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దాసస్తేహం దేహదృష్ట్ య ాస్మి శంభో జాతస్తేశో జీవదృష్ట్ య ా త్రిదృష్ట్యా సర్వస్యాతినాతి దృష్ట్ య ా తవమేవ త్వవవం మే ధీర్నిశ్చితా సర్వ శాస్త్రైః || daasasthae aham daehadrishtya asmi Sambho jaathasthaeso jeeva drishtyaa thri drishtyae sarvasya athman athma drishtyaa thwamaeva thwaevam mae dheer nishchithaa sarva saasthraih || O! Lord, the three eyed one (who is the all knower of the past, present and future)! In the form of this physical equipment, the body, I am the servant of You and thus of all. In the form of the life principle with in me, I am the part and parcel of You and thus of all. In the form the soul, You are within me and similarly in every other being or animal or thing that I behold. I have arrived at this conclusion after thorough reflection in my intellect illuminated by all the sacred texts. “The greatest possibility of evil in selfmedication is the use of too small doses so that instead of clearing up infection, the microbes are educated to resist penicillin and a host of penicillin-fast organisms is bread out which can be passed to other individuals and from them to others until they reach someone who gets a septicemia or a pneumonia which penicillin cannot save.” Sir Alexander Fleming … 1954 M.D., M.Sc.(Canada), FIMSA, Senior Consultant Physician & Cardio-Metabolic Specialist Food Venti lators Air, Dust Endo scopes Water Patient Cathe ters Disinfe ctants IV Fluids Wash basins Toilets Cell Wall Lactams (Penicillins, Cephalosporins, Carbapenems, Monobactams) Vancomycin, Bacitracin Protein Synthesis Macrolides, Lincosamides, Chloramphenicol, Tetracycline, Aminoglycosides, Mupirocin, Linezolid Nucleic Acid synth Rifampin, Metronidazole DNA Synthesis Quinolones, Novobiocin Cell Membrane Polymyxin B, Gramicidin, Daptomycin Inappropriate empiric antibiotic therapy can lead to increases in: – mortality – morbidity – length of hospital stay – cost burden – resistance selection A number of studies have demonstrated the benefits of early use of appropriate empiric antibiotic therapy for patients with nosocomial infections Inappropriate antibiotic therapy can be defined as one or more of the following: – ineffective empiric treatment of bacterial infection at the time of its identification – the wrong choice, dose or duration of Rx. – use of an antibiotic to which the pathogen is resistant 18 14 12 Resistance Number of agents approved 16 10 8 6 4 2 0 0 1983-87 1988-92 1993-97 1998-02 2003-05 2008 Bars represent number of new antimicrobial agents approved by the FDA during that period •Infectious Diseases Society of America. Bad Bugs, No Drugs. July 2004; Spellberg B et al. Clin Infect Dis. 2004;38:1279-1286; •New antimicrobial agents. Antimicrob Agents Chemother. 2006;50:1912 • Uncontrolled, improper and indiscriminate use of antibiotics for therapy and prophylaxis • Inadequate lengths of therapy • unnecessary use, lack of activity, insufficient doses • low penetration to body sites • Poor patient compliance • Poor hand hygiene & failure of infection control measures • Excessive use of cleaners, detergents & anti bacterials • Antibiotics in livestock, animals, birds & agriculture Antibiotics are the medical miracle of the last 50yrs • Selection Pressure – “Survival of the fittest” • Innate genetic mutation • Destruction or Inactivation (-Lactamase) • Efflux of the antibiotic that entered the bacteria • Accepting resistance genes from other bacteria • Genetic Transfer by Plasmids, Transposons • Conjugation, Transformation and Transduction Penicillinase Plasmid Gene for -Lactamase This organism can freely grow in the presence of Penicillin –Lactam Ring Active –Lactamase Inactive Structurally modified antibiotic target site, resulting in: – Reduced antibiotic binding – Formation of a new metabolic pathway preventing metabolism of the antibiotic Antibiotics normally bind to specific binding proteins on the bacterial cell surface Antibiotic Binding Target site Cell wall Interior of organism Antibiotics are no longer able to bind to modified binding proteins on the bacterial cell surface Antibiotic Modified target site Cell wall Changed site: blocked binding Interior of organism Altered uptake of antibiotics, resulting in: • Decreased permeability • Increased efflux Antibiotics normally enter bacterial cells via porin channels in the cell wall Antibiotic Porin channel into organism Cell wall Interior of organism New porin channels in the bacterial cell wall do not allow antibiotics to enter the cells Antibiotic New porin channel into organism Cell wall Interior of organism Antibiotics enter bacterial cells via porin channels in the cell wall Porin channel Antibiotic through cell wall Entering Entering Cell wall Interior of organism Once antibiotics enter bacterial cells, they are immediately excluded from the cells via active pumps Antibiotic Porin channel through cell wall Entering Exiting Cell wall Interior of organism Active pump Antibiotic inactivation • Bacteria acquire genes encoding enzymes that inactivate antibiotics Examples include: • -Lactamases • Aminoglycoside-modifying enzymes • Chloramphenicol acetyl transferase Inactivating enzymes target antibiotics Antibiotic Enzyme Binding Target site Cell wall Interior of organism Enzymes bind to antibiotic molecules Enzyme binding Antibiotic Enzyme Binding Target site Cell wall Interior of organism Enzymes destroy antibiotics or prevent binding to target sites Antibiotic destroyed Antibiotic altered, binding prevented Antibiotic Enzyme Target site Cell wall Interior of organism -lactam Glycopeptide Aminoglycoside Tetracycline Chloramphenicol Macrolide Sulphonamide Trimethoprim Quinolones Modified target Altered uptake Drug inactivation + + – – + ++ + + – ++ ++ ++ ++ – – – + + Three mechanisms of -lactam antibiotic resistance are recognised: • Reduced permeability • Inactivation with -lactamase enzymes • Altered penicillin-binding proteins (PBPs) AmpC and Extended-Spectrum -lactamase (ESBL) production are the most important mechanisms of -lactam resistance in nosocomial infections The antimicrobial and clinical features of these resistance mechanisms are highlighted in the following slides Worldwide problem: • Incidence increased from 17% to 23% between 1991 and 2001 in UK Very common in Gram-negative bacilli AmpC gene is usually sited on chromosomes, but can be present on plasmids Enzyme production is either constitutive (occurring all the time) or inducible (only occurring in the presence of the antibiotic) Pfaller et al. Int J Antimicrob Agents 2002;19:383–388; Sader et al. Braz J Infect Dis 1999;3:97–110; Livermore et al. Int J Antimicrob Agents 2003;22:14−27 An increasing global problem Found in a small, expanding group of Gram-negative bacilli, most commonly the Entero-bacteriaceae spp. Usually associated with large plasmids Enzymes are commonly mutants of TEM- and SHV-type -lactamases Jones et al. Int J Antimicrob Agents 2002;20:426–431; Sader et al. Diagn Microbiol Infect Dis 2002;44:273–280 Inhibited by -lactamase inhibitors Usually confer resistance to: • 1, 2 and 3rd generation Cephalosporins eg. Ceftazidime • Monobactams eg. Aztreonam • Carboxypenicillins eg. Carbenicillin Varied susceptibility to Piperacillin / Tazobactam Typically susceptible to Carbapenems and Cephamycins Often non-susceptible to fourth generation Cephalosporins Genomic Islands e.g. Escherichia Coli Prophages Common: 4.1 Mb K12 Islands: 0.53 Mb 0157:H7 Islands: 1.34 Mb Conjugative Transposons (gram +ve) Minimal species Genomic backbone Insertion Sequences Transposons Super Integrons (Mainly Protobacteria) Integrons Infectious Disease Society of America Superbugs – Resistant to two or more wide spectrum antibiotics – Acintobactor baumannii – Pseudomonas aeruginosa – ESBL-producing Enterobacteriaceae – Klebsiella pneumoniae (carbapenemase producing) – Methicillin Resistant Staphylococcus aureus (MRSA) – Vancomycin Resistant Enterococcus (VRE), VRSA – NDM1 – Escherichia coli •1. Infectious Diseases Society of America. Bad Bugs, No Drugs: As Antibiotic Discovery Stagnates, A Public Health Crisis Brews. http://www.idsociety.org/pa/IDSA_Paper4_final_web.pdf. July, 2004. Accessed March 17, 2007. 2. Talbot GH, et al. Clin Infect Dis. 2006;42:657-68. MRSA (Staph. aureus) Streptococcus pneumoniae ESBL Escherichia coli MRSA NDM1 – Esch. coli Grundmann H et al. Lancet 2006;368:874. Published Online - August 11, 2010 • Gram-negative Enterobacteriaceae • Resistance to Carbapenem & other antibiotics • Conferred by New Delhi Metallo β Lactamase-1 • Called as NDM-1 • Potentially a major global health problem • The prevalence of NDM-1 was investigated • Multidrug resistant E. coli in India, Pakistan, & UK • In India - Chennai, Haryana • Carbapenems resistance gene blaNDM-1 by PCR • 44 isolates with NDM-1 in Chennai, 26 in Haryana, 37 in the UK, and 73 in other sites in India and Pakistan. NDM-1 was mostly found among Escherichia coli (36) and Klebsiella pneumoniae (111), which were highly resistant to all antibiotics except to Tigecycline and Colistin. • Most isolates carried the NDM-1 gene on plasmids • Those from UK and Chennai were readily transferable whereas those from Haryana were not conjugative. • Many of the UK NDM-1 positive patients had travelled to India or Pakistan within the past year. • The potential of NDM-1 to be a worldwide public health problem is great. Co-ordinated international effort is needed. Lancet Infect Dis 2010; 10: 597–602 Lancet Infect Dis 2010; 10: 597–602 Lancet Infect Dis 2010; 10: 597–602 Lancet Infect Dis 2010; 10: 597–602 Antibiotic resistance in the hospital or community setting is increasing at an alarming rate and the following steps are essential to counter this menace • Selecting the most appropriate antibiotic based on the patient, risk factors, suspected infection and resistance • Administering antibiotics at the right dose and duration • Changing antibiotic dosage or therapy based on resistance • Recognising that prior antimicrobial administration is a risk factor for the presence of resistant pathogens • Knowing ones area’s antimicrobial resistance profile and choosing antibiotics accordingly Cosgrove et al. Arch Intern Med 2002;162:185–190 Hand washing plays an important role in nosocomial pneumonias Wash hands before and after suctioning, touching ventilator equipment, and/or coming into contact with respiratory secretions. Use a continuous subglottic suction ET tube for intubations expected to be > 24 hours Keep the HOB elevated to at least 30o unless medically contraindicated • Dalbavancin • Oritavancin • Telavancin • Garenoxacin (FQ) • Ceftobiprole (Zeftera®) • Daptomycin (Cubicin®) • Ceftaroline, Faropenem Malabarba A et al. J Antimicrob Chemother. 2009