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244 Cards in this Set
- Front
- Back
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Fluoroquinolone 1st generation
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Nalidixic acid
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Fluoroquinolone 2nd generation
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Ciprofloxacin
Levofloxacin |
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Fluoroquinolone 3rd generation
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Gatifloxacin
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Fluoroquinolone 4th generation
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Moxifloxacin
Gemifloxacin |
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Fluoroquinolone mechanism of action
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Inhibits DNA gyrase/topoisomerase II (supercoiling) and topoisomerase IV (separate replicated DNA) thus inhibiting DNA synthesis.
Thus resistance requires "double hit" |
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Fluoroquinolone pharmacokinetics
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Oral or IV
Enterohepatic circulation results in high concentration in stool Excellent tissue penetration Renal excretion (high urinary levels) Relatively long t1/2 |
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Fluoroquinolone adverse effects (9)
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1. GI sx
2. Cartilage damage in young animals 3. Tendonitis 4. CNS (headache, insomnia, restless) 5. C diff infection 6. Hyper/hypoglycemia (gatifloxacin) 7. Liver toxicity (Trovafloxacin) 8. Prolonged QTc/arrythmias 9. Macular rash |
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Therapeutic uses of fluoroquinolones (9)
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Good GN coverage
1. Cipro for Pseudomonas 2. Diarrhea from enterobacteriaceae 3. UTI (high renal and prostate concentrations) 4. Chronic bone infection/osteomyelitis (Pseudo, S aureus, Enterobacteriaceae) 5. GN facultative intracellular (Legionella, Brucella, Salmonella, atypical Mycobacteria) 6. New FQ: some GP coverage (MSSA but not MRSA or Enterococcus) and atypical bacteria (Legionella, Mycoplasma, Chlamydia) so good for CA-pneumonia 7. Moxi: intra-abdominal infections b/c broad against anaerobes 8. Skin (esp GN) 9. CA- and nosocomial pneumonia. |
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Fluoroquinolone resistance
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Point mutations of DNA gyrase enzyme
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Respiratory fluoroquinolones (3)
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1. Levofloxacin
2. Gemifloxacin 3. Moxifloxacin |
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Fluoroquinolone drug interactions
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1. Xanthines (caffeine, theophylline): xanthine metabolism inhibited, so levels increase
2. Antacids, Iron-Zinc: divalent cations chelate with FQ and prevent its absorption. |
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Aminoglycosides (8)
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1. Streptomycin
2. Kanamycin 3. Gentamicin 4. Tobramycin 5. Neomycin 6. Amikacin 7. Netilmicin 8. Paromomycin |
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Aminoglycoside Mechanism of Action
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Binds to 30s ribosomal subunit and inhibits protein synthesis by misreading
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Aminoglycoside pharmacokinetics
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IV or IM (but not oral)
Diffuses across cell wall of microbes, so synergistic with penicillin Crosses CNS ONLY IF meninges are inflamed NOT metabolized Excreted renally Poor distribution |
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Aminoglycoside adverse effects (4)
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1. Vestibular and auditory ototoxicity (CN VIII damage)
2. Nephrotoxicity 3. Neuromuscular blockade (muscular paralysis, apnea) 4. Rash |
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Aminoglycoside therapeutic uses (6)
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1. GN enteric organisms
2. Tularemia 3. Yersinia pestis 4. Brucellosis 5. Mycobacterium tuberculosis 6. Paramomycin: amoebiasis, cryptosporidiosis |
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Streptomycin
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Oldest aminoglycoside
Many bacteria are resistant |
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Gentamicin
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Most commonly used aminoglycoside
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Tobramycin
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Effective against Pseudomonas
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Amikacin
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Broadest spectrum of all aminoglycosides; effective against nosocomial infections
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Neomycin
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Very toxic, so only used topically.
Very broad spectrum |
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Netilmicin
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Preoperative for GI surgery
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Mechanism of resistance to aminoglycosides
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Mutation in 30s conformation
Alteration in transport (cell wall permeability) Enzymatic inactivation of drug Amikacin affected least (need two-step hit to inactivate) |
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Spectinomycin mechanism of action
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Binds 30s ribosomal subunit and inhibits protein synthesis
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Spectinomycin pharmacokinetics
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IM
Excreted in urine NOT metabolized |
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Spectinomycin adverse effects
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No adverse effects
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Therapeutic uses of spectinomycin
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Gonnorhea in pen-allergic
Not effective against syphilis or Chlamydia |
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Tetracycline mechanism of action
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Binds ot 30s ribosomal subunit and inhibits protein synthesis by blocking tRNA binding and elongation of peptide chain
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Tetracycline pharmacokinetics
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Oral absorption from the stomach and small intestine
Absorption impaired by food, milk, Ca2+ and Mg2+ salts. IV available Concentrates in liver and undergoes extrahepatic circulation Excreted in urine (tetracycline) and stool (doxycycline) |
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Tetracycline adverse effects (8)
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1. GI problems
2. Phototoxicity 3. Renal and hepatic toxicity (fatty liver, azotemia) 4. Fanconi syndrome 5. Superinfections (C diff, Candida) 6. Decreases bone growth in fetus 7. Discolors teeth and stains bone at site of bone calcification 8. Neuro (vertigo) |
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Tetracycline resistance
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Decreased influx, increased efflux
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Tetracycline therapeutic uses (9)
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1. Rickettsia/Ehrlichiosis
2. Chlamydia/PID 3. Mycoplasma 4. Entamoeba histolytica 5. Spirochetes (Lyme) 6. Brucella 7. Nocardia 8. Acne 9. CA- and atypical pneumonia |
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Tetracycline drug interactions
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Anticonvulsants increase metabolism
Methoxyflurane may increase nephrotoxicity Diuretics elevate BUN May increase metabolism of oral contraceptives May potentiate coumadin |
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Quinupristin/Dalfopristin mechanism of action
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Inhibits 50s ribosome
Quinipristin = peptide chain elongation Dalfopristin = peptidyl transferase |
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Quinupristin/Dalfopristin pharmacokinetics
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IV only
Doesn't cross placenta Accumulates in macrophages |
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Quinupristin/Dalfopristin adverse effects
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1. Hyperbilirubinemia (increase in bilirubin, liver enzymes, creatinine, anemia, thrombocytopenia)
2. Infusion site pain/inflammation 3. Myalgia/arthralgia |
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Quinupristin/Dalfopristin therapeutic uses
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1. Complicated skin infections with Group A Strep and Staph aureus (including MRSA)
2. Life-threatening bacteremia with VRE (E faceium only; not E faecalis) |
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Quinupristin/Dalfopristin resistance
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1. Plasmid mediated methylation of target site
2. Drug modifying enzyme 3. Efflux |
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Drug interactions of quinupristin/dalfopristin
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Inhibits CYP-450 3A4
Cyclosporine Midazolam Nifedipine Terfenadine |
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Linezolid Mechanism of action
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Binds to 50s ribosomal subunit and inhibits protein synthesis by preventing the 30s-70s initiation complex
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Linezolid pharmacokinetics
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Oral or IV
Metabolized partially in the liver; metabolized by oxidation Metabolites and unchanged drug excreted in urine No dose change for renal failure |
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Linezolid adverse effects
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1. Bone marrow suppression (thrombocytopenia, anemia, neutropenia after 2 weeks)
2. Headache 3. GI problems 4. Rash |
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Linezolid therapeutic uses
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1. Nosocomial pneumonia
2. Complicated skin and soft tissue infections 3. MRSA 4. VRE |
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Drug interactions of Linezolid
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Well absorbed with food
MAO-inhibitors SSRI's Avoid tyramine containing foods |
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Daptomycin Mechanism of action
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Derived from Streptomyces roseoporus
Disruption of bacterial membrane through formation of transmembrane channels - leakage of intracellular ions causes depolarization of membrane potential - inhibits macromolecular synthesis causing cell death |
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Daptomycin pharmacokinetics
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IV administration
92% protein bound (high) Not extensively metabolized Renal excretion (adjust dose in renal disease) |
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Daptomycin therapeutic uses
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1. Broad GP coverage (including methicillin and vancomycin resistant organisms)
2. Complicated skin and skin structure infections due to Staph, Strep and Enterococcus 3. Anaerobic GP organisms (Clostridium, Peptostreptococcus, Corynebacterium jeikeium) |
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Daptomycin adverse effects
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When IV:
1. Hearing loss is rare 2. Red Man Syndrome (red rash on torso due to nonimmunologic histamine release) 3. Problems with HMB-CoA reductase inhibitors/statins 4. Myopathies (muscle pain, weakness, CPK elevation) |
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Macrolides
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Erythromycin
Azithromycin Clarithromycin Dirithromycin |
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Macrolide mechanism of action
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Derived from Streptomyces erythreus
Inhibits protein synthesis by binding to the V domain of the 23s of the 50s rRNA subunit and inhibiting protein synthesis. Inhibits translocation of tRNA |
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Macrolide pharmacokinetics
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Well absorbed orally
Erythromycin and azithromycin also given IV |
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Macrolide adverse effects
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1. GI upset (gastric motility stimulation; most in erythromycin)
2. Rare cholestatic jaundice 3. Prolonged QT 4. Ototoxicity 5. Pyloric stenosis in <6w |
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Erythromycin therapeutic uses
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1. Staph aureus
2. Strep 3. Mycoplasma 4. Bordetella 5. Chlamydia 6. Legionella 7. Campylobacter 8. Clostridium 9. Peptococcus 10. Peptostreptococcus |
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Clarithromycin therapeutic uses
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Same as erythromycin
Increased activity for Chlamydia, MSSA, Strep Covers H flu, Moraxella and Mycobacterium avium |
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Azithromycin therapeutic uses
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Similar to erythromycin but less active against Staph and Strep
More active against H flu and Moraxella |
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Mechanism of macrolide resistance
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Alteration in 23s rRNA by methylation
Changes in permeability and active drug efflux Macrolide inactivating enzymes |
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Metabolism of macrolides
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Metabolized by CYP-450
Concentrated in liver, excreted in bile. Concentrates in neutrophils and macrophages. |
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Clarithromycin pharmacokinetics
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50% bioavailability
Excreted by bile/urine Adjust for renal failure |
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Azithromycin pharmacokinetics
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High tissue penetration
Concentrates in phagocytes t1/2 of 2-4d in tissue Eliminated hepatically No adjustment for renal/hepatic failure No drug interactions or CYP-450 induction |
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Clarithromycin and Erythromycin drug interactions (6)
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1. Warfarin
2. Carbamazepine 3. Cyclosporine 4. Digoxin 5. Theophylline 6. Valproate |
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Telithromycin mechanism of action
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A ketolide
Binds 50s ribosomal subunit and inihibits protein synthesis by binding to II and V domains of 23s of 50s rRNA subunit. Low inducer of MLSB resistance, less susceptible to efflux pumps, better antimicrobial activity, more acid stable. |
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Telithromycin pharmacokinetics
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Oral only
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Telithromycin activity and therapeutic uses
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1. Bronchitis
2. Sinusitis 3. CA-pneumonia 4. Similar to macrolides but better GP coverage (esp Strep pneumo) |
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Telithromycin adverse effects (4)
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1. GI upset
2. QT prolonged (arrythmias) 3. Exacerbates myasthenia gravis 4. Interferes with CYP-450 |
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MOA of Penicillins
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1. Inhibit transpeptidation by binding to PBP
2. Activate autolytic enzymes in bacteria |
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Resistance to penicillins
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1. Beta-lactamase
2. Alter PBPs |
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Penicillins concentration dependent or time dependent?
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Time dependent
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Natural penicllins (4)
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1. PenG (IV)
2. PenV (oral) 3. Procaine PenG (not used) 4. Benzathine PenG (only used in hypersensitive) |
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Spectrum of penicillin
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GP organisms
N meningitidis Susceptible N gonorrhoeae |
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Penicillinase-resistant penicillins (5)
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1. Methicillin
2. Nafcillin 3. Oxacillin 4. Cloxacillin 5. Dicloxacillin |
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Aminopenicillins (2)
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1. Ampicillin (hydrophilic)
2. Amoxicillin |
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Spectrum of Action of Aminopenicillins
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Similar to Natural penicillins but add
1. Listeria 2. Enterococcus 3. Some GN |
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Side effects of ampicillin (4)
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1. Allergy
2. Ampicillin rash (w/ mono) 3. Diarrhea 4. Pseudomembranous colitis |
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Carboxypenicillins (2)
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1. Ticarcillin
2. Carbenicillin |
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Ureidopenicillins (3)
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1. Piperacillin
2. Mezlocillin 3. Azlocillin |
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Spectrum of Carboxypenicillins
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Like natural penicillins, but with greater gram negative spectrum
Pseudomonas |
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Spectrum of Ureidopenicillins
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Like carboxypenicillins, but even wider gram negative spectrum and anaerobes
Includes Pseudomonas |
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Distribution of carboxypenicillins and ureidopenicillins
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Widespread diffusion, including across meninges
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Excretion of carboxypenicillins/ureidopenicillins
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Renal excretion
Has high urine concentration |
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Mechanism of action of beta-lactamase inhibitors
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1. Form covalent bonds with catalytic site of beta-lactamase
2. Binds PBP Must be used in conjunction with penicillin |
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Penicillin/Beta-lactamase inhibitor compounds (4)
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1. Amoxicillin/Clavulanic acid
2. Ticarcillin/Clavulanic acid 3. Ampicillin/Sulbactam 4. Piperacillin/Tazobactam |
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Amox/Clav pharmacokinetics
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Oral (high bioavailability)
Low T1/2 Low protein binding High Vd |
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Excretion of Amox/Clav
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Renally excreted (use with UTIs)
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Spectrum of action of amox/clav
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Staph aureus
Many GN Bacteroides Some Enterobacteriaceae |
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Clinical uses of amox/clav (6)
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1. URI
2. LRI 3. Bronchitis 4. UTI 5. Skin/soft tissue infections 6. Intraabdominal and pelvic infections |
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Ampicillin/sulbactam pharmacokinetics
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IV or IM
Low T1/2 |
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Clinical uses of ampicillin/sulbactam (4)
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1. Skin/soft tissue infections
2. Intraabdominal/pelvic infections 3. LRI 4. Some activity against ESBL-producers and other MDR-GNRs |
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Ticarcillin/clavulanate Pharmacokinetics
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IV
Renal excretion Short T1/2 |
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Specturm of ticarcillin/clavulanate
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Beta-lactamase producing GNR
Anaerobes Pseudomonas |
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Clinical uses of ticarcillin/clavulanate (4)
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1. Nosocomial infections
2. Neutropenic fevers 3. Complicated intraabdominal infections 4. Pelvic infections |
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Piperacillin/Tazobactam Pharmacokinetics
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Renal excretion
Short T 1/2 Low protein binding |
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Spectrum of piperacillin/tazobactam
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Most anaerobes
Aerobic and fastidious GN Staph, Strep Enterococcus (main dfiference between this and ticarcillin) |
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Clinical uses of piperacillin/tazobactam (4)
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1. Nosocomial infections
2. Neutropenic fevers 3. Complicated intraabdominal infections 4. Pelvic infections |
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Side effects of penicillin/beta-lactamase inhibitors (4)
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1. Anaphylaxis
2. Allergic reactions (fever, rash, serum sickness) 3. GI irritation 4. Superinfections (C diff, Candida) |
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Monobactam
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Aztreonam
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Spectrum of aztreonam
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Aerobic GNR
Pseudomonas |
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Aztreonam pharmacokinetics
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IV or IM
Low T1/2 Renal excretion |
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Clinical uses of aztreonam
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1. Complicated UTI
2. Nosocomial GN pneumonia/sepsis 3. Neutropenic fevers in penicillin-allergic patients |
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Acyclovir pharmacokinetics
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Oral, topical, IV
Low oral bioavailability Acts selectively on herpes infected cells Renal excretion (failure --> dose adjustment) |
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Side effects of acyclovir
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Minimal-- renal dysfunction due to acyclovir crystals
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Mechanism of resistance to acyclovir
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Mutation of thymidine kinase or DNA polymerase
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Side effect of valacyclovir
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Thrombocytic microangiopathy
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Valacyclovir
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Product of acyclovir
Better bioavailability |
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Famciclovir
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Prodrug of penciclovir
Higher bioavailability than valacyclovir |
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Ganciclovir Pharmacokinetics
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IV and PO
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Ganciclovir MOA
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Same as acyclovir
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Ganciclovir uses
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CMV
Compromised host Retinitis Colitis Pneumonia CNS |
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Valganciclovir
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Better oral absorption than ganciclovir
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Ganciclovir toxicity
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More toxic than acyclovir
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Foscarnet MOA
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Inhibits DNA polymerase of herpes viruses
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Indication of Foscarnet
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Used to treat acyclovir and ganciclovir resistant CMV
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Toxicity of foscarnet
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Moderate renal toxicity
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Amantadine/Rimantadine MOA
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Interferes with influenza A by blocking M2 protein channel
No effect on influenza B |
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Side effects of amantadine/rimantadine
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CNS side effects (can be severe)
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Amantadine/rimantadine metabolism and excretion
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Hepatic metabolism
Renal excretion (adjust dose in renal dysfunction) |
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Resistance to amandatine/rimantadine
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Mutations in viral M2 protein gene
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Neuraminidase inhibitors
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1. Oseltamavir
2. Zanamivir |
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Spectrum of neuraminidase inhibitors
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Type A and B influenza
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Administration of neuraminidase inhibitors
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Oseltamavir = oral
Zanamivir = inhaled |
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Side effects of neuraminidase inhibitors
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Oseltamavir = GI
Zanamivir = broncospasms |
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Types of antiretroviral agents (6)
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1. Nukes
2. Non-nukes 3. Entry/fusion inhibitors 4. Protease inhibitors 5. Integrase inhibitors 6. Co-receptor antagonists |
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Nucleoside reverse transcriptase inhibitors (Nukes) (6)
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AZT
d4T 3Tc ddI ddC Abacavir |
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Nonnucleoside RTI (non-nukes (3)
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1. Neviripine
2. Efaverenz 3. Etravirine |
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Protease inhibitors (4)
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1. Saquinavir
2. Ritonavir 3. Indinavir 4. Nelfinavir |
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Entry/fusion inhibitor (1)
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Enfuvirtide
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Co-receptor antagonist (1)
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Maraviroc
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Integrase inhibitor (1)
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Reltagravir
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HAART combination pill
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Atripla
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When to treat with antiretroviral therapy (4)
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1. CD4 < 350
2. Pregnant women 3. HIV-associated nephropathy 4. Hepatitis B coinfection |
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HIV-drug toxicities
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Lipodystrophy (hyperlipidemia, buffalo hump)
Insulin antagonism Bone effects (AVN, osteopenia) Mitochondrial toxicity (hyperlactatemia, peripheral neuropathy, pancreatitis) Hepatotoxicity |
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Treatment of active TB
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4 for 2, 2 for 4
First two months: Isoniazid, rifampin, pyrazinamide, ethambutol Next 4 months: isoniazid and rifampin |
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Treatment of latent TB
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1. Isoniazid 1 year (can use rifampin if can't use INH)
2. Three for three (isoniazid, rifampin and pyrazinamide for 3 months) |
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Who to treat if TBST >15mm
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All patients
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Who to treat if TBST > 10mm
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Immigrants from high risk countries
IV drug users Homeless Kids/adolescents |
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Who to treat if TBST >5mm
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HIV
Recent contact with TB+ pts Fibrotic changes on CXR Organ transplant pts Immunosuppressed |
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Side effects of isoniazid
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1. Peripheral neuropathy (prevent with pyridoxine)
2. Liver toxicity (worse in alcoholics, Europeans) - hepatitis has 9% death rate |
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Rifampin side effects
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Orange color to body fluids (urine, tears)
Induce P-450 enzymes |
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Rifabutin
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Alternative to rifampin
Very long half-life Less induction of liver enzymes than rifampin Used instead of Rifampin to treat HIV pts |
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Rifapentine
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Used in place ot rifampin once weekly for DOT (directly observed therapy)
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Ethambutol is bactericidal or bacteriostatic?
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Bacteriostatic
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Reason for ethambutol use
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Curtails resistance
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Side effects of ethambutol
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Usually well tolerated
Causes optic neuritis Impaired red-green color vision NO drug interactions |
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Additional drugs for TB (3)
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1. Streptomycin
2. Fluoroquinolones 3. Linezolid (in MDR-TB) |
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Side effects of Linezolid
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Bone marrow suppression (reversible thrombocytopenia)
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Tx of MAC pneumonitis (30)
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Clarith/azith+ rifampin/rifabutin + ethambutol/fluoroquinolone for 1-2 years
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Tx for disseminated MAC (3)
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Clarithro + ethambutol + HAART for HIV
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Clarithromycin drug-drug interactions
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Rifampin reduces clarithromycin levels
Clarithromycin increases rifampin, theophylline, digoxin and carbamazepine levels, potentiates coumadin |
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Prophylaxis for disseminated MAC
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Begin at CD4 of <50
Treat with azithromycin, clarithromycin or rifabutin |
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Treatment for Hansen's disease (3)
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1. Dapsone
2. Rifampin 3. Clofazimine |
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Dapsone pharmacokinetics
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long T 1/2
Screen for G6PD deficiency |
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Clofazimine Pharmacokinetics
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Very long T 1/2
Bacteriostatic |
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Reasons for Clofazimine
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Anti-inflammatory properties
Treat reversal reactions or ENL |
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Side effects of clofazimine
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Cause skin discoloration
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Treatment regimen for tuberculoid leprosy
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Dapsone + rifampin for 6 months, followed by dapsone for 3-5 years
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Treatment regimen for lepromatous leprosy
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Dapsone + rifampin fr 3 years, followed by dapsone for 10 years to life
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Tx of reversal reaction
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Dapsone/clofazimine with prednisone
Discontinue rifampin |
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Tx of ENL
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Add thalidomine and/or prednisone
High dose clofazimine + prednisone |
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MOA of isoniazid
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Inhibit synthesis of mycolic acid in Mycobacterium
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MOA of rifampin
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Inhibits DNA-dependent RNA polymerase
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MOA of pyrazinamide
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unknown
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MOA of ethambutol
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Inhibits arabinosyl transferase (cell wall in Mycobacterium)
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MOA of Dapsone
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Inhibits dihydropteroate
Similar to sulfa |
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MOA of clofazimine
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Related to iron chelation
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Sulfonamide MOA
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PABA analogue
PABA + Pteridine --> [dihydropteroate synthase] --> dihydrofolic acid |
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Folate reductase inhibitor MOA
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Block dihydrofolate reductase action (converts dihydrofolic acid to tetrahydrofolic acid)
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Types of folate reductase inhibitors
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1. Trimethoprim (bacteria)
2. Pyrimethamine (protozoa) 3. Methotrexate (mammals) |
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TMP-SMX bactericidal or bacteriostatic?
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Bacteriostatic
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TMP-SMX pharmacokinetics
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TMP:SMX given 1:5, but serum concentration is 1:20 b/c TMP has higher Vd (more lipophilic)
High oral bioavailability First order kinetics |
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TMP-SMX excretion
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TMP excreted unchanged in urine
SMX acetylated and glucuronide conjugated in liver Avoid if CrCL <10mL/min Can be oral (SS, DS) or IV; dose based on TMP component |
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Spectrum of activity of TMP-SMX (7)
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1. Aerobic GP (not pen-R pneumococci, E faecalis, some MRSA)
2. GN bacteria 3. Pneumocystic jiroveci 4. Some protozoa 5. Listeria 6. Mycobacterium marinum 7. Nocardia |
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Clinical uses of TMP-SMX (8)
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1. UTIs
2. Respiratory tract pathogens 3. GI pathogens 4. Nosocomial (Burkholderia, Stenotrophomonas, Serratia) 5. Traveler's diarrhea 6. Nocardiosis 7. Listeria infections 8. DOC for pneumocystis |
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TMP-SMX side effects (8)
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Well-tolerated but more likely/more severe reaction in HIV-patients.
1. GI (N/V/D, hepatotoxicity) 2. Skin (rash, Stevens-Johnson, erythema multiforme, TEN) 3. Hematologic (pancytopenia, anemia, neutropenia); treat these with folinic acid 4. Renal (TMP --> hyperkalemia, SMX --> crystalluria, acute interstitial nephritis) |
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TMP-SMX contraindications
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1. Pregnancy (TMP in 1st trimester, SMX at delivery)
2. Breast-feeding 3. Folate or G6PD deficiency 4. Taking methotrexate |
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Clindamycin pharmacokinetics
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Oral, IV, IM, topical
Very high oral bioavailability Good penetration, especially into bones but NOT CSF - also in PMNs and macrophages Metabolized by liver Excreted in urine and bile (dose modifications in renal or hepatic failure) |
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Clindamycin MOA
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Bind 50s subunit to inhibit protein synthesis
- inhibits chain elongation by blocking transpeptidation |
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Clindamycin is bactericidal or bacteriostatic?
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Bacteriostatic
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Spectrum of Clindamycin activity (7)
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1. Staph (including most MRSA)
2. Strep 3. Anaerobes (B fragilis, Cl pefringens) 4. Toxoplasma 5. Actinomyces 6. Nocardia 7. Plasmodium |
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Clindamycin clinical uses (8)
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1. Anaerobic bronchopulmonary infections
2. Polymicrobial intra-abdominal infections 3. Polymicrobial gynecologic infections 4. Soft tissue group A Strep infections in penicilin allergic 5. PCP with primaquine in AIDS 6. Toxoplasmosis with pyrimethamine 7. Acne 8. Bacterial vaginosis |
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Clindamycin side effects (5)
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1. C diff colitis
2. GI upset 3. Allergy 4. Hematologic (neutropenia, leukopenia, agranulocytosis) 5. Drug interaction with neuromuscular blocking agents |
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Chloramphenicol MOA
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Binds to 50S, inhibiting bacterial protein synthesis
-antagonistic with macrolides and clindamycin |
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Chloramphenicol pharmacology
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Oral, IV, topical
Lipophilic (so high Vd, will cross uninflamed meninges) High oral bioavailability Hepatic metabolism, urinary excretion |
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Spectrum of chloramphenicol (5)
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1. Pneumococci
2. Meningococci 3. H flu [3 main causes of meningitis] 4. Bacteroides 5. Salmonella typhi |
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Chloramphenicol side effects
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1. Gray baby syndrome (low glucuronosyltransferase --> gray cyanosis, respiratory failure, hypotension/shock)
2. Hematologic rxn (dose-dept reversible by ferrochetolase block, fatal aplastic anemia) |
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Vancomycin MOA
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Inhibit cell wall synthesis by binding D-alanyl-D-alanine
Also alters cell membrane permeability and inhibits RNA synthesis |
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Spectrum of vancomycin
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1. GP only
Includes MRSA and VSE, Listeria, Corynebacterium, Clostridium |
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Vancomycin pharmacology
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IV only except in C diff use oral (low absorption b/c large)
T 1/2 = 6 hours Penetrates inflamed meninges Eliminated by glomerular filtration; not dialyzable. Dose adjustment needed in renal dysfunction |
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Side effects of vancomycin
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1. Fever/chills
2. Phlebitis 3. Red man syndrome (not allergy; from release of histamine) 4. Allergy/rash 5. Leukopenia, eosinophilia 6. Hearing loss 7. Nephrotoxicity common when used with gentamicin |
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Vancomycin clinical uses
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Serious infections only
1. MRSA 2. Diphtheroids 3. Penicillin/cephalosporin-resistant Strep pneumo 4. Serious staph/strep infections in penicillin allergic 5. C difficile colitis (oral) |
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Tigecycline
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Glycylcycline similar to tetracyclines
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Spectrum of tigecycline
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Broad
Includes aerobes, anaerobes, MRSA, VRE GP GN except Pseudomonas - works against Acinetobacter and Stenotrophomonas |
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Tigecycline metabolism
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Eliminated in biliary-fecal route
No dose adjustment in renal failure (not dialyzable), but needs adjustment in end-stage liver disease Doesn't affect CYP-450 |
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Tigecycline side effects/contraindications
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similar to tetracyclines
1. Photosensitivity 2. Pancreatitis 3. Pregnancy (discolor teeth) 4. N/V 5. Increased pro-time of Coumadin 6. Severe diarrhea (like C diff) |
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Carbapenem MOA
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Similar to penicillin- inhibit cell wall synthesis by binding PBPs
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Spectrum of carbapenems
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Very broad
1. GPC (NOT MRSA, Entero) 2. GNC 3. GNR 4. Anaerobic (NOT C diff) |
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Imipenem pharmacokinetics
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IV only
Renal elimination - dose adjustment in renal dysfunction, dialyzable |
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Meropenem vs. Imipenem
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Meropenem doesn't need cilistatin
Meropenem causes less seizures Both absorbed orally, have renal excretion and are dialyzable |
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Side effects of carbapenems (5)
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1. Seizures (more in pts with CNS problems and renal dysfunction)
2. Cross-react with penicillin 3. Nausea, diarrhea 4. Abnormal liver function 5. Hematologic: neutropenia, thrombocytopenia, hypoprothrombinemia |
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Clinical uses of carbapenems (4)
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1. Mixed infections, especially involving anaerobic, resistant or nosocomial organisms
2. Empiric therapy in febrile neutropenics 3. Resistant GNR infections (nosocomial pneumonia) 4. Acinetobacter |
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Metronidazole spectrum of activity (5)
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1. Trichomonas
2. E histolytica 3. Giardia 4. Anaeorbic bacteria (Bacteroides, Clostridium) 5. Microaerophilic bacteria (Helicobacter, Campylobacter) |
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Metronidazole MOA
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Prodrug requiring activation by anaerobes and protozoa
Pyruvate-ferredoxin oxidoreductase in organisms reduce nitro group in metronidazole, activating it Metronidazole disrupts DNA structure by inhibiting nucleic acid synthesis |
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Metronidazole pharmacokinetics
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Oral, IV, intravaginally, topical
High bioavailability and penetration First order kinetics 80% free in plasma |
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Metronidazole metabolism/excretion
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Metabolized by liver and gut flora
Excreted in urine |
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Metronidazole drug-drug interactions (4)
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1. Phenobarbital, prednisone, rifampin and ethanol induce metabolism
2. Cimetidine inhibits metabolism 3. Precipitate lithium 4. Prolong prothrombin time in pts using warfarin |
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Clinical uses of metronidazole (8)
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1. Trichomonas vaginalis
2. Bacterial vaginosis 3. Entamoeba histolytica/liver abscess 4. Giardia 5. Serious anaerobic infections 6. H pylori infections (with proton pump inhibitors) 7. DOC for C diff 8. Crohns with perianal fistulas |
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Metronidazole side effects
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Uncommon
1. Headache, N/V, dry mouth, metallic taste in mouth, diarrhea 2. Neuro sx: ataxia, encephalopathy, convulsions 3. Stevens-Johnson 4. Disulfiram-like effect with ETOH: abdominal pain, N/V, dizziness, headache |
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Spectrum of Rifampin activity
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Most GP organisms
Some GN, including Pseudomonas - N meningitidis, H flu, Legionella Mycobacterium (not M fortuitum) |
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MOA of metronidazole
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Inhibits DNA-dependent RNA polymerase, suppressing chain formation in RNA synthesis
Is bactericidal |
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Mechanism of resistance to rifampin
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Altered enzyme
Develops rapidly, so don't treat with rifampin alone |
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Rifampin pharmacokinetics
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Highly protein bound
Good penetration Hepatic metabolism Bile and urine excretion (red fluids) Crosses placenta |
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Clinical uses of rifampin
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1. TB
2. Prophylaxis for meningococcal disease 3. Prophylaxis for H flu meningitis 4. Combine with beta-latam or vancomycin to treat Staph |
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Side effects of rifampin (4)
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1. Rash
2. Fever 3. N/V 4. Treat carefully in liver failure, alcoholics, elderly, flu-like symptoms |
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Drug interactions with riampin
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1. Revs up CYP-450 (induces protease inhibitor metabolism, and other drugs)
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Nitrofurantoin spectrum
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Wide:
GP GN except Pseudomona and Proteus |
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Clinilcal use of nitrofurantoin
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DOC: Genitourinary infections and catheter-associated UTIs
Acute uncomplicated cystitis UTI prophylaxis |
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MOA of nitrofurantoin
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Inhibition of bacterial enzymes involved in DNA and RNA synthesis, CHO metabolism,
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Nitrofurantoin pharmacokinetics
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2 forms: macro and microcrystalline forms
Very short T 1/2 Glomerular filtration, tubular secretion Food enhances bioavailabilty |
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Adverse effects of Nitrofurantoin
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Well tolerated in short term
1. Nausea, headache, flatulence 2. hemolysis with G6PH deficiency 3. Acute pneumonitis Long term has serious effects: 4. Pulmonary/interstitial pulmonary fibrosis 5. Hepatic 6. Peripheral neuropathy 7. Hypersensitivity |
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Nalidixic acid MOA
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Inhibits DNA gyrase
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Nalidicix acid excretion
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Renally excreted
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Spectrum of Nalidixic acid
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Activity against GN except Proteus and Pseudomonas
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Adverse effects of Nalidixic acid (6)
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1. GI
2. Glucosuria 3. Rash 4. Photosensitivity 5. Visual disturbances 6. CNS stimulation |
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Drugs to treat UTI (3)
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1. Nitrofurantoin
2. Nalidixic acid 3. Methenamine |
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Methenamine spectrum of activity (2)
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1. E coli
2. Staph |
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Methenamine side effects
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1. Urate crystals in urine of gout pts
2. Sulfonamide precipitation 3. Ammonia is a metaoblite, so don't use in liver failure |
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Cephalosporin structure
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Beta lactam ring fused to 6-membrane dihydrothiazine ring
Position 3: changes pharmacokinetics and metabolism Position 4: changes oral bioavailaility Position 7: changes antibacterial activity |
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Cephalosporin MOA
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Interferes with peptidoglycan synthesis in bacterial cell wall by binding PBPs
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Mechanism of resistance to cephalosporins
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Beta-lactamase most common
Altered PBP Reduced outer membrane permeability, especially in GN |
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Spectrum of 1st generation cephalosporins
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GPC except enterococci and MRSA
PEcK: Proteus, E coli, Klebsiella (almost all UTIs) |
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1st generation cephalosporin drugs
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Cefazolin
Cefadroxil |
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Cefazolin uses (2)
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1. Prophylaxis in prostheses
2. IV therapy for skin/soft tissue infections |
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Cefadroxil uses (2)
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Oral therapy for skin infections
Oral therapy for UTIs |
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Spectrum of 2nd generation cephalosporins
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Less GP than first gen
HEN PEcKS H flu, Enterobacter, Neisseria, Proteus, E coli, Klebsiella, Serratia Bacteroides |
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Types of 2nd generation cephalosporins (4)
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1. Cefuroxime (H flu)
2. Cefoxitin 3. Cefotetan 4. Cefmetazole |
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Cefoxitin uses (2)
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1. Prophylaxis in abdominal and pelvic surgery
2 Mild intraabdominal infections (cholecystitis) |
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Spectrum of 3rd generation Cephalosporins
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Poor GP activity except ceftriaxone and cefotaxmine (Strep pneumo)
Excellent aerobic GNR activity (H flu) Some anaerobic activity Ceftazidime treats Pseudomonas Ceftriaxone treats gonococcus |
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uses of ceftriaxone and cefotaxmine (2)
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1. Bacterial meningitis
2. CA-pneumonia |
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Uses of ceftazidime
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Pseudomonas and other GN infections
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Spectrum of 4th generation cephalosporins
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significant GP and GN activity, including Pseudomonas
Significant anaerobic activity Significant MDR-GNR activity |
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4th generation cephalosporin drugs
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Cefepime
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Cephalosporins readily penetrating CSF (5)
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Cefotaxime and ceftriaxone (3rd) cover pneumococcus
Ceftazidime (3rd)for Pseudomonas meningitis Also: cefuroxime (2nd) and ceftizoxime (3rd) |
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Excretion of cephalosporins
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Most excreted by kidneys so need dose adjustment in renal failure
Hepatobiliary excretion in: ceftriaxone, cefotaxmine |
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Longest T1/2 of cephalosporins
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Ceftriaxone (so once-a-day administration in home IV therapy)
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Side effects of cephalosporins
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Usually very safe
1. Hypersensitivty most common, with maculopapular rash 2. Anaphylaxis/utricaria is rare; cross-reaction with penicillin only 1-2% 3. Nephrotoxicity/interstitial nephritis 4. Diarrhea 5. Antabuse/disulfiram-like rxn (MTT at position 3 blocks ETOH metabolism at acetaldehyde) <-- cefotetan, cefmetazole 6. Hypoprothrombinemia in renal failure, poor nutrition --> excessive bleeding 7. "Biliary sludge"/cholecystitis if ceftriaxone exceeds excretion in bile, forms crystals (children, long/high doses) |
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Uses of cefixime
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3rd gen cephalosporin
Used for FQ resistant gonococcus |
