Antimicrobial Chemotherapy part I

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Antimicrobial Chemotherapypart I

• Dr. Ross Davidson
• Rm 309, MacKenzie Building
• QE II HSC
• ph 473-5520

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Antimicrobial Chemotherapy

• Use of drugs to combat infectious agents
• Antibacterial
• Antiviral
• Antifungal
• Antiparasitic

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Antimicrobial Chemotherapy

• Differential toxicity based on the concept that
  the drug is more toxic to the infecting organism
  than to the host
• Majority of antibiotics are based on naturally
  occurring compounds
• or may be semi-synthetic or synthetic

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What is the ideal antibiotic

• Have the appropriate spectrum of activity for the
  clinical setting.
• Have no toxicity to the host, be well tolerated.
• Low propensity for development of resistance.
• Not induce hypersensitivies in the host.

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What is the ideal antibiotic

• Have rapid and extensive tissue distribution
• Have a relatively long half-life.
• Be free of interactions with other drugs.
• Be convenient for administration.
• Be relatively inexpensive

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Principles / Definitions

• Spectrum of Activity Narrow spectrum - drug is
  effective against a limited number of
  speciesBroad spectrum - drug is effective
  against a wide variety of species
• Gram negative agentGram positive
  agentAnti-anaerobic activity

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Principles / Definitions

• Minimum Inhibitory Concentration (MIC)- minimum
  concentration of antibiotic required to inhibit
  the growth of the test organism.
• Minimum Bactericidal Concentration (MBC)-
  minimum concentration of antibiotic required to
  kill the test organism.
• Bacteriostatic
• Bactericidal
• Time dependent killing
• Concentration dependent killing

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Principles / Definitions

• Treatment vs prophylaxis
• Prophylaxis - antimicrobial agents are
  administered to prevent infection
• Treatment - antimicrobial agents are administered
  to cure existing or suspected infection

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Combination Therapy

• To prevent the emergence of resistance -
  M.tuberculosis
• To treat polymicrobial infections
• Initial empiric therapy
• Synergy

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Combination Therapy

• Why not use 2 antibiotics all the time?
• Antagonism
• Cost
• Increased risk of side effects
• May actually enhance development of resistance
  inducible resistance
• Interactions between drugs of different classes
• Often unnecessary for maximal efficacy

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What influences the choice of antibiotic?

• Activity of agent against proven or suspected
  organism
• Site of infection
• Mode of administration
• Metabolism and excretion
• renal and hepatic function
• Duration of treatment / frequency of dose
• Toxicity / cost
• Local rates of resistance

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How do antimicrobial agents work

• must bind or interfere with an essential target
• may inhibit or interfere with essential metabolic
  process
• may cause irreparable damage to cell

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Targets of antibacterial agents

• Inhibit cell wall production - penicillin
  binding proteins
• Inhibit protein synthesis - bind 30s or 50s
  ribosomal subunits
• Inhibit nucleic acid synthesis - binding
  topoisomerases / RNA polymerase
• Block biosynthetic pathways - interfere with
  folate metabolism
• Disrupt bacterial membranes - polymixins

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Antimicrobial resistance

• Resistance the inability to kill or inhibit the
  organism with clinically achievable drug
  concentrations
• Resistance may be innate (naturally resistant)
• Resistance may be acquired -
  mutation - acquisition of
  foreign DNA

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Antimicrobial resistance

• Factors which may accelerate the development of
  resistance - inadequate levels of antibiotics
  at the site of infection - duration of treatment
  too short - overwhelming numbers of organisms -
  overuse / misuse of antibiotics

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Antimicrobial resistance

• General mechanisms of resistance
• Altered permeability
• Inactivation / destruction of antibiotic
• Altered binding site
• Novel (new) binding sites
• Efflux (pumps) mechanisms
• Bypass of metabolic pathways

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Antimicrobial Chemotherapypart II
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Antibiotic Classes

• Cell Wall Active Agents bactericidal, time
  dependent killing
• B-lactams - penicillins / cephalosporins /
  - cephamycins / carbapenems
• Glycopeptides - vancomycin / teicoplanin
  - gram positive agents

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Structure of ?-lactam drugs
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Penicillins

• Penicillin G / V - good gram positive (not
  Staph)-moderate anaerobic activity
• Synthetic penicillins (Ampicillin)- good gram
  positive (not Staph)- moderate gram negative
  (not Pseudomonas)
• Anti-staphylococcal penicillins- Cloxacillin
• Anti-pseudomonal penicillins- Piperacillin

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Cell Wall Active Agents

• B-lactams bind to penicillin binding proteins
  (PBP)-PBP are essential enzymes involved in cell
  wall synthesis-weakened / distorted cell wall
  leading to cell lysis and death
• Glycopeptides bind to the terminal D-ala of
  nascent cell wall peptides and prevents
  cross-linking of these peptide to form mature
  peptidoglycan

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Vancomycin Mechanism of Action

• Inhibit peptidoglycan synthesis in bacterial cell
  wall by complexing with the D-alanyl-D-alanyl
  portion of the cell wall precurser

carboxypeptidase
-L-ala-D-glu-L-lys-D-ala-D-ala

2L-ala
2D-ala
D-ala-D-ala
UDP-L-ala-D-glu-L-lys
UDP-L-ala-D-glu-L-lys-D-ala-D-ala
pentapeptide--
racemase
transpeptidase
-L-ala-D-glu-L-lys-D-ala-D-ala
ligase (ddl)
transglycosidase
-L-ala-D-glu-L-lys-D-ala-D-ala
adding enzyme
--L-ala-D-glu-L-lys-
-D-ala-D-ala
vancomycin
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Cell Wall Active Agents

• B-lactam resistance1. Production of a
  B-lactamase (most common)2. Altered PBP
  (S.pneumoniae)3. Novel PBP (MRSA)4. Altered
  permeability
• Glycopeptide resistance- primary concern is
  Enterococcus / S.aureus- altered target-
  bacteria substitutes D-lac for D-ala- vancomycin
  can no longer bind

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Cephalosporins

• History
• Discovered in sewage in Sardinia in the mid
  1940s.
• Cephalosporium sp was recovered and proved a
  source of cephalosporin.
• Subsequently, four generations of cephalosporins
  have emerged.

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Cephalosporins

• 1st generation- mainly gram pos, some gram neg
  (cefazolin) 2nd generation- weaker gram pos,
  better gram neg (cefuroxime)3rd generation -
  excellent gram neg, some gram pos (ceftriaxone)
  4th generation - excellent gram neg, good gram
  pos (cefepime)

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First-Generation Cephalosporins What do they
cover?

• Cefazolin (Kefzol) and cephalexin (Keflex)
• Activity includes
• Methicillin susceptible staphylococci
• Streptococci excluding enterococci
• E. coli, Klebsiella sp., and P. mirabilis
• Many anaerobes excluding B. fragilis

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Where do you think they should be used?

• Simple mixed aerobic infections.
• In penicillin allergic (not immediate) patients.
• Surgical prophylaxis.
• Convenience drug for S. aureus and streptococci?

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What about second generation cephalosporins?

• Cefuroxime
• Think Haemophilus in addition to 1st generation
  specturm
• A respiratory drug

• Cefoxitin/cefotetan
• 1st generation plus-anaerobes
• A mixed, non-serious infection surgeon drug
• Think cefazolin/metro which is what we would use

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Third-Generation Cephalosporins

• Cefotaxime, ceftriaxone (IV)
• Enhanced activity against Enterobacteriaceae
• Enhanced activity against streptococci, including
  penicillin resistant S. pneumoniae.
• Long half life favors ceftriaxone
• Less diarrhea favors cefotaxime
• Ceftazidime (IV)
• Active against P. aeruginosa.
• Decreased activity against gram positive cocci.

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Fourth generation cephalosporins

• Cefepime
• Marginal improvements
• Not available at the QE II

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Carbapenems What dont they get?

• Everything except
• MRSA and MRSE
• Enterococcus faecium
• Stenotrophomonas maltophilia
• Burkholderia cepacia

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When to use carbapenems?

• Life threatening polymicrobial infections
• Intra abdominal sepsis in ICU esp nosocomial in
  origin
• Gram negative/ nosocomial pneumonia in intubated
  patient
• Monotherapy of febrile neutropenia (high risk
  patients)

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What are the beta-lactamase inhibitors?

• Clavulanate (with amoxicillin or ticarcillin)
• Tazobactam (with piperacillin)

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What additional bugs do they cover?

• S. aureus
• H. influenzae
• Neisseria sp.
• Bacteroides fragilis
• E. coli and Klebsiella
• Not better for Pseudomonas or Enterobacter

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Inhibitors of protein synthesis

• Ribosomes are the site of protein synthesis
• many classes of antibiotics inhibit protein
  synthesis by binding to the ribosome
• binding may be reversible or irreversible
• Macrolides, ketolides, lincosamides,
  streptograminsTetracyclinesAminoglycosides

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Inhibitors of protein synthesis

• Macrolides (erythromycin, clarithromycin,
  azithromycin) - primarily gram positive,
  mycoplasma, chlamydia - bacteriostatic, time
  dependent killing Lincosamides (clindamycin)
  - gram positive, anaerobic activity
• Resistance (acquisition of a gene) - M
  phenotype macrolides only
  efflux - MLSB phenotype
  macrolides, lincosamides, streptogramins
  target site modification
  constitutive, inducible

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Inhibitors of protein synthesis

• Aminoglycosides gentamicin, tobramycin,
  amikacin - excellent gram negative, moderate
  gram positive - bactericidal, concentration
  dependent
• ResistancePrimarily due to aminoglycoside
  modifying enzymes

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Inhibitors of nucleic acid synthesis

• Fluoroquinolones (ciprofloxacin, norfloxacin,
  levofloxacin, moxifloxacin)- bactericidal,
  concentration dependent- bind to 2 essential
  enzymes required for DNA replication- DNA gyrase
  and topoisomerase IV- gram pos and gram neg-
  atypical bacteria, some have anaerobic activity
• Resistance - altered permeability (porin
  channels) - altered target site - efflux

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Inhibitors of metabolic pathways

• Trimethoprim/sulfamethoxazole (Septra, TMP/SMX)
  - good gram negative, some gram positive
• block folic acid synthesis at two different
  pointsTMP and SMX act synergistically
• Resistance may arise if the organism can bypass
  the pathway making it redundant

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Mechanism of action of TMP-SMX