medchem561 exam2

  1. Why do cell wall inhibitors fail?
    • resistant pathogens (altered pbp, beta-lactamases, etc.)
    • allergic reaction
    • insufficient drug levels at targeted site/tissue (beta-lactams have poor abscess penetration)
  2. Metronidazole, class, ROA, activity, MOA
    • Nitromidazole antibiotic
    • PO, IV, or topical
    • antianaerobic activity
    • antiprotozoal activity(single-celled eukaryotes)
    • acts as prodrug, gets converted to "suicide substrate"
  3. metronidazole, spectrum-protozoa?
    • trichomonas vaginalis
    • -trichomoniasis (STD)
    • -treat partner also to prevent reinfection
    • entamoeba histolytica
    • -amebiases (intestinal and liver abscesses, "flask ulcers")
    • giardia lamblia
    • -giardiasis (infects small intesting-diarrhea)
  4. metronidazole, spectrum-anaerobes?
    • bacterial vaginosis (gardnerella vaginalis and many other anaerobes)
    • helicobacter pylorii (peptic ulcers, used w/ ppi, bismuth, and other anitbiotics)
    • clostridium difficile
  5. clostridium difficile?
    • causative organism of antibiotic-associated diarrhea and pseudomembranous colitis (PMC)
    • if resistant, use vancomycin (PO)
  6. metronidazole-other uses?
    • intra-abdominal infections(polymicrobial, but commonly involves bacteroides fragilis (gram - anaerobe))
    • topical use in acne rosacea(anti-inflammatory)
    • CNS infections, often given w/ another antibiotic
  7. metronidazole- adverse effects?
    • metallic taste-lasts for duration of therapy
    • disulfuram reaction-avoid alcohol for at least 3 days after
    • rare peripheral neuropathy
    • seizures
  8. metronidazole-drug interactions?
    CYP2C9 inhibitor-interacts with warfarin, tolbutamide, diclofenac, phenytoin, etc.
  9. metronidazole-mechanisms of resistance?
    • rare in anaerobes but:
    • 1) reduced drug activation-less reductase activity and reduced uptake
    • 2) drug inactivation-nim genes encode and alternate nitroreductase that converts mtz to nontoxic derivative.
    • 3) efflux pumps
    • 4) increased repair of damaged DNA
  10. sulfonamides moa? and roa?
    • competitive inhibitor for PABA in biosynthesis of folic acid.
    • depleting folic acid hinders eventual production of DNA so bacteria cant divide
    • often given with trimethoprim (SMX/TMP)
    • given PO or IV
  11. sulfonamides spectrum?
    • UTI-E.coli, proteus mirablis
    • H.influenze
    • Salmonella
    • Toxoplasma gondii
    • Pneumocystis jiroveci-causes pneumocystis pneumonia(PCP) in HIV patients
    • CA-MRSA
  12. sulfamethoxazole/trimethoprim(SMX-TMP, co-trimoxzaole)
    • UTI
    • CA-MRSA
  13. Sulfadiazine
    chloroquine resisitant plasmodium falciparum (malaria)
  14. sulfadoxine-pyrimethamine
  15. sulfadiazine-pyrimethamine
  16. dapsone
    mycovacterium leprae (causes skin lesions and nerve damage)
  17. sulfonamide metabolism and excretion
    • slow acetylators have higher risk of developing toxicity
    • G6PD enzyme deficient pts have higher risk of developing hemolytic anemia due to reduced capacity to regenrate glutathione
  18. sulfonamides adverse effects
    • kernicterus-brain damage due to excessive jaundice, sulfonamides displace bilirubin from albumin inc bilirubin, dont give to children <2 months
    • megaloblastic anemia(folate deficient pts)
    • hemolytic anemia
    • crystalluria-acetylated sulfonamides are insoluble in urine(take with full glass of water
    • rash
    • photosensitivity
    • stevens-johnson syndrome
  19. sulfonamides DI?
    SMX is a CYP2C9 inhibitor
  20. sulfonamide and other sulfas cross reactivity?
    • very low risk due to two important stuctural differences.
    • N1 nitrogen-containing heterocyclic ring(Type 1 IgE)
    • N4 arylamine group associates with non-type 1 hypersensitivity (SJS) and is mediated by hydroxylamine metabolites
    • in practice avoid if serious sulfa allergy otherwise not significant
  21. sulfonamides mechanism of resistance
    • 1. reduced binding due to mutations in dihydropteroate synthase gene
    • 2. some bacteria do not synthesize folic acid therefor "naturally resistant"
    • 3. decreased drug permeability
    • 4. efflux pumps
  22. clindamycin roa? moa?
    • IV, PO, and topical
    • binds 50S ribosomal subunit to prevent translocation
    • 50S is site shared by other protein synthesis inhibitors(potential for cross resistance)
  23. clindamycin spectrum
    • gram + cocci, especially strep- may be sensitive although resistance is imp to consider. Enterococcus faecalis and E. faecium are resistant
    • Anaerobes- propionibacterium acnes, due to inc B. fragilis ressistance no longer recommended for intra-abdominal infections
    • No gram - aerobes
  24. clindamycin uses
    • alt drug for treatment of serious strep and staph infections in penicillin allergic pt(generally not first or second line therapy)
    • alternative agent for:
    • STDs: gardnerella vaginalis(BV), chlamydia trachomatis (PID)
    • parasites: toxoplasma gondii, pneumocystis jiroveci

    • necrotizing faeciitis-dec toxin productions (s. pyogenes)
    • good penetration into bone
    • topical for acne
  25. clindamycin metabolism, distribution, excretion
    • metabolized (inactivated) and excreted in urine
    • distributes very well into tissues and abscessses but not CNS
    • high gut levels even with IV
    • extensively excreted in bile and undergoes enterohepatic recycling
  26. clindamycin adverse effects
    • diarrhea-20-30%, risk for PMC but not worse than others, "boxed warning" for PMC, low risk for topical because not absorbed, counsel for prolonged diarrhea
    • hepatic toxicity(reversible)-elevation of transaminases, rare jaundice
    • hypersensitivity reactions
    • hematopoietic abnormalities (neutropenia)
    • renal toxicity
  27. clindamycin mechanisms of resistance
    • 1. production of methylated ribosomal binding sites(MRSA resistant)
    • 2. Efflux pumps
    • 3. Enzymatic drug inactivation
  28. macrolides?
    • erythromycin
    • clarithromycin
    • azithromycin
    • telithromycin
  29. macrolides chemistry
    large macrocytic lactone ring attached to 3 amino sugars
  30. macrolides moa
    • bind 50S to inhibit protein synthesis
    • bacteriostatic, but cidal at high doses
  31. macrolides spectrum
    • gram + (s.pneumo, s. pyogenes, mssa but not mrsa)
    • gram - (h.flu,, clarithro and azithro most potent)
    • atypicals(not identifiable by gram staining or cultivatable on standard bacteriologic media)
    • -mycoplasma pneumoniae(walking pneumonia)
    • -legionella pneumonphilia(legionnaires' disease)
    • -chlamydia trachomatis(std) and chlamydia pneumoniae
  32. macrolides general points
    • useful for infections of upper and lower respiratory tract, skin, otitis media, stds, and atypical infections
    • excellent tissue penetration (esp azithro & clarithro) but not CNS penetration
    • alternative drug in pen-allergic pt unable to take sulfonamides due to staph, strep, and h.flu infections
    • risk of PMC
  33. erythromycin roa? spectrum? AE? counseling point?
    • PO, IV, ophthalmic
    • good gram + and - activity
    • can cause diarrhea and gi irritation (13-32%)-acts as motilin agonist, activates receptors in small intestine that initiate peristalsis
    • unstable in acid environment, take on empty stomach
  34. erythromycin DI
    • p-glycoprotein(pgp) inhibitor=interacts w/ digoxin
    • inhibits CYP3A4=interacts w/ carbamazepine and cyclosporine
    • inhibits CYP1A2=interacts with theophylline and caffeine
  35. clarithromycin roa? best for? ae?
    • PO only, 2-4x more potent than erythro
    • choice for:
    • -mycobacterium avium comple (MAC)-common opportunistic infection in AIDS
    • -H. pylori
    • Metallic taste
  36. clarithromycin DI
    weak inhibitor of CYP3A4 and CYP1A2 but interactions can still be significant
  37. azithromycin roa? spectrum? best for? ae?
    • PO, IV, ophthalmic
    • much better gram- (but less gram + )
    • choice for:
    • -chlamydia trachomatis-1g stat
    • -chlamydia pneumoniase, and h.flu
    • -neisseria gonorrhea(for beta-lactam allergic pts)
    • -legionella infection
    • alternative to clarithro for MAC
    • rare hepatotoxicity
  38. azithromycin DI?
    • avoid concurrent use with antacids(minor dec in Cmax, but not a chelation interaction)
    • minimal CYP3A4 inhibition
  39. Telithromycin brand? moa? spectrum?
    • Ketek
    • binds 2 sites on 50S and doesn't induce erm
    • dose not cover mrsa, but covers prsp
    • similar spec to azithro
    • long half life (QD for 5-7d)
  40. telithromycin ae?
    • prolonged qt interval
    • muscle weakness
    • hepatotoxicity
    • blurred or double vision
    • exacerbates myasthenia gravis (contraindicated)
  41. telithromycin di
    cyp3a4 inhibitor
  42. macrolides resistance mechanisms
    • 1.erythro ribosomal mehtylase(erm):50s methylation due to erm A,B,C genes
    • -erm is inducible, cross resistance with clindamycin
    • -leads to resistance to all mecrolides except telithro
    • 2.cleavage of lactone ring by esterases
    • 3.decreased permeability
    • 4.efflux pumps
    • not very useful for enterobacteriaceae
    • -poor membrane penetration
    • -esterase production
  43. tetracyclines chemistry
    • consist of 4 fused rings with substitutions on positions 5,6, and 7
    • different pharmacokinetic properties but same spectra
    • -short acting-tetracycline
    • -long acting-doxycycline, minocycline, tigecycline
  44. tetracyclines moa?
    • bind 30s to inhibit protein synthesis
    • broad spectrum, bacteriostatic
  45. tetracyclines spectrum gram +
    • strep and staph if sensitive, but resistance common
    • s.pneumo may be sensitive to doxycycline
    • CA-MRSA may be sensitive also
  46. tetracyclines spectrum gram -
    • many are becoming resistant but includes
    • -N. gonorrhea
    • -many enterobacteriaceae(h.flu, e.coli, klebsiella, shigella, etc)
  47. tetracyclines spectrum unusual
    • rickettsia rickettsii (rocky mountain spotted fever)
    • borellia burgdoferi (lyme disease)
    • chlamydia trachomatis
    • m. pneumoniae
    • pasturella multocida(from animal bites)
    • brucella, francisella, treponema pallidum(syphilis), actinomyces
  48. tetracycline administration
    PO, short acting (often QID)
  49. Doxycycline administration
    • oral or IV
    • prolonged half life, convenient BID
    • gram + coverage, including mrsa
    • h. pylori
    • malaria prophylaxis for trips<4 months
    • traveler's diarrhea prophylaxis (cipro preferred)
    • chlamydia trachomatis (azithro preferred)
  50. minocycline specifics
    • gram + coverage, including mrsa
    • used in asymptomatic n. meningitis carriers
    • vertigo as possible side effect
  51. tigecycline specific
    • Tygacil
    • glycylcycline
    • iv only
    • used agains multiple-drug resistant organisms, includign gram -, but not psudomonas
    • also covers mrsa, vre, and bacteroides
  52. tetracyclines ae?
    • accumulates in growing bones and teeth in children therefore not recommended for children under 8yr or during pregancy(category D)
    • chelates with divalent cations-avoid dairy, iron, or antacid products for 2hrs
    • avoid taking with meals (doxy ok with)
    • esophagitis-take with lots of water and remain upright for at least 30 mins
    • photosensitivity
    • do not use outdated products dur to higher renal toxicity(Fanconi syndrome)
    • superinfection risk due to impact on normal flors(candida and c.diff)
  53. tetracyclines resistance mechanisms
    • tetracycline resistance genes (tet) on plasmids, transposons, and integrons
    • -efflux pumps
    • -30s ribosomal modifications
    • Tigecycline is able to overcome resistance mechanisms
  54. aminoglycosides?
    • tobramycin
    • amikacin
    • gentamicin
    • kanamycin
  55. aminoglycosides chemistry?
    • contain 2 or more sugars linked to aminocyclitol ring.
    • very water soluble, but not orally absorbed and are cationic at physiological ph
  56. why are AG often reserved for serious infections only?
    • toxicity concerns
    • requires peak and trough monitoring
  57. AG general points?
    • excreted renally, largely unchanged
    • PO forms (kanamycin) used for gut sterilization since not well absorbed
    • not for CNS infections (dont cross BBB)
  58. why AG ineffective in anaerobes?
    diffuse through porin channels in outer membrane but need active transport to cross inner membrane. transport doesn't occur in anaerobes isnce it require oxygen
  59. AG MOA
    • binds 30s, inhibits protein synthesis
    • creates fissures in the outer membrane, leakage of intracellular contents
    • concentration-dependent, bactericidal
  60. AG synergy with cell-wall inhibitors
    • gram + activity of ag limited w/o beta-lactam or vanco
    • disrupts peptidoglycan layer to allow more rapid entry of AGs into cell
    • some beta-lactams inactivate AGs when mixed so administer seperately
  61. AG spectrum gram -
    • -enterobacteriaceae-enterobacter, klebsiella, proteus, providencia, morganella, serratia
    • -p. aeruginosa-use is being replaced by less toxic cephs and fluoroguinolones. 2 drug regimens for serious infections still useful
  62. AG spectrum gram +
    • -E. faecalis and E.faecium (combined with vanco or possibly pen g or ampicillin) use alone has 40-60% resistance
    • -staph infections (MRSA) as an alternate to other antibiotics (combined with vanco)
  63. AG AE renal toxicity?
    • -accumulate in proximal tubules of renal cortex
    • -characterized by dec in CrCl, gradual inc in SrCr, oliguria, proteinuria or evidence of nitrogen retention
    • -usually reversible
    • -occurs in 5-10% of treated
  64. AG AE ototoxicity?
    • -results from destruction of cochlear hair cells, less common than nephrotoxicity
    • -vestibular toxicity: imbalance, tinnitus, vertigo, or nystagmus; more predominant with gentamicin
    • -auditory toxicity; high tone hearing loss; mroe common with kanamycin, and amikacin
    • -trobramycin affects both vestibular and auditory toxicity equally
    • -irreversible(cochlear hair cells cannot regenerate)
    • -can be potentiated by loop diuretics (i.e. furosemide)
  65. rationale for extended-interval dosing
    • 1. concentration-dependent bactericidal action
    • 2. significan post antibiotic effect
    • 3. rate of ag uptake in inner ear and renal cortex is saturable (risk of nephro/ototoxicity is equal or less)
    • 4. avoid adaptive post-exposure resistance by bacteria(initial exposure down-regulates subsequent uptake of AGs)
  66. Gentamicin details
    • IV/IM, ophthalmic, topical
    • -from micromonospora purpurea
    • -all-purpose agent of choice in gram - aerobic infections
  67. tobramycin details
    • IV/IM, ophthalmic
    • greater efficacy than gentamicin against p. aeruginosa
  68. amikacin details
    • IV/IM
    • fewer sites available to enzymatic modification
    • reserved for infection resistant to gentamicin and tobramycin
    • if pathogen resistant to amikaciin, resistant to all AGs
  69. kanamycin details
    • IV/IM, PO
    • can be used PO for gut infections such as intestinal amebiasis
  70. AG mechanisms of resistance
    • 1. production of plasmid mediated ag modifying enzymes (most common mech)
    • -acetylation, adenylation, and phosphorylation
    • -presence of the substituent amide at position 1 w/ amikacin confers resistance to enzymatic derivatization at all positions except 6'
    • 2. impaired transport into cell via cation pump in inner membrane. (gram - and anaerobes have this resistance, possibly pseugomonas)
    • 3. altered ribosomal binding site
  71. cause of drug-induced photosensitivity
    • 1.phototoxicity
    • -direct cellular damage
    • -photodegeneration of drug by UV light, formation oxidative radicals, attack cellular lippid membranes, inflammatory processes and eventual DNA damage
    • 2. photoallergy
    • -photoallergen(hapten) formation
    • -immediate or delayed hypersensitivity
  72. flurorquinolones?
    • ciprofloxacin, levofloxacin - 3rd gen
    • moxifloxacin - 4th gen
  73. FQ chemistry
    • quinolone nucleus with fluorine at position 6 and piperazinyl moiety at position 7
    • concentration dep bactericidal
    • significant post-antibiotic effect
  74. FQ MOA?
    • inhibit type II topoisomerases
    • -DNA gyrase (primary target in gram -) negatively supercoils bacterial DNA and repairs nicks in single stranded DNA
    • -Topoisomerase IV(primary target in gram +) ensures proper segregation of daughter chromosomes
  75. FQ spectrum gram +
    • – Organisms vary in sensiGvity
    • – The newer agents include Strep. as well as PRSP
    • – NOT MRSA or enteroccoci
  76. FQ gram -
    • – AcGvity against most aerobes, even Pseudomonas
    • – Excellent against Enterobacteriaceae
  77. FQ anaerobes
    only moxifloxacin
  78. FQ spectrum other
    • – Chlamydia
    • – Mycobacterium tuberculosis
    • – MAC and certain other
    • – Mycoplasma
  79. cipro roa? spectrum?
    • • PO, IV, or ophthalmic
    • • Excellent gram (‐) activity but limited gram(+) activity
  80. cipro indications
    • – Respiratory: Acute sinusiGs, LRI, nosocomial pneumoniae (IV)
    • – Skin or skin structure
    • – Bone/joint
    • UTI
    • – Uncomplicated cysGGs (bladder infecGon
    • )– Chronic bacterial prostaGGs
    • – InfecGous diarrhea
    • – Gonorrhea (500 mg stat), but resistance is increasing
  81. cipro DI
    ciprofloxacin is a CYP1A2 inhibitor and has beenreported to increase blood levels of theophylline and caffeine
  82. levofloxacin roa? spectrum?
    • • PO, IV, or ophthalmic
    • • Has both excellent gram(‐) activity and gram (+) activity
  83. levofloxacin indications
    • – Respiratory: acute sinusitis, acute exacerbation of chronic bronchitis,nosocomial pneumonia, community acquired pneumonia
    • – Complicated and uncomplicated skin and skin structure
    • – Complicated and uncomplicated UTI
    • – Acute pyelonephitis
    • – Prostatitis
  84. moxifloxacin roa? spectrum?
    • • PO, IV, or ophthalmic• C‐8‐methoxy group: believed to confer dual targeting activity
    • – binds to BOTH DNAgyrase and topoisomerase IV in gram(+), whereas other FQs bind to just one
    • • Has the best gram (+) activity, but limited gram(‐) activity– Best FQ for respiratory infections by S. pneumoniae, including PRSP
  85. moxifloxacin indications
    • – Respiratory: acute sinusitis, acute exacerbation of chronic bronchitis, nosocomialpneumonia, community acquired pneumonia
    • – Complicated and uncomplicated skin and skin structure
    • – Complicated and uncomplicated UTI
    • – Acute pyelonephitis
    • – Prostatitis
    • • Not exclusively eliminated by kidney, so not a good drug for UTI
  86. moxifloxacin ae
    QT‐interval prolongation (↑risk with concurrent QT‐interval prolonging agents)
  87. QT-interval prolongation pathophysiology
    • • QT interval prolongation
    • ‐ delayed cardiac cell repolarization phase
    • • Can result in early afterdepolarizations (EADs)  torsades depointes  sudden cardiac death
  88. FQ AE
    • • Chelates with divalent cations  avoid dairy, iron, or antacidproducts for at least 2 hours
    • • Prolonged diarrhea (for C. difficile overgrowth)
    • • Photosensitivity (mostly ciprofloxacin)
    • • Potential risk of tendonitis or tendon rupture
    • – 0.14% to 0.4% incidence
    • – Ischemic vascular process (narrowed vasculature of the tendon)
    • – Direct toxicity to the collagen (tendon necrosis)– Risk factors: concurrent steroid use (i.e., prednisone), renal disease, organtransplant, advanced age (>60 y.o.)
    • – FQs are contraindicated in <18 y.o. and pregnancy (risk of carGlagedamage). Also not recommended during breastfeeding.
  89. FA resistance mechanisms
    • 1. Altered DNA gyrase and topoisomeraseIV  decreased FQ binding
    • 2. Efflux pumps
  90. nitrofurantoin dosage form?
    (PO only)– Microcrystalline (Furadantin)– Macrocrystalline (Macrodantin and Macrobid): absorbed moreslowly, less GI distress
  91. nitrofurantoin uses
    • Used for UTIs, not for systemic infections
    • – One of the few non‐penicillins active against enteroccoci (includingVRE) and S. aureus
    • – Also active against many gram(‐) aerobes, especially E.coli
    • – Little to no acGvity against Proteus, Serratia, Klebsiella, Enterobacterspp. or Pseudomonas
  92. nitrofurantoin moa?
    • • Bactericida
    • l• Multiple complex mechanisms
    • – Reduction by bacterial flavoprotein systems (i.e.,nitroreductase) to form reactive intermediates binds ribosomes, DNA, and enzymes involved incellular respiration
    • – Parent drug also has activity
    • – Resistance from already susceptible organisms has not yet developed, no cross resistance to MTZ
  93. nitrofurantoin ae?
    • • GI effects (dose related): nausea, vomiting
    • • Rare but serious adverse effects (<<1%)
    • – Peripheral neuropathy
    • – Hepatotoxicity
    • – Pulmonary toxicity (bronchitis, asthma)
    • – Hemolytic anemia, especially in G6PD deficient patients
    • • Renally cleared, so contraindicated in renal insufficiency
    • • Also contraindicated in pregnancy (38‐42 weeks gestation)
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medchem561 exam2
exam 2