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30 Cards in this Set
- Front
- Back
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Some definitions in antibx tx
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THE GOAL is to achieve sufficient conc. of the drug at the site of infx to inhibit the growth of the pathogen without significantly harming the host:
-bactericidal kill bacteria -bacteriostatic inhibit bacterial growth -selective toxicity, destruction of pathogen without harming host cells -spectrum of action, is the group of organisms that the drug is effective against -hypersensitivity, allergic rx to antibx -superinfection, secondary infx occurring as a result of antbx tx (often due to shift in normal flora, ex C. dificil) |
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Antibx resistance
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-Intrinsic resistance: organism lies outside the spectrum of action of a drug
-Acquired resistance: a previously susceptible organism undergoes a genetic change or acquires new genetic material resulting in loss of sensitivity to a drug |
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Major mechanisms of antibiotic resistance
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1. altered target sites, due to gene mutations (as observed with B-lactams)
2. decreased uptake, change in membrane or acquisition of an efflux pump (as observed with tetracyclines) 3. enzymatic inactivation or modification of the drug (as observed with aminoglycosides and B-lactams) 4. emergence of "bypass" pathways (as observed with sulfonamides and trimethoprim) |
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Common targets of antibacterial drugs
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1. cell wall synthesis
2. protein synthesis 3. Folic acid metabolism 4. DNA synthesis |
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Cell wall synthesis inhibitors
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B-lactam antibx
-penicillins -cephalosporins -monobactams -carbapenems Glycopeptide antibx -vancomycin -telavancin |
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Bacterial cell wall (membrane structure)
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-Gram + thick peptidoglycan layer
-Gram - thinner peptidoglycan, also outer membrane has porins that allow hydrophilic compunds thru -PBP penicillin binding proteins in both -often both types of membranes will have B-lactamases to break down the B-lactam antibx |
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Mechanism of action of the cell wall synthesis inhibitos
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-B-lactams inhibit the function of the transpeptidases (by competiciely binding ot the active site of the enzyme) which usually cross-link pentapeptides
-the glycopeptide antibx inhibits transglycosylase and inhibit glycosididic bond formation |
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B-lactams
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-4 membered lactam ring in all of them
-the B-lactamases open up the ring, cleave it open -generally bactericidal -bind to PBPs which include the transpeptidases that cross link peptidoglycan as well as inappropraitely activate autolysins that promote reversible breakdown of the cell wall during cell division |
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B-lactams mechanisms of resistance
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-****expression of B-lactamase that inactivates drug
-expression of mutant PBPs with reduced affinity for the drug -mutations of outer membrane in gram - that reduce permeability -increased expression of drug efflux pumps |
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B-lactams toxicities
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-very safe and well tolerated drugs, major problem is hypersensitivities
-all penicillins are cross sensitizing and cross reacting (if you have a hypersensitivity to one penicillin, you probably are allergic to all of them, you can still take cephalosporins tho!) -cephs with methylthiotetrazole group (e.g. cefotetan), can inhibit vitamin K dependent blood clotting enzymes and can cause a disulfuram like rxn with alcohol |
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Penicillin G
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-spectrum of gram +, and some gram - cocci, and non B-lactamase anaerobes (but no effect on bacteroides fragilis, and also today most staph and gonococci are resistant)
-water soluble and excreted by the kidneys (can increase drug levels in blood by lowering kidney fn) -widely distributed except CNS (unless there is inflammation in which case there is CNS penetration) -Penicillin V is less acid sensitive so it can be given orally -Benazathine penicillin and procaine penicillin are slow release forms available for intramuscular injection |
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Extended spectrum penicillins
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-aminopenicllins (ampicillin, amoxicillin) improved activity for gram - organisms, but still susceptible to B-lactamse
-Antipseudomonal penicillins (ticarcillin, piperacillin, carbenicillin) -***often administered with a B-lactamase inhibitor (clauvulanic acid, tazobactam, sulbactam) no antibx activity themselves but extend activity of the B-lactams |
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B lactamase resistant penicillin
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- methicillin, nafcillin, oxacillin, cloxacillin, dicloxacillin
-originally developed for activity against B-lactamase producing penicillin resistant staph (not really active on enterococci and gram -) -MRSA is on the rise, resistance from PBP mutations |
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Cephalosporins
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-numerous generations (one thru five now)
-they are somewhat distinct in spectrum of action -1 is much like PenG and going up the gens you get more gram - activity |
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1st gen cephalosporin
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-cefazolin (parenteral) and cephalexin (oral) (drugs with -ph- are first gen)
-more stuff |
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2nd gen cephalosporin
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-cefoxitin, cefaclor, cefuroxime, cefotetan
-HENPEcK (the E is going away due to resistance!) |
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3rd gen cephalosporin
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-broad coverage!
-cefotaxime, cetriaxone, ceftazidime (anti-psuedomonal!) -t means 3rd gen |
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4th gen cephalosporin
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-cefipime, enterobacter and psuedomonal activity
-current cephs are not active on listeria, atypicals, MRSA, enterococci (LAME) |
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Other B-lactams
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-Monobactams: aztreonam, monocyclic ring, resistant to most B-lactamases, narrow spectrum, limited to aerobic gram - rods including pseudomonas (NO gram + coverage)
-Carbapenems: meropenem, doripenem, imipenem, slightly different B-lactam ring, confers resistance to B-lactamases, very broad spectrum of activty |
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Glycopeptide antibx
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-Vancomycin, inhibits transglycosylase, binds to the D-ala-D-ala of the pentapeptide thus blocking elongation
-resistance due to altered biosynthetic pathway that produces new pentapepti ending in serine or lactate -VRSA and VRE are becoming common in hospital settings -broad spectrum of action on gram + (not gram -, too big can't get thru pores) used for serious MRSA and MRSE -poor oral absorption (good for C. diff) -toxicities ototoxicity, nephrotoxicity, and skin flushing (mast cell histamine releasing) -Telavancin, vanco derives and longer half life |
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Lipopeptide antibx (RANDOM DUDE)
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Daptomycin, membrane permeabilization and depolarization, Ca dep. manner oligimeraizes to form pore in membrane
-bactericidal against most gram + MRSA and VRSA -toxicicities, myocarditis and allergic pneumonitis, antagonized by pulmonary surfactant (don't use for pneumonia!) |
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Protein synthesis inhibtors
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1) initiation
2) elongation 3) peptide synthesis 4) translocation |
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Aminoglycosides
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-examples: gentamicin, tobramycin, neomycin, amikicine, streptomycin
-broad gram (-) activity -bactericidal, reversibly binds to 30s, prevents formation of initiation complex, causes misreading of mRNA, crosses porins in gram - , O2 dep't active transport across inner membrane (not active on anaerobes!), improved penetration in presence of cell wall inhibitors -often given in conjunction with B-lactams as they help with aminoglycoside entry into bacteria |
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Aminoglycosides mechanism of resistance
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-chief mechanism is the acquisition of drug-modifying enzymes that inactivate drug (clincally important, cross resistance to all the aminoglycosides usually does not occur)
-mutations and environmental conditions that impair entry across membrane |
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Aminoglycosides pharmacokinetics
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-concentration dependent killing, and significant post antibiotic effect
-poor oral absorption and tissue distribution, cleared by kidneys -toxicities are ototoxicities, nephrotoxicities, time and concentration dep't -risks associated with low therapeutic window with once daily dosing |
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Tetracyclines
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-doxycycline, minocycline, tetracycline
-bacteriostatic, reversibly binds 30s and inhibits tRNA attachment -resistance due to plasmid encoded efflux pumps -GI disturbances, discoloring teeth, altered bone growth (no no for kids and pregnancy), photosensitivity, superinfection (CANDIDA) -used for atypical bacteria, Chlamydia, Rickettsia, Legionella, Mycoplasma - *NEW* Tigecycline, glycylcycline antibx, broad activity MRSA, VRSA, VRE, very broad activity MRSA, VRSA, VRE and other tetracycline resistant strains expressing efflux pumps |
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Macrolides
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-erythromycin, azithromycin, clarithromycin
-bacteriostatic, binds 23s rRNA of 50s subunit and blocks translocation -resistance arises from methylation of binding site or expression of esterases that inactivate drug -toxicities, are rare, mostly GI. (high dose ototoxic, nephrotoxic) -**all of them except azithromycin inhibit CYP450 -clinically used for corynbacterial inf, legionella, chlamydia, mycoplamsa -Fidaxomicin (Dificid) used for C.diff |
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Other protein synthesis inhbitors
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-chloramphenicol, binds 50s and inhibits peptidyl transferase
-clindamycin, binds 50s, used for anaerobes -linezolid, binds 23S rRNA in 50s, used for skin MRSA, VRE |
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DNA synthesis inhibitors
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-fluoroquinolones: ciprofloxacin, levofloxacin, gemifloxicin, moxifloxicin
-MOA bactericidal, inhibits DNA gyrase and at higher conc. topoisomerase IV -resistance from efflux pumps, mutations in target enzymes, drug sequestering proteins, cross resistance is common -most aerobic gram (-) and newer drugs gram (+) -GI disturbance common, QT elongation with gemiflox and moxiflox -GU and GI infx by gram (-) |
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Inhibitors of folic acid synthesis
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-SULFONAMIDES, rarely used as monotherapy, usually given with trimethoprim
-structural analog to PABA, competitively inhibits enzyme that makes folic acid -resistance is widespread, due to decreased drug entry, increased PABA, mutation in enzyme -active against many gram (-) and (+) -rare hypersensitivity (Stevens-Johnson syndrome, severe skin eruptions), nephrotoxic, kernicterus in neonates, hemolytic anemia in G6P dehydrogenase deficient pts. -TRIMETHOPRIM, blocks biosynthesis of folate by inhibiting dihydrofolate reductase -TRIMETHOPRIM + SULFONAMIDES = BACTRIM has a synergistic killing effect, used in complex UTI |
