• Share
  • Email
  • Embed
  • Like
  • Save
  • Private Content
Antimicrobials
 

Antimicrobials

on

  • 6,439 views

 

Statistics

Views

Total Views
6,439
Views on SlideShare
6,439
Embed Views
0

Actions

Likes
12
Downloads
1
Comments
9

0 Embeds 0

No embeds

Accessibility

Categories

Upload Details

Uploaded via as Microsoft PowerPoint

Usage Rights

© All Rights Reserved

Report content

Flagged as inappropriate Flag as inappropriate
Flag as inappropriate

Select your reason for flagging this presentation as inappropriate.

Cancel

19 of 9 previous next Post a comment

  • Full Name Full Name Comment goes here.
    Are you sure you want to
    Your message goes here
    Processing…
Post Comment
Edit your comment
  • Selective toxicity - greater harm to microbes than host, done by interfering with essential biological processes common in bacteria but not human cells. LD 50 vs. MIC - Therapeutic index (the lowest dose toxic to the patient divided by the dose typically used for therapy). High TI are less toxic to the patient. Bactericidal vs. bacteriostatic Static rely on normal host defences to kill or eliminate the patogen after its growth has been inhibited. (UTIs) CIDAL given when host defenses cannot be relied on to remove or destroy pathogen. Favorable pharmacokinetics - drug interxns, how drug is distributed, metabolized and excreted in body (unstabel in acid, can it cross the Blood-brain barrier, etc) Spectrum of activity broad spectrum - wide Narrow spectrum - narrow range (pathogen must be ID’d) Lack of “side effects” allergic, toxic side effects, suppress normal flora Little resistance development
  • Treat infection not colonization
  • High therapeutic index some block NAM elongation - Vancomycin precursor transport blockage - Bacitracin β-lactam drugs beta lactam ring has structural similarity between normal substrate (for enzymes known as penicillin binding proteins (PBPs) By mimicking the substrate the beta lactam drugs are bound by PBPs thus competitively inhibiting their enzymatic activity. This causes a disruption in CW synthesis. B/c CW are only synthesized in actively multiplying cells, these are only effective against growing bacteria. Some make beta lactamse, an enzyme that breaks down the ring structure and thus inactivates penicillins
  • Sulfonamides, which resemble p-aminobenzoic acid and dapsone (leprosy and pneumocytis) competitively inhibit dihydropterate synthase. Trimethoprim inhibits the enzymatic action of dihydrofolate reductase. Both of these actions cause interference with the synthesis of folic acid, which is required by bacteria.
  • MRSA deaths exceeds death rate for AIDS in US. Globally – TB resistance Institute of Medicine estimates 1998 JAMA 2007 Klevens et al. Costs can be looked at patient, physician, provider, industry, public.
  • Introduction of every new class of antimicrobial drug is followed by emergence of resistance. By the 1950s, penicillin-resistant S. aureus were a major threat in hospitals and nurseries. By the 1970s, methicillin-resistant S. aureus had emerged and spread, a phenomenon that encouraged widespread use of vancomycin. In the 1990s, vancomycin-resistant enterococci emerged and rapidly spread; most of these organisms are resistant to other traditional first-line antimicrobial drugs. At the end of the century, the first S. aureus strains with reduced susceptibility to vancomycin were documented, prompting concerns that S. aureus fully resistant to vancomycin may be on the horizon.
  • Bacteria have evolved numerous mechanisms to evade antimicrobial drugs. Chromosomal mutations are an important source of resistance to some antimicrobials. Acquisition of resistance genes or gene clusters, via conjugation, transposition, or transformation, accounts for most antimicrobial resistance among bacterial pathogens. These mechanisms also enhance the possibility of multi-drug resistance.
  • Once resistant strains of bacteria are present in a population, exposure to antimicrobial drugs favors their survival. Reducing antimicrobial selection pressure is one key to preventing antimicrobial resistance and preserving the utility of available drugs for as long as possible.

Antimicrobials Antimicrobials Presentation Transcript

    • ANTIMICROBIALS
    • Dr Kamran Afzal
    • Asst Prof Microbiology
  • Fleming and Penicillin P. chrysogenum destroyed S. aureus 1928
  • Rapidly I ncreasing A ntibiotic R esistance C onstitutes O ne of the M ost I mportant C linical, E pidemiological and M icrobiological P roblems of T oday
  • What is an Antimicrobial?
    • A substance of biological, semi-synthetic or synthetic origin, produced by a fungus or bacterium as secondary metabolites, that inhibits or stops growth of other microorganisms in vitro and in vivo selectively, when used in low concentration
    • Antibiotic
      • Chemical produced by a microorganism that kills or inhibits the growth of another microorganism
    • Antimicrobial agent
      • Chemical that kills or inhibits the growth of microorganisms
    • Selective toxicity
      • A drug that kills harmful microbes without damaging the host
    • Therapeutic index
      • Toxic dose/ Effective dose
  • Microbial Sources of Antibiotics
  • The Ideal Drug
    • Selective toxicity against target pathogen but not against host
    • Bactericidal vs. bacteriostatic
    • Favorable pharmacokinetics
      • Reach target site in body with effective concentration
    • Spectrum of activity
      • Broad vs. narrow
    • Lack of “side effects”
    • Therapeutic index
      • Effective to toxic dose ratio
    • Little resistance development
    • Adverse effect profile
    • Cost
    * There is no perfect drug
  • Use of Antimicrobial Therapy
    • Prophylaxis
      • Prevention of infection to which patient is felt to be at high risk of acquiring
    • Empiric
      • Target empiric therapy to likely pathogens and local antibiogram
    • Definitive
      • Target definitive therapy to known pathogens and antimicrobial susceptibility results
  • Terminology (1)
    • Antibacterial spectrum
    • Range of activity of an antibiotic against microorganisms
    • A broad spectrum
      • Antibiotic that can inhibit wide range of Gram positive and Gram negative bacteria
      • (Carbapenems, 3-4th generation cephalosporins, quinolones)
    • A narrow spectrum
      • Antibiotic that is active only against a limited number of bacteria
      • (Penicillin G)
  • Terminology (2)
    • Bacteriostatic activity
      • Level of antimicrobial activity that inhibits the growth of bacteria
    • Bactericidal activity
      • Level of antimicrobial activity that kills the bacteria
    • Minimum inhibitory concentration (MIC)
      • The lowest concentration that inhibits the growth of bacterial population
    • Minimum bactericidal concentration (MBC)
      • The lowest concentration that kills 99.9% of the bacterial population
  • Terminology (3)
    • Antibiotic combinations
    • Antibiotic synergism
      • Combination of antibiotics have enhanced activity when tested together compared with each antibiotic alone (e.g. 2 + 2 = 6)
      • (Ampicillin+gentamicin in entercoccal carditis)
    • Additive effect
      • Combination of antibiotics has an additive effect (e.g. 2 + 2 = 4)
      • (Combination of two β -lactam antibiotics)
    • Antibiotic antagonism
      • Combination in which the activity of one antibiotic interferes with the activity of the other (e.g. 2 + 2 < 4)
  • Antibiotics - Mechanisms of Action Anti-Mycobacterials
  • Antibiotics - Mechanisms of Action
  • Gram-positive and Gram-negative cell wall
  • Structure of Peptidoglycan β -lactams inhibit synthesis of crosslinks
  • Cell Wall Synthesis Inhibitors
    • β-Lactam ring structure
    • Exposure to β-Lactams – Gram pos.
    • Exposure to β-Lactams – Gram neg.
  • Inhibition Of DNA Synthesis
  • tetrahydrofolic acid Anti-metabolite Action
  • Clinical Uses Ampicillin, gentamicin, etc. Ticarcillin, tobramycin Clindamycin Gram negative Enterics, etc. Pseudomonas B. fragilis Penicillin G (oral or IM) Methicillin, Nafcillin Gram positive Pen-ase (-) Pen-ase (+) TYPICAL DRUG PATHOGENS
  • Chloroquine Metronidazole, Quinacrine Parasites Plasmodium Giardia Nystatin Amphotericin B, ketoconazol Fungi Cutaneous Deep Streptomycin, rifampicin Iso-nicotinic hydrazide (INH) Mycobacterium TYPICAL DRUG PATHOGENS
    • ANTIBIOTIC RESISTANCE
  • The Problem of Antibiotic Resistance
    • Penicillin resistance first identified in 1940’s
    • Since then, antibiotic resistance has developed faster than new drugs
    • Estimated cost of infections: $4-5 million per year
    • Antibiotic resistance previously concentrated in hospitals, especially ICUs
    • MRSA recently estimated to kill 18,000 Americans yearly
  • Examples of overuse/misuse
    • Empiric use (no known etiologic agent)
    • Increased use of broad spectrum agents
    • Prescription not taken correctly
    • Antibiotics sold without medical supervision
    • Prophylactic use before surgery
    • Antibiotics for viral infections
    • Spread of resistant microbes in hospitals due to lack of hygiene
    • Patients who do not complete course (TB, AIDS)
    • Antibiotics in animal feeds
  • Unnecessary Antibiotic Prescriptions
  • Antibiotic Resistant Microorganisms
    • MRSA: methicillin-resistant S. aureus
    • VRE: vancomycin-resistant enterococci
    • VRSA & VRSE: vancomycin-resistant S. aureus and S. epidermidis
    • VISA: vancomycin intermediately susceptible S. aureus
    • GISA: glycopeptide intermediately susceptible S. aureus
    • PRSP: penicillin-resistant S. pneumoniae
    • QRNG: quinolone-resistant N. gonorrhoeae
    • ESBL producer: extended spectrum β -lactamase producer
  • Evolution of Drug Resistance in S. aureus S. aureus Penicillin [1940s] Penicillin-resistant S. aureus Methicillin [1970s] Methicillin-resistant S. aureus (MRSA) Vancomycin-resistant enterococci (VRE) Vancomycin [1990s] [1997] Vancomycin intermediate- resistant S. aureus (VISA) 2004 Vancomycin- resistant S. aureus
  • Terminology (4)
    • Resistant organism
    • MICs of organism are higher than achieved drug concentrations in tissues
    • Intermediately resistant
    • The antibiotic may still be effective but higher doses should be used
    • Highly resistant
    • The antibiotic tissue concentrations are likely not to exceed MICs of the microorganisms
  • Terminology (5)
    • Bacteriophage
    • Virus, infecting bacteria (virus of bacteria)
    • Integron
    • Slice(s) of DNA, cassette of gene that may be entered into other cell
    • Plasmid (R factors)
    • Circular double stranded DNA molecule, located separately of the chromosomal RNA
    • Transposon
    • Genes moving from one point to another (jumping genes)
    Resistance Genes
  • Antibiotic Resistance
    • Types of resistance
    • Intrinsic or natural resistance
      • G-neg bacteria are resistant to vancomycin (large molecule)
      • Lack of transport system (Xanthomonas)
      • Lack of target (Mycoplasma)
    • Acquired resistance
      • Mutations (PBP) - spontaneous
    • Acquisition of foreign DNA
      • Plasmid exchange
      • Transposons
      • Conjugation
      • Transduction
      • Transformation
  • Mechanisms of Resistance Gene Transfer
  • Emergence of Antimicrobial Resistance Susceptible Bacteria New Resistant Bacteria Mutations XX Resistant Bacteria Resistance Gene Transfer
  • Selection for antimicrobial-resistant Strains Resistant Strains Rare x x Resistant Strains Dominant Antimicrobial Exposure x x x x x x x x x x
  • Mechanisms of Resistance
    • Antibiotics exert selective pressure that favours emergence of resistant organisms
    • Bacteria employ several biochemical strategies to become resistant
  • Mechanisms of Resistance
    • Altered influx
      • Gram negative bacteria
    • Altered efflux
      • quinolones, tetracyclines
    • Inactivation
      • β -lactamase
      • Chloramphenicol acetyl transferase
    • Modification of target sites
      • Altered PBP (penicillins)
      • New PBP (MRSE, MRSA)
      • Modification in ribosomes (macrolide-resistant S. pneumoniae )
    • Replacement of a sensitive pathway
      • Acquisition of a resistant enzyme (sulfonamides, trimethoprim)
  • Antibiotic Susceptibility Testing (AST)
    • Disk diffusion (Kirby Bauer)
    • Serial dilution (Macro and micro)
    • Antimicrobial gradient method (E test)
    MBC MIC
  • Review
    • Modification of precursor
    Bind to precursor of peptidoglycan Glycopeptides
    • Altered target enzyme
    • Efflux pumps
    Inhibit DNA gyrase (DNA synthesis) Quinolones
    • Methylation of rRNA
    • Efflux pumps
    Inhibit protein synthesis (bind to 50S subunit) Macrolides
    • Modifying enzymes (add adenyl or PO 4 )
    Inhibit protein synthesis (bind to 30S subunit) Aminoglycosides
    • Beta-lactamases
    • Low affinity PBPs
    • Decreased transport
    Inactivate PBPs (peptidoglycan synthesis) Beta-lactams Main resistance mechanisms Mechanism of action