Antibiotics and resistance wk 5

  1. 4 targets of antimicrobials
    • cell wall (penicillins, cephalosporins)
    • cell membrane (polymixin B)
    • protein synthesis (tetracyclines, chloramphenicol, macrolides, Lingcosamides, aminoglycosides)
    • nucleic acid synthesis (sulfonamides, metronidazole, rifampin, fluoroquinolones
  2. Penicillins
    • abx attacking cell wall.  Have beta lactam ring that looks like peptidoglycan, incorporated but too weak.  Bacteria are hypertonic, cell blows apart. (doesn't work on mycoplasma, deactivated by beta lactamase (strep, staph))
    • Bactericidal, very safe (mammals don't have cell walls).  
    • gram + (can't get to peptidoglycan in -), anaerobes, later generations better at gram -
    • "-illin"
    • Pen G, procaine + Pen G (PPG, pro-pen-G, 12h, IM or SQ, NEVER IV)
    • Potassium Pen G (IV, 6h)
    • ampicillin, amoxicillin are broad-spectrum
    • clavamox = + clavulanic acid (beta lactamase inhibitor)
  3. cephalosporins
    • abx attacking cell wall, beta lactam ring looks like peptidoglycan but weaker, incorporated into cell wall and lyses cell.  Doesn't work on mollicutes/mycoplasma, deactivated by beta lactamase (strep, staph)
    • bactericidal, very safe (mammals don't have a cell wall)
    • gram +, anaerobes, later generations better at gram -
    • "ceph-" or "cef-"
    • Cefovicin - Convenia, hooks into plasma proteins and stays for 14 days.  
    • Ceftiofur for LA
  4. Polymixin B
    • Cell membrane targeting abx - solublizing, loses integrity, leaking
    • Bactericidal for gram -
    • nephrotoxic (not bacteria-specific)
    • Neosporin, polysporin (okay for eyes and topical, NOT for systemic)
    • Involved in triple antibiotic (polymixin, neomicin (aminoglycoside), bacitracin (cell wall))
  5. tetracyclines
    • bacteriastatic protein synthesis-inhibiting antibiotic, attacks ribosomes (safe because we have different ribosomes). Has to get INTO bacteria
    • VERY broad spectrum (+, -, anaerobe, intracellular), mycoplasma, rickettsia, chlamydophila
    • "-cyclin"
    • oxytetracycline, doxycycline
  6. chloramphenicol
    • bacteriastatic protein synthesis-inhibiting antibiotic, attacks ribosomes (safe because we have different ribosomes). Has to get INTO bacteria
    • Broad spectrum (+, -, anaerobe, intracellular, mycoplasma, rickettsia, chlamydophila), VERY lipid soluble (lung abscess)
    • causes aplastic anemia in people.  
    • florfenicol is the production animal version
  7. macrolides
    • bacteriastatic protein synthesis-inhibiting antibiotic, attacks ribosomes (safe because we have different ribosomes). Has to get INTO bacteria
    • good for respiratory infections, mycoplama, chlamydophila
    • azithromycin, erythromycin
  8. lincomsamides
    • bacteriastatic protein synthesis-inhibiting antibiotic, attacks ribosomes (safe because we have different ribosomes). Has to get INTO bacteria
    • gram + aerobes
    • used for toxoplasmosis (protozoa)
  9. aminoglycosides
    • bacteriacidal protein synthesis-inhibiting antibiotic (only one), irreversibly attacks ribosomes. Has to be PUMPED into bacteria - anaerobes don't have the energy to pump so not good for them.
    • Gram - aerobes (and staph)
    • dose-dependent nephrotoxicity
    • gentamicin
    • amikasin
    • neomicin
  10. Sulfonamides
    • bacteriostatic (and protozoa) folic acid precursor (nucleic acid synthesis) inhibitor. Sulfonamides look like PABA, COMPETITIVE inhibition.
    • Chlamydophila, protozoa
    • Lots of resistant, so sulfonamide + trimethoprim (DHFA inhibitor, nucleic acid synthesis), causes to become bactericidal.
  11. Sulfonamide Trimethoprim
    • bactericidal combination drugs, both folic acid synthesis inhibitors (competitive)
    • nucleic acid synthesis inhibitors
    • good for gram + and gram -
  12. Metronidazole
    • bacteriacidal nucleic acid synthesis inhibitor
    • breaks up DNA (controversial).  
    • Limited spectrum, good for anaerobes, some protozoa
    • no food animals.
  13. Rifamycin
    • bacteriacidal nucleic acid synthesis (mRNA synthesis) inhibitor.  
    • limited spectrum
    • good for lung abscesses
    • rifampin
  14. fluoroquinolones/quinolones
    • DNA gyrase inhibitor (prevents unfolding of DNA in bacteria, prevents replication)
    • gram negative aerobes, some intracellular (mycoplasma, chlamydia)
    • "-flox-"
    • Enrofloxacin, ciprofloxacin, orbifloxacin, marbofloxacin
  15. mechanisms of resistance
    • modification of target
    • protection of target
    • degradation of drug
    • modification of drug
    • decreased permeability
    • efflux pump
  16. cross-resistance
    • single mechanism confers resistance to entire class or multiple classes of antimicrobials (like a non-specific efflux pump). 
    • Resistance to overlapping targets (but evolved for a single mechanism/abx)
  17. co-resistance
    when an organism harbors several resistance genes, each to a different class of antimicrobials (often co-selection when several genes are on same integrin or plasmid)
  18. ways bacteria acquire DNA
    • conjugative plasmids
    • transducing phages
    • transformation (picking up free DNA from lysis)
  19. how bacteria ORIGINALLY developed resistance (where the genes come from)
    • bacteria and fungi SYNTHESIZE abx anyway, so have resistance mechanisms
    • Lots have cross-resistance, so they're also resistant to synthetic antibiotics (soil bacteria)
  20. ways bacteria can acquire resistance 4 (3 in 1)
    • gain DNA/gene: conjugative plasmids, transducing phages, transformation (free DNA)
    • proto-resistance: genes that only require a small mutation to become much more active than they already are
    • silent/cryptic resistance: functional but not expressed.  Most bacteria have them. A small mutation will make them expressed
    • collective antibiotic resistance: where communities survive exposure that's lethal to individuals.  Biofilms (multiple species, exopolysaccharide layer, lots of free DNA, water channels for transport)
  21. quiescence
    bacteria that is susceptible to a drug escapes death because it is not currently dividing.  PERSISTERS
  22. therapeutic use of antibiotics in food animals
    • individual or small group treatment of illness
    • considered judicious by FDA
  23. metaphylactic use of antibiotics in food animals
    • treatment of entire herd when 10-15% of animals are sick
    • considered judicious by FDA
  24. prophylactic use of antibiotics in food animals
    • treatment of individual animals or entire herd during high-risk periods
    • considered judicious by FDA
  25. growth promotion use of antibiotics in food animals
    • use of antimicrobials in feed at sub-therapeutic doses to increase nutrient absorption and prevent disease.  
    • NOT considered judicious by FDA
  26. FDA regulations on abx
    • Only "judicious" if used to treat or prevent disease, not for growth promotion
    • scrip required to purchase abx to be used in food and water
    • veterinary client patient relationship required
  27. Spongiform encephalopathy
    • Prions: PRotein Infectious ONly
    • fatal neurodegenerative dz due to accumulation of altered protein. Hereditary or acquired (ingestion).  
    • Ingested, travel to lymphoid organs, replicate in FDCs due to B lymph.  Accumulate in symp nerve endings in lymphoid organs.  Retrograde axonal to CNS.  Accumulates, neuronal cell death and spongiform vacuolation of the brain.  No inflammation (no antigen)
    • Long incubation, ID'd by immunohistochemistry (ELISA).
    • Behavioral changes, head tremor, muscle fasciculations, blindness, nystagmus, dysphonia.  Sheep get pruritus and excoriations from rubbing.  Can last 1 year, may be emaciated.
  28. non-suppurative inflammation
    • viruses
    • Intracellular, MHC II, CD4 (IFNy) and MHC I, CD8 (kill infected cells)
    • cell necrosis, inclusion bodies (intranuclear vs cytoplasmic), syncytia, vesicles, cell proliferation
    • intracellular bacteria, intracellular parasites and chronic can all look similar.
  29. suppurative inflammation
    • pyogenic bacteria (extracellular, gram+ cocci, gram- bacilli)
    • tissue damage causes acute inflammation.
    • Abscess, bacteremia, cellulitis/fasciitis, empyema (pus in body cavity). 
    • Other infections can cause similar signs (fungal, protozoal, viral)
  30. necrotizing inflammation
    • clostridia, fusobacterium necrophorum, bacteriodes nodusus
    • commensals in GI or MM, or free-living in soil
    • anaerobes - invade damaged areas. Toxins cause more anaerobic (= necrosis)
    • foul odor, emphysema (gas production in tissues)
    • Rapid onset and loss of blood = few inflammatory cells.  May appear like infarcts.
    • Myonecrosis, gangrene, enteric necrosis.
  31. Granulomatous Inflammation
    • "higher" bacteria (mycobacteria, actinomyces, nocardia, rhodococcus), fungi (yeast or mold), parasites (protozoa like toxo, coccidia, neosporum, trypanosoma, leishmania; metazoan like roundworms, flat worms, ectoparasites)
    • FB-reaction looks similar, as does histiocytic proliferative disorders
    • macrophages predominate - infections resist eradication, stimulate strong cell-mediated response
    • disorganized macrophages is granulomatous inflammation, organized makes a granuloma, which can undergo caseous necrosis in center (tuberculosis).
  32. hyaline molds (zygomycetes, hyphomycetes)
    • colorless hyphae
    • Zygomycetes: broad sparsely septate hyphae (Rhizopus, mucor, absidia)
    • Hyphomycetes: parallel walls, septations, dichotomous branching (Apergillus). Hyphae often invade into wall, causing thrombosis and infarction
  33. dematiacious fungi
    • hyphae have varying degrees of pigment
    • disease is caused phaeohyphomycosis - localized SQ infection (splinter, thorn)
    • Systemic rare, but cladosporium likes CNS
  34. eosinophilic inflammation
    • metozoan parasites that are in great contact with host tissues call more eosinophils (Heartworms cause eosinophilic endarteritis and eosinophilia).  Ascarids in SI don't until their larvae migrate out. (hookworms, lungworms, strongyles, flukes and ectoparasites)
    • Eosinophils in GI but no other tissues normally. IL-5 and eotaxin call from BM (eotaxin, chemokine CCR-3)
    • Presentation varies
    • Allergies look like parasite reactions
  35. kirby-bauer disc diffusion assay
    • determines antimicrobial sensitivity, not used as much any more.  
    • bacteria spread on Mueller-Hinton agar, paper discs of abx are dropped onto it.  abx diffuse out, nothing susceptible grows in those spots--measure diameter and apply to chart.  Size is different with each drug, so use the chart
  36. minimum inhibitory concentration (MIC)
    • quantitative checks sensitivity of bacterial isolate.  Lowest dilution where it's not cloudy--automated common (sensititre)
    • STATIC, not necessarily cidal
  37. epsilometer test
    like kirby bauer - strip of cellophane with gradient of abx on agar plate, semi-quantitiative.  Bacteria grows everywhere but where inhibited.
  38. Minimum bacteriocidal concentration
    measure of KILLING of organisms--lowest concentration required to kill 99.9% in vitro.  Like MIB, but then plate out sample without abx and see if it grows.  Anything less than 10 colonies is okay.  If MBC is different than MIC, abx is bacteriostatic.  Same is bactericidal.
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Antibiotics and resistance wk 5
IV wk 5 antibiotics and resistance