecycline
Quinupristin–dalfopristin Enzymes that inactivate quinupristin–dalfopristin,target modification
Daptomycin, linezolid, tigecycline
Escherichia coli, Klebsiella species and Enterobacter species
Cephalosporins Extended-spectrum β-lactamases (includeshyperproduction of the AmpC enzymes)
Carbapenems, tigecycline
Carbapenems Production of carbapenemases, decreasedpermeability
Polymyxins, tigecycline
Acinetobacter species/ Pseudomonas aeruginosa
Carbapenems Decreased permeability, increased efflux,and production of carbapenemases
Polymyxins
Tigecycline and colistin- nephrotoxic
Non clinical threats
• Presence of MRSA without clinical signs
• Condition remains unnoticed till admitted in clinics (Leonard and Markey, 2008)
• Marine mammals also inhabit MRSA without signs and can transmit to sea divers
• Strastkova et al. (2009) reported MRSA from goat milk- no signs- potential to transmit
• Pigs are also a major source without signs
• Affect medical tourism
Through food products• MRSA can also be transmitted through meat
products
• USA300 and USA100- isolated from meat shops
• Studies from Japan, Turkey reveals the same
• Recently NDM-1 DNA has been recovered from drinking water and sewage in INDIA
• MRSA is found everywhere and can be isolated commonly from all places in hospitals where hygienic conditions are poor.
CONCLUSION
• Hygienic measures are required
• Use of antibiotics in a proper way
• Need to find new antibiotics
• Time to shift towards antibiotic alternatives?
• Infectious disease society of America (IDSA)
– Bad bugs, No drugs- 2004
– Bad bugs, need drugs- 2010
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