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313 Cards in this Set
- Front
- Back
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Cell membrane target
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Polymyxin
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Protein synthesis target
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Aminoglycosides (Gentimicin)
Chloramphenicol Linezolid (Clindamycin) Macrolides (Azithromycin) Tetracycline (Doxycycline) |
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Cell wall synthesis target
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Cephalosporins
Penicillins Imipenem Glycopeptides (Vancomycin) Monobactams Bacitracin |
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Nucleic acid synthesis target
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Fluoroquinolones
Metronidazole Rifampin |
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Intermediary metabolism target
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Sulfonomide
Trimethoprim |
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MIC
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minimum inhibitory concentration - the lowest concentration that prevents visible growth
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MBC
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minimum bactericidal concentration - the lowest concentration required to kill the germ
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time dependent killing
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the bactericidal effect of an antibiotic is best enhanced by keeping the drug concentration above the MBC for as long as possible
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concentration dependent killing
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the bactericidal effect is best enhanced by maximizing the peak concentration of an antibiotic, even for a relatively short period
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pulse dosing
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intermittent dosing protocol with high peak concentrations (maximize concentration dependent killing) and low trough concentrations (minimize toxicity)
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post-antibiotic effect
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common delay in the resumption of bacterial growth following removal of an antibiotic. this assists the effectiveness of pulse dosing.
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common biofilm problems in antibiotic therapy
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s. aureus on implanted artificial materials
pseudomonas in lungs of CF patients |
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Fluoroquinolones
Broad spectrum |
Ciprofloxacin
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Fluoroquinolones
Extended spectrum |
Moxifloxacin
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Nitroheterocyclic Anti-infectives
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Metronidazole
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Sulfanomide
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Sulfamethoxazole
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Dihydrofolate reductase inhibitor
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Trimethoprim
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Co-trimoxazole
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Sulfamethoxazole + Trimpethoprim
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Ciprofloxacin - bacterial activity
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Gram + and Gram -
Better at Gram - |
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Moxifloxacin - bacterial activity
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Gram + and Gram -
Improved for Gram + |
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Fluoroquinolone topoisomerase Gram -
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Gyrase
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Fluoroquinolone topoisomerase Gram +
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Type 4 Topoisomerase
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Fluoroquinolone - mechanism
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Fluoroquinolones prevent DNA resealing and cause the enzyme to dissociate from DNA. The DNA strand is left broken and fragmented after gyrase dissociation.
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Fluoroquinolone - bacterial coverage
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Gram + cocci or bacilli
Gram - cocci Gram - bacilli Gaps in anaerobes and staphylococci |
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Fluoroquinolone - BS or BC
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BC
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Fluoroquinolone - elimination
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Most drug is excreted in urine (good for UTI)
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Fluoroquinolone - distribution
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Distributes well into some hard to access compartments, but not CNS
Prostate and macrophage |
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Fluoroquinolone - infections
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Respiratory (sinusitis, bronchitis, community-acquired pneumonia)
Uncomplicated UTI Prostatits |
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Fluoroquinolone - AE
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Risk of tendinitis and tendon rupture
Cardiac arrhythmias (prolonged QT interval with moxifloxacin) Photosensitivity (w/ ciprofloxacin) Epilepsy CYP1A2 inhibition (only ciprofloxacin) |
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Why is ciprofloxacin not recommended for children under 18?
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Because of risk of tendinitis and permanent lesions of developing cartilage
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Fluoroquinolone - resistance
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Mutated topoisomerase proteins
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Metronidazole - BC or BS
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BC (obligate anaerobes)
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Metronidazole - mechanism
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Nitroreductase converts drug to short-lived cytotoxic reactive metabolite, which binds to DNA and causes fragmentation
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Metronidazole - elimination
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Hepatic and Renal excretion
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Metronidazole - AE
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Darkens urine
Peripheral neuropathy inhibits acetaldehyde dehydrogenase (AE with small amounts of ethanol) |
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Metronidazole - resistance
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Altered nitroreductase
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Sulfanomide - mechanism
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Competitive antagonist of PABA for dihydropteroate synthase
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Sulfanomide - BC or BS
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BS
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Sulfanomide - pharmokinetics
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Suitable for systemic or topical use
Sulfamethoxazole is extensively bound to plasma proteins Widely distributed in body (INCLUDING CNS) |
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Sulfanomide - resistance
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Increased bacterial PABA production
Dihydropteroate synthase with a mutated sulfonamide binding site |
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Why do you not use sulfanomides in late pregnancy, nursing mothers and neonates?
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Sulfanomides compete with bilirubin for binding in albumin
Bilirubin deposits in brain tissue to cause encephalopathy (kernicterus) in neonates |
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Sulfanomide - AE
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Hypersensitivity
Cross react with other drugs Precipitation of drug in acidic urine. (prevent with fluids and sodium bicarb) Hemolytic anemia in certain individuals (G6PD deficiency) |
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Stevens-Johnson syndrome
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Extensive epidermal loss is the most serious skin reaction with sulfanomides
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Trimethoprim - mechanism
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Competitive antagonist of dihydrofolate for dihydrofolate reductase
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Trimethoprim - BS or BC
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BS
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When is Trimethoprim used alone?
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If patient is hypersensitive to sulfamethoxazole
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Trimethoprim - oral bio
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Good oral bioaval
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Trimethoprim - resistance
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Mutated dihydrofolate reductase
Seen in Enterococci, Pseudomonas |
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Co-trimoxazole - resistance
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Less likely (must have multiple mutations)
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Co-trimoxazole - mechanism
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Sulfonamides decrease bacterial dihydrofolate levels
Decreased dihydrofolate enhances trimethoprim binding to dihydrofolate reductase |
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Co-trimoxazole - BC or BS
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BC
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Co-trimoxazole - bacterial target
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Gram + cocci or bacilli
Gram - cocci or bacilli |
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Co-trimoxazole - infections
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Uncomplicated UTI
Prostatitis Pneumonia (P. jiroveci: almost exclusive to AIDS patients) Skin infections of pneumonia caused by community-acquired MRSA |
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Co-trimoxazole - AE
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Most are due to sulfonamide
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Penicillins - Regular
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Penicillin G
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Penicillins - Extended Spectrum
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Amoxicillin
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Penicillins - Anti staph
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Nafcillin
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Penicillins - Anti pseudomonal
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Piperacillin
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Cephalosporins -1
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Cefazolin
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Cephalosporins - 2
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Cefuroxime
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Cephalosporins - 3
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Ceftriaxone
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Cephalosporins - 4
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Cefepime
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Carbapenems
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Imipenem
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Monobactam
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Aztreonam
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Beta-lactamase inhibitors
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Clavulanic acid
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Glycopeptides
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Vancomycin
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Beta Lactams
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Penicillins, Cephalosporins, Carbapenems, Monobactams
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Inhibit synthesis step - Bacitracin
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Translocation of monomers across the cell membrane
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Inhibit synthesis step - Vancomycin
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Polymerization of monomers
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Inhibit synthesis step - Beta lactams
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Polymer cross-linking
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Bacterial Selectivity - Penicillin G
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Good G + and spirochete coverage
Some G - cocci and anaerobe coverage Vulnerable to Beta-lactamases |
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Bacterial Selectivity - Amoxicillin
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Improved G - coverage due to better movement through porins
Vulnerable to beta-lactamases |
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Bacterial Selectivity - Nafcillin
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Best penicillin for staph (NOT MRSA)
Decreased sensitivity to beta-lactamases (but not other resistance mechanisms) |
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Bacterial Selectivity - Piperacillin
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Better coverage against select G - rod
Vulnerable to beta lactamases |
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Penicillins - resistance
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Decreased drug influx through porins
Enzymatic drug inactivation (Beta lactamases: used by MRSA) Decreased drug binding to penicillin binding protein |
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Penicillins - AE
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Oral can cause GI distress
Intramuscular injection can be painful CNS excitability and seizure with high penicillin blood levels Hepatotoxicity (amoxicillin) |
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Penicillins - Hypersensitivity
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Immediate (<30 min) : anaphylaxis
Accelerated (<2 days) : wheezing, urticaria, local reactions and inflammation Delayed (>2 days) : skin rashes |
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Penicillins - distribution
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Do not distribute in the body (bone,CNS) as well as other antibiotics
Meningeal inflammation increases CNS penetration |
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Penicillins - oral bio
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Oral bioaval. is poor (amoxicillin is good for oral)
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Penicillin G - infections
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Minor infections of very susceptible bacteria
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Amoxicillin - infections
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Amoxicillin most often used for sinusitis (outpatient)
Ampicillin more commonly used for more serious infections (IV) |
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Nafcillin - infections
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For sensitive, beta-lactamase secreting S aureus strains (NOT MRSA)
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Pipercillin - infections
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Pseudomonas. Often combined with an aminoglycoside
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Clavulanic acid - mechanism
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Covalently bind to many beta-lactamases
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Trend with cephalosporin generations
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As you increase the generation:
Gram - coverage improves Gram + coverage decreases |
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Cephalosporins - mechanism
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Inhibit peptidoglycan cross-linking by binding to PBP
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Cefazolin - bacterial coverage
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Very active against G + and many anaerobic cocci
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Cefuroxime - bacterial coverage
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Have either improved Bacteriodes fragiles or H. influenza activity
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Ceftriaxone - bacterial coverage
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Further improved G - rod coverage
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Cefepime - bacterial coverage
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Like 3rd generation but with better Pseudomonas activity
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Cephalosporins - AE
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can induce hypersensitivity reactions (cross allergenicity with the penicillins is around 5-10%)
Somewhat more toxic than the penicillins (some are nephrotoxic) |
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Cephalosporins - elimination
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most have short durations of action and are actively secreted in the kidney
Ceftriaxone undergoes biliary elimination |
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Cephalosporins - Distribution
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Most distribute more widely than penicillins
3rd and 4th generation get into CNS better than the older drugs |
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Cefazolin - uses
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Most commonly used for wound infections and surgical prophylaxis
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Cefuroxime - uses
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Used for less serious infections (sinusitis)
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Ceftriaxone - uses
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Used for serious infections or more resistant bacterial infections
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Imipenem - coverage
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Gram + cocci or bacilli
Gram - bacilli Anaerobes Gaps in MRSA, Enterococcus, C. diff |
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Imipenem - mechanism
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Similar to other beta-lactams
Insensitive to most beta-lactamases |
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Imipenem - AE
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Injections site reactions
GI effects Cross-hypersensitivity to penicillins |
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What problems occur with epileptics and imipenem?
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High drug levels seen with renal failure can trigger seizures
All carbapenems decrease valproate levels (anti-convulsant and mood stabilizing drug) |
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Imipenem - elimination
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Renally eliminated, but then converted to inactive, nephrotoxic metabolite
Cilastatin is included with imipenem to inhibit the renal dehydropeptidase |
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Aztreonam - mechanism
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Similar to other beta-lactams
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Aztreonam - coverage
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Gram - bacilli
Most important for covering Pseudomonas |
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Aztreonam - AE
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Beta-lactam least likely to cross-react with penicillins
Serious AE uncommon |
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Aztreonam - resistance
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Insensitive to most beta-lactamases
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Aztreonam - elimination
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Rapid elimination can require frequent dosing
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Vancomycin - coverage
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Only active against Gram + bacteria
BC when they are dividing |
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Vancomycin - mechanism
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Inhibits transglycosylases and proteoglycan polymerization
Binds to terminal D-Ala-D-Ala and prevents attachment of new monomer |
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Vancomycin - resistance
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Modified binding site (D-Ala is replaced with D-lactate)
Thicker proteoglycan layers that have more targets for vancomycin |
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Vancomycin - AE
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Enhances ototoxicity and nephrotoxicity of other drugs (aminoglycosides)
Red man syndrome |
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Red Man syndrome
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AE of vancomycin in which histamine release happens during infusion
Prevent by slow vancomycin infusion and pre-administration of antihistamines |
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Vancomycin - distribution
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Oral form isn't absorbed and only used for GI infections
Only crosses BBB during inflammation |
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Vancomycin - uses
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Main antibiotic used for MRSA
Anti-staph penicillins are preferred for other strains of S aures. (kill rate is faster) Used for severe or recurrent C. diff-induced diarrhea |
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Daptomycin - mechanism
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Targets cell membrane of G + bacteria.
Forms pore through the membrane Depolarization and disrupted ion gradients cripples cell functions |
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Daptomycin - coverage
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Gram +
Most useful for multi-drug resistant bacteria (MRSA) Resistance so far has been rare |
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Daptomycin - AE
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Myopathy
Avoid use with myopathy-inducing drugs (statins) |
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Daptomycin - pharmacokinetics
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Inactivated by surfactant (useless in pneumonia)
Renal elmination |
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Bacitracin
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Inhibit bactoprenol pyrophosphate (a lipid carrier that transfers peptidoglycan monomers across Gram + membranes)
topical due to nephrotoxicity |
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Aminoglycosides
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Gentamicin
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Lincosamides
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Clindamycin
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Macrolides
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Azithromycin, Telithromycin
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Oxazolidinones
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Linezolid
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Stretogramins
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Quinupristin/Dalfopristin
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Tetracycline
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Doxycycline, Tigecycline
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Bind to the 50s
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Macrolides
Chloramphenicol Lincosamides Streptogramins Oxazolidinones |
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Bind to the 30s
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Aminoglycosides
Tetracyclines |
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Tetracycline - oral bio
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Doxy: Excellent. Least food interaction
Tige: poor |
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Tetracycline - distribution
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Excellent except for CNS
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Tetracycline - elimination
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Doxy: Renal; hepatic glucuronidation and enterohepatic recycling
Tige: Mostly hepatic metabolism |
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Tetracycline - mechanism
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Bind to 30s and prevent binding of aminoacyl tRNA to A site
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Tetracycline - BC or BS
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BS
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Tetracycline - coverage
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Gram + cocci or bacilli
Gram - cocci or bacilli spirochetes Gaps in anaerobes |
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Tetracycline - resistance
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Ribosomal protection proteins
Bacterial efflux proteins |
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How does tigecycline combat Tetracycline resistance?
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Poor efflux pump substrate
NOT easily displaced by RPP |
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Tetracycline - AE
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GI distress
Photosensitivity Bind to teeth and bone in young children (permanently discolors teeth) |
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Tetracycline - uses
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Non-typical infections (Lyme, rickettsioses)
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Aminoglycosides -BC or BS
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BC
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Aminoglycosides - mechanism
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Bind and change conformation of 30s, inducing multiple types of translation defects
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Aminoglycosides - coverage
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Gram + cocci or bacilli
Gram - bacilli |
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Why do Aminoglycosides not cover anaerobes?
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Aminoglycosides transport into bacteria is facilitated by a high membrane potential
Anaerobic bacteria are more depolarized |
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Aminoglycosides - resistance
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Acetylation of drug
Mutated binding site |
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Aminoglycosides - AE
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Nephrotoxicity
Ototoxicity Vestibular toxicity NMJ block |
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How do you limit nephrortoxicity with Aminoglycosides?
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Keep trough concentrations low
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Aminoglycosides- oral bio
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Not absorbed
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Aminoglycosides - distribution
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Don't enter restricted body compartments well, including the CNS
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Aminoglycosides - elimination
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Predominately renal elimination with short half-life
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Aminoglycosides - uses
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Used for serious hospital setting infections
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Chloramphenicol - mechanism
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Binds to 50s and prevents the transfer of the polypeptide chain to the waiting tRNA at the A site and inhibits peptide bond formation
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What three drug class bind adjacently on the 50s?
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Chloramphenicol, clindamycin, macrolides
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Chloramphenicol - coverage
|
Some Gram + cocci and bacilli
Gram - bacilli Anaerobes |
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Chloramphenicol - resistance
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Acetylation of drug
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Chloramphenicol - AE
|
Hemolysis with G6PD
Idiopathic aplastic anemias Dose-dependent bone marrow depression Gray Baby syndrome |
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Gray Baby syndrome
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Result of slow Chloramphenicol metabolism in neonates
See skin discoloration, flaccidity, respiratory distress, shock |
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Chloramphenicol - distribution
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Well, gets into the CNS
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Chloramphenicol - elimination
|
Hepatic glucuronidation
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What effect does Chloramphenicol have on P450?
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Inhibits it --> Increases blood levels of anticoagulants and anti-convulsants
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Clindamycin - Mechanism
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Binds to 50s and prevents the peptide from moving from the P site to the A site tRNA. Peptide bond formation is inhibited.
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Clindamycin - BS or BC
|
BS
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Chloramphenicol - BS or BC
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BS
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Clindamycin - coverage
|
Gram + cocci or bacilli
Anaerobes |
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Clindamycin - resistance
|
Induced receptor methylation
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Clindamycin - AE
|
High incidence of diarrhea
Possible thrombocytopenia or agranulocyctosis Can cause C-diff mediated pseudomembraneous colitis |
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Clindamycin - oral bio
|
Good
|
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Clindamycin - distribution
|
well-distributed in the body except for CNS
|
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Clindamycin - elimination
|
Hepatic oxidation
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Macrolides - resistance
|
Enzymatic methylation of the binding site
Can actively transport drug out of bacteria Ketolides are less affected by these resistance mechanisms |
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Macrolides - mechanism
|
Bind to the 50s and prevent translocation. Does not allow nascent polypeptide
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Macrolides - BS or BC
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BS
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Macrolides - coverage
|
All except anaerobes
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Macrolides - AE
|
Toxic erythromycin or telithromycin levels can induce cardiac arrhythmias
Unpleasant upper GI contractions (by stimulating motilin receptors) |
|
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Macrolides - oral bio
|
All absorbed well. Eryhtromycin is acid-sensitive and must be enteric-coated
|
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Macrolides - distribution
|
Well into most compartments EXCEPT for CNS
|
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Macrolides - elimination
|
Hepatic elimination for most drugs (azithromycin: biliary excretion
telithromycin: CYP3A4) Good portion of clarithromycin is eliminated renally Azithromycin has longer half-life than others |
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What is the relationship between Macrolides and CYP3A4?
|
All Macrolides are except azithromycin are CYP3A4 inhibitors. (Can elevate blood levels of anticonvulsants and immunosuppresants)
|
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Macrolides are the drug of choice for which organisms?
|
Mycoplasma and chlamydia infection
|
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Group A Streptogramin
|
Dalfopristin
|
|
|
Group B Streptogramin
|
Quinupristin
|
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|
How do the two Streptogramin groups interact?
|
Group A promotes the binding of Group B.
Not structurally related Given together, they have a synergistic effects on protein synthesis |
|
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Streptogramins - mechanism
|
Group A inhibit binding of tRNA to both the P and A sites
Group B may inhibit peptide bond formation |
|
|
Streptogramins - coverage
|
Gram + cocci or bacilli
(MRSA and VRE) |
|
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Streptogramins - BS or BC
|
Depends on the microbe
|
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Streptogramins - AE
|
Arthralgias or myalgias can occur
Substantial injection site irritation can occur |
|
|
How do prevent injection site irritation with Streptogramins?
|
Infuse the drug slowly
Use a central line if needed |
|
|
Streptogramins - pharmacokinetics
|
Hepatic metabolism and biliary secretion
|
|
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Streptogramins and CYP3A4
|
CYP3A4 inhibitors, which decrease the metabolism of a large range of drugs
|
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Streptogramins - uses
|
Drug-resistant Gram +
MRSA VRE |
|
|
Linezolid - mechanism
|
Binds to P site of 50s and prevents formation of the 70s complex
|
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Linezolid - coverage
|
Gram + cocci or bacilli
|
|
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Linezolid - BS or BC
|
BS
BC for strep |
|
|
Linezolid - resistance
|
Rare but can happen with a mutated binding site
|
|
|
Linezolid - AE
|
Reversible, mild to moderate thrombocytopenia or neutropenia
|
|
|
Linezolid - distribution
|
Well distributed EXCEPT for CNS
Good oral absorption |
|
|
Linezolid - elimination
|
Non-enzymatic oxidation in hepatocytes
|
|
|
Linezolid - uses
|
Multiple drug resistant pathogens
MRSA Drug resistant Strep pneumonia VRE |
|
|
Drugs that inhibit ergosterol synthesis
|
Azoles, Fluconazole, Miconazole
|
|
|
Azole - mechanism
|
Inhibit lanosterol demthylase (CYP51)
|
|
|
Azole - AE
|
Can cause AE through inhibition of cytochrome P450 proteins.
Can alter metabolism of other drugs. All members of this class of antifungls are potential teratogens |
|
|
Azole - Resistance
|
Mutations of the target protien, lanosterol demethylase
|
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|
Fluconazole (Diflucan) - use
|
Candidosis (DOC)
Cryptococcal meningitis (DOC) Coccidioidal meningistis (DOC) |
|
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Fluconazole - dosage
|
Effective orally and also given via I.V.
Minimally metabolized Can cross the BBB |
|
|
Fluconazole - AE
|
Significant drug interactions with:
warfarin, cyclosporine, phenytoin, lovastatin, oral hypoglycemics and protease inhibitors Can cause nausea, vomiting or rash. |
|
|
Miconazole - uses
|
Applied topically for tinea corporis, tinea pedis and vaginal candidosis
|
|
|
Miconazole - application
|
Less than 1% absorbed into bloodstream.
Available as ointment, cream, solution, spray or lotion |
|
|
Miconazole - AE
|
Local burning, itching or irritation
|
|
|
Drugs that bind and disrupt the fungal cell membrane
|
Amphotericin B
Nystatin |
|
|
Amphotericin B - mechanism
|
Kills cells by binding to ergosterol. Disrupts the cell membrane, causing leakage of electrolytes and small molecules
|
|
|
Amphotericin B - uses
|
Broad spectrum of fungi. Resistance is uncommon.
|
|
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Amphotericin B - AE
|
Principal, dose-limiting toxicity is renal dysfunction.
|
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Nystatin - uses
|
Used only for topical treatment or oral candidosis.
|
|
|
Nystatin - administration
|
Minimal absorption orally. Bitter taste that can be corrected with additives.
|
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Nystatin - AE
|
Highly toxic with parenteral administration
|
|
|
Drugs that block fungal DNA and protein synthesis
|
Flucytosine
|
|
|
Flucytosine - mechanism
|
Enters cells via cytosine-specific permease enzyme, where it is converted to 5-flurouracil and 5-fDUMP that disrupt DNA and protein synthesis.
|
|
|
Flucytosine - resistance
|
Arises through decreased uptake of the drug or decreased cytosine deaminase activity
|
|
|
Flucytosine - administration
|
Absorbs well orally. Penetrates into the CNS. Always given with amphotericin (synergy)
|
|
|
Flucytosine - AE
|
May depress function of the bone marrow (leucopenia and thrombocytopenia)
|
|
|
What is the proposed mechanism behind why flucytosine can cause the same AE as chemotherapy drugs?
|
Release of 5-FU by the GI flora can give you nausea, vomiting or diarrhea
|
|
|
Drugs for treating nail bed infections
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Griseofulvin
Terbinafine |
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Griseofulvin - mechanism
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Binds to polymerized MTs, disrupting the mitotic spindle and blocking replication in mitosis
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Griseofulvin - administration
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Oral administration. It concentrates in skin at sites of newly synthesized keratin-containing tissues.
Induces cytochrome P450 enzymes which can lead to possible drug interactions |
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Terbinafine - mechanism
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Inhibits squalene epoxidase (essential enzyme for fungi since it is used in the ergosterol synthesis pathway)
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Terbinafine - administration
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Administered orally, it concentrates in skin and especially at nail beds. Also used for tinea infections
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Terbinafine - AE
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Minimal toxicity after topical use, but can cause allergic reactions when given orally. Terbinafine cannot be given to patients with hepatic impairment; does must be adjusted for patients with renal impairment.
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Drugs that disrupt fungal cell wall synthesis
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Caspofungin
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Caspofungin - mechanism
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Non-competitively inhibits the synthesis of the fungal cell wall. It is a lipopeptide that causes fungal cells to lyse.
Active against Candida and Aspergillus but not Histoplasma |
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Caspofungin - uses
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Approved for use in invasive aspergillosis and esophageal candidosis where amphotericin or fluconazole have failed.
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Caspofungin - administration
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Not abdsorbed in the GI tract and MUST be injected via I.V.
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Caspofungin - AE
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Limited, although phlebitis and histamine-like reactions at the injection site have been reported
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RNA virus prototype
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Influenza A
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RNA virus prototype drug
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Oseltamivir
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DNA virus prototype
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Herpes Simplex Virus
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DNA virus prototype drugs
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Acyclovir, Valacyclovir
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RNA retrovirus prototype
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HIV-1
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RNA retrovirus prototype drugs -
Reverse Transcriptase Inhibitors (nucleoside) |
Zidovudine, Tenofovir, Emtricitabine and Lamivudine
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RNA retrovirus prototype drugs -
Reverse Transcriptase Inhibitors (non-nucleoside) |
Efavirenz
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RNA retrovirus prototype drugs -
Reverse Transcriptase Inhibitors |
Efavirenz, Zidovudine, Tenofovir, Emtricitabine and Lamivudine
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RNA retrovirus prototype drugs -
protease inhibitors |
Saquinavir, Ritonavir
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RNA retrovirus prototype drugs -
fusion inhibitors |
Enfuvirtide (T-20)
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RNA retrovirus prototype drugs
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Saquinavir, Ritonavir, Efavirenz, Enfuvirtide (T-20), Zidovudine, Tenofovir, Emtricitabine and Lamivudine
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Hemagglutinin (HA)
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Mediates initial attachment of virus to sailic acid residues on carbohydrate side chains of cell surface proteins
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Neuraminidase (NA)
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new viral particles are aggregated - via interactions between HA and sialic acid residues on envelope proteins
neuraminidase disaggregates viruses by removing sialic acid residues |
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Non-structural membrane protein (M2)
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H+ transporter
M2 lowers endosome pH, required for viral uncoating step |
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Oseltamivir (Tamiflu) - general
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Neurominidase Inhibitor, a sialic acid analog
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Oseltamivir (Tamiflu) - administration
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Oral (can prevent or shorten duration of symptoms of Influenza A)
Best results if administered within 48 hours of symptoms |
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Oseltamivir (Tamiflu) - target groups
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Give to following patients:
Severe symptoms of hospitalization Children under 2 Adults over 65 Pregnant women Chronically ill (the weak) |
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Oseltamivir (Tamiflu) - AE
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nausea, vomiting, abdominal pains during early treatment
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Oseltamivir (Tamiflu) - pharmacokinetics
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Prodrug that requires activation by hepatic esterases
Half life of 6-10 hours Excretion mostly urinary |
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Zanamavir (Relenza) - general
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Administered via inhaler
Same MOA as oseltamivir Equally recommended for Flu A |
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Acyclovir (Zovirax) - general
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Guanosine analog, acyclic side chain
Active against herpes family |
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Acyclovir (Zovirax) - mechanism
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Selective inhibition of viral DNA polymerase (DNA replication)
AC has higher affinity for DNA polymerase of virus than host Selective incorporation of AC into viral DNA causes chain termination |
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Activation of Acyclovir
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AC requires activation to a triphosphate form to be recognized as a substrate for viral DNA polymerase.
Viral thymidine kinase is responsible for 1st phosphate group |
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Acyclovir is the first anti-viral agent described that requires a viral enzyme for activation. Why is this a desirable characteristics?
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AC binds to viral TK with a 200-fold higher affinity than cellular kinases
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Acyclovir (Zovirax) - pharmacokinetics
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Oral availability is poor
IV is common in adults AC distributes well (less in CSF and aqueous humor) Clearance primarily renal |
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Acyclovir (Zovirax) - HSV
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very effective in treatment of HSV symptoms; no effect on latency
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Acyclovir (Zovirax) - Varicella zoster
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Vaccines recomm. for adults over 60
Improves symptoms IV and oral AC improve pain in older patients |
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Acyclovir (Zovirax) - CMV
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Gancyclovir is preferred for treatment of (AIDS/CMV retinitis, organ transplants)
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Acyclovir (Zovirax) - EBV
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therapy usually not required
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Valacyclovir (Valtrex)
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DOC for genital herpes, herpes zoster
Valine ester of AC; improves oral absorption Converted to AC via esterase activity in intestines, liver (first-pass) |
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Zidovudine/AZT (Retrovir) - general
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Pyrimidine analog
Inhibits many retroviruses (targets reverse transcriptase) |
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Zidovudine/AZT (Retrovir) - activation
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All kinase steps are taken care of by host TK
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Zidovudine/AZT (Retrovir) - mechanism
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Competitive inhibitor of reverse transcriptase
Higher affinity for RT than does dTTP Higher affinity for RT than for host DNA polymerase |
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Zidovudine/AZT (Retrovir) - pharmacokinetics
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Oral bioaval. 60-65%; rapidly absorbed 30-90min
Distributes well, including CSF Rapid glomerular elimination (half-life 1 hour: biggest barrier) |
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Zidovudine/AZT (Retrovir) - AE
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leukopenia, nausea, muscle atrophy, dementia, hepatitis
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Tenofovir
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Half-life 17 hours (permits once daily dosing)
Diarrhea, nausea, vomiting and dizziness Potentially renotoxic |
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Emtricitabine
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Long half-life (1 dose/day)
Headache, fatigue, nausea |
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Lamivudine
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Less toxic than AZT
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Efavirenz (Sustiva)
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Very potent NNRT, low pill burden
Supplanted most PI's in 1st line regimen CNS/neuropsychiatric disorders |
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Main advantage of NNRTIs
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MOA different from nucleoside RTI
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Saquinavir - advantages
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Extensive experience, distinct mechanism of action
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Saquinavir - disadvantages
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Lipodystrophy, multiple drug interactions
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Fusion inhibitor
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Enfuvirtide (T-20)
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Enfuvirtide - disadvantages
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Expensive
Twice daily subQ injecitons (painful) |
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Enfuvirtide - mechanism
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Binds to coiled-coil domain on gp41, which prevents conformational change necessary for attachment and penetration of the protein into cell membrane
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HAART example
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Tenofovir (nuke) + Emtricitabine (nuke) + Efavirenz (NNRTI)
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Atripla
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one pill, once daily dosing of HAART treatment
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HAART therapy with virologic failure
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2 NRTI (selected by resistance tests) + PI (Saquinavir) + another PI: RTV (Ritonavir)
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Isoniazid - mechanism
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Interferes with the synthesis of mycolic acid
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Isoniazid - resistance
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Overexpression or mutations in the target protein, enoyl reductase
Mutations in a catalase/peroxidase, called KatG, that activates the drug Mutations in other virulence genes that are not related to the target |
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Isoniazid - pharmacokinetics
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Well-absorbed orally (Al-containting antacids may inhibit uptake)
Metabolized by liver NAT Slow acetylation |
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Isoniazid - distribution
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Wide distribution including the CNS
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Isoniazid - excretion
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75-95% in urine within 24 hours
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Isoniazid - AE
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Neuritis (reversed with pyridoxine)
Significant AE in 5% of people |
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Rifampin - mechanism
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Tuberculocidal
DNA dependent RNA polymerase (Beta subunit) |
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Rifampin - resistance
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Mutations in the target DNA-dependent RNA polymerase
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Rifampin - activation
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De-acetylated in the liver
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Isoniazid - activation
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Pro-drug that is converted to the active form by the mycobacterium
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Rifampin - pharmacokinetics
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Effective oral absorption
Half-life 1.5-5 hours Wide tissue distribution |
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Rifampin - excretion
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Biliary excretion/enterohepatic reabsorption
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Rifampin - AE
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Orange secretions and urine
Well-tolerated |
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Rifampin - drug interactions
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Potent inducer of multiple cytochrome P450 proteins
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Rifapentine
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new drug of rifamycin class that has better patient compliance due to simpler regimen (1X vs 2X weekly)
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Pyrazinamide - mechanism
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unknown
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Pyrazinamide - pharmacokinetics
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Well absorbed orally
Half-life = 2 hours Wide distribution including CSF Metabolized in liver |
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Pyrazinamide - excretion
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70% excreted in urine
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Pyrazinamide - AE
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Hepatitis
Hyperuricemia |
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Ethambutol - mechanism
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unknown
tuberculocidal |
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Ethambutol - pharmacokinetics
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Well-absorbed orally
half-life = 2-4 hours |
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Ethambutol - excretion
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very little metabolism
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Ethambutol - AE
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Optic neuritis (reversible)
Generally well-tolerated |
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Ethionamide - mechanism
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Prodrug that inhibits the same pathway as INH but by a different mechanism = inhibit mycolic acid synthesis
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Ethionamide - pharmacokinetics
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Peak concentration reached in 3 hours
Half-life = 2 hours Widely distributed and reached the CSF |
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Ethionamide - AE
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Postural hypertension, depression, drowsiness and GI effects
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Primary TB regimen
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Rifampin
Isoniazid Pyrazinamide Ethambutol |
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Treatment regimen for MDR TB
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Streptomycin
Ethionamide A p-amino salicylic acid |
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R207910 - AE
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Minimal
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R207910 - mechanism
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Inhibits ATP synthase (the bacterial energy source)
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Fluoroquinolone - oral bio
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Good oral bioaval. (decreased by divalent or trivalent cations)
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Metronidazole - oral bio
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Good oral bioaval.
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Metronidazole - distribution
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Good tissue distribution (INCLUDING CNS)
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Sulfanomide - elimination
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Hepatic and Renal elimination (therapeutic concentrations in urine)
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Trimethoprim - distribution
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Distributes in the body (INCLUDING CNS)
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Trimethoprim - elimination
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Hepatic and Renal elimination (present in the urine)
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Penicillins - elimination
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Hepatic and Renal elimination (probenecid slows elimination)
Nafcillin undergoes mixed biliary/renal elimination |
