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280 Cards in this Set
- Front
- Back
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What are 5 important nosocomial pathogens?
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- staphylococcus aureus
- acinetobacter baumannii - klebsiella pneumonia - pseudomonas aeruginosa - enterococcus faecium |
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What percentage of staphylococcus aureus is resistant to methicillin?
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60%
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What are two examples of antibiotics which exhibit concentration-dependent killing?
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- aminoglycosides
- fluoroquinilones |
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What are two examples of antibiotics which exhibit time-dependent killing?
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- beta-lactams
- vancomycin |
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What is an example of a superinfection?
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- pseudomembraneous colitis due to growth of Clostridium difficile
- often after clindamycin |
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What are three general mechanisms of antibiotic resistance?
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1) mutation and selection
2) uptake of extracellular DNA from related bacteria and recombination 3) plasmid mediated acquisition of R-factors |
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In which bacteria is mutation and selection often the mechanism of antibiotic resistance?
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mycobacterium tuberculosis
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In which 3 bacteria are recombination often the mechanism of antibiotic resistance?
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- Haemophilus
- Neisseria - Streptococcus |
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In which 4 bacteria are plasmid-borne R-factors often the mechanism of antibiotic resistance?
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- Klebsiella
- Pseudomonas - E. coli - Staphylococcus |
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What are the 3 most common bacterial pathogens causing acute respiratory infections?
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- streptococcus pneumonia
- haemophilus influenza - mycoplasma pneumonia |
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What classes of drugs inhibit nucleic acid synthesis? (4)
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- sulfonamides
- trimethoprim - fluoroquinolones - quinolones |
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What is sulfonamide MOA?
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- analog of PABA
- inhibits folic acid synthesis |
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What is trimethoprim MOA?
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- analog of dihydrofolate
- inhibits DHFR |
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Which two nucleic acid inhibitors are often combined and why?
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- TMP/SMZ (trimethoprim and sulfamethoxazole)
- they inhibit two distinct steps in the same pathway so they are synergistic - SMZ inhibits earlier step in pathway |
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Which two nucleic acid inhibitors are never combined and why?
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- nalidixic acid and nitrofurantoin
- antagonistic effect |
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What is therapeutic use of sulfonamides?
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- sulfadiazine + pyrimethamine for treating toxoplasmosis
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What is therapeutic use TMP/SMZ? (4)
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- UTIs
- RTIs caused by H. influenza and S. pneumonia - Shigella enteritis - PCP in AIDS patients |
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What are 3 major toxicities with sulfonamides?
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- blood dyscrasias
- skin rashes - kernicterus in newborns (from displacing protein-bound bilirubin which deposits in basal ganglia) |
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What is important drug interaction with sulfonamides and precaution must be taken?
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- they inhibit P450-mediated metabolism of warfarin
- must monitor INR |
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In addition to sulfonamide toxicities, what are additional toxicities with TMP/SMZ? (2)
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- megaloblastosis, leukopenia, and thrombocytopenia in patients with folic acid deficiencies (alcs, homeless, malnourished)
- rash, fever, and hepatitis in AIDS patients treated for PCP |
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What are 3 mechanisms of resistance to sulfonamides?
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- **synthesis of altered dihydropteroate synthase which has lower affinity for sulfonamide
- overproduction of PABA - reduced uptake of sulfonamide |
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What are 2 mechanisms of resistance to TMP/SMZ?
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- overproduction of DHFR
- expression of altered DHFR with reduced affinity for trimethoprim |
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What is the MOA of quinolones and fluoroquinolones?
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- inhibit two enzymes in DNA replication:
- DNA gyrase (gyrA) - topoisomerase IV (parC) |
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Which two enzymes are inhibited by quinolones and fluoroquinolones?
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- DNA gyrase (gyrA)
- topoisomerase IV (parC) |
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What are the common fluoroquinolone drugs? (3)
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- ciprofloxacin
- ofloxacin - levofloxacin |
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What drugs end in "floxacin"?
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fluoroquinolones
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What is normal function of DNA gyrase (gyrA) and topoisomerase IV (parC) and which antibiotics inhibit these?
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- relieves positive supercoiling to allow DNA replication to continue
- inhibited by quinolones and fluoroquinolones |
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How do fluoroquinolones show selective toxicity?
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- inhibit bacterial DNA gyrase at much lower concentrations than the mammalian enzyme
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What are therapeutic uses of fluoroquinolones? (4)
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"broad spectrum, oral administration"
- UTIs (inc Pseudomonas aeruginosa) - enteritis (Salmonella, Shigella, E. coli, Campylobacter) - vibrio cholerae infections - respiratory, bone, soft tissue infections |
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What are major toxicities of fluoroquinolones?
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- nausea and GI distress
- CNS effects - damages growing cartilage (contraindicated in kids and pregnant women) |
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In which patients are use of fluoroquinolones contraindicated?
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- kids (< 18) and pregnant women
- damages growing cartilage |
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What is important drug interaction of fluoroquinolones?
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- inhibits P450-mediated degradation of theophylline (asthma drug) and caffeine
- can lead to seizures |
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What are 2 mechanisms of resistance to fluoroquinolones?
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- alterations In DNA gyrase (gyrA) and topoisomerase IV (parC) lower affinity for drug
- decreased permeability of the drug (mutations in porins) |
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What kind of drug is nalidixic acid and what is its use?
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- older quinolone
- used to treat uncomplicated UTIs |
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What kind of drug is nitrofurantoin and what is it used for?
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- prodrug that is reduced by bacterial enzymes into reactive species that destroys DNA
- used to treat uncomplicated UTIs |
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What are the main 2 drug types that inhibit cell wall synthesis?
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- beta lactams
- vancomycin |
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What are the 4 types of beta-lactams?
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- penicillins
- cephalosporins - monobactams - carbapenems |
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Which of the beta-lactams have the widest spectrum of activity?
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carbapenems
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What 2 processes of cell wall synthesis are inhibited by beta-lactams?
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- transpeptidation
- carboxypeptidation |
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How do beta-lactams work?
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- they are analogs of the acyl-D-ala-D-ala C terminus of the peptide chain
- when it binds the PBP, the bond is stable so the enzyme is inhibited and cell wall synthesis can't proceed |
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What is the most important determinant of a beta-lactams effectiveness against an organism?
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- the "affinity" for any one of the essential PBPs
- high affinity = low concentration of antibiotic = high acylation rate for the PBP |
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Compare ampicillin and penicillin G against E. coli
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- they have equal affinity for PBPs
- ampicillin is more polar and diffuses through porin channels more easily so it has much lower MIC |
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What 2 properties define intrinsic resistance of an organism to a beta-lactam?
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- affinity of drug for PBPs
- ability of drug to reach the PBPs in the periplasm of gram(-) bacteria |
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What 4 mechanisms define extrinsic resistance to beta-lactams?
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- production of beta-lactamase that hydrolyzes anti-biotic
- decrease in outer membrane permeability - overexpression of efflux pump that pumps drug out of periplasm - mutations in essential PBPs that decrease rate of inactivation by antibiotic |
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What is meant by "extrinsic resistance" of an organism?
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- resistance existing above and beyond that found in a wild-type strain
- compared to intrinsic resistance which would be typical of wild-type |
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What is similar and different between PBPs and beta-lactamases?
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SAME: serine in beta-lactamase and PBP attacks beta-lactam bond, forming an acyl-enzyme complex
DIFF: beta-lactamases rapidly hydrolyze which inactivates the drug |
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In what 2 ways is beta-lactamase mediated?
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- chromosomally: inducible
- plasmid: found on R factors and transmitted among strains |
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How do beta-lactamases differ between gram(+) and gram(-) bacteria?
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gram(+): b-Ls are extreted into the medium
gram(-): b-Ls are retained in periplasm |
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Are gram(+) or gram(-) organisms more susceptible to beta-lactamases?
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- gram(-) because the beta-lactamase is retained in the periplasm where it is needed
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What drugs were developed to be resistant to beta-lactamse? (5)
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- methicillin (no longer used)
- oxacillin - nafcillin - 2nd and 3rd generation cephalosporins - carbapenems |
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Which beta-lactamase does not form an acyl-enzyme complex with antibiotics and what are 2 problems from this?
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metallo-beta-lactamse (NDM-1)
- hydrolyzes most beta-lactams - not inhibited by clavulanic acid |
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What bacteria often has mutations in the promoter region to increase expression of efflux pumps?
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Neisseria gonorrhoeae
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Which bacteria (4) commonly confer resistance to beta-lactams through alterations in PBPs?
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- Staph. aureus
- Strep. pneumoniase - Haemophilus influenza - Neisseria gonorrhoeae |
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What is PRSP and what drugs are used to treat it?
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- penicillin-resistant Strep. pneumoniae
- contains mutations in all of the essential PBPs - treated with vancomycin, linezolid, or streptogramins |
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What is relationship between PBP acylation rate and MIC of a beta-lactam?
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the PBP with a higher acylation rate has a lower MIC
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In what 2 ways does Neisseria become resistant to penicillin?
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- plasmid-mediated production of a beta-lactamase
- chromosomal mutations in endogenous genes |
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What chromosomal mutation occurs in Neisseria strains which are penicillin or ceftriaxone resistant?
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PBP2
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Mutations of PBP2 in Neisseria gonorrhoeae cause resistance to what 2 drugs?
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- peniccilin
- ceftriaxone |
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What drugs are used to treat MRSA? (3)
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- vancomycin
- linezolid - streptogramins (dalfoprisin/quinupristin) |
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How did MRSA develop resistance?
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- acquired new PBP (PBP2a) from an animal pathogen (Staph. fleurettii)
- PBP2a shows very low rate of acylation with almost all beta-lactams |
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What are therapeutic uses of PenG and PenV? (4)
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"mainly gram(+)"
- neisseria meningitidis (ceftriaxone is preferred) - strep. pneumoniae - enterococci (with aminoglycoside) - syphillis |
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What is therapeutic use of penicillinase-resistant penicillins?
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- staphylococcus aureus (NOT MRSA)
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What are therapeutic uses of ampicillin and amoxicillin?
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"wider gram(-) coverage than PenG and PenV"
- E. coli - H. influenzae, Pen-sensitive strep. pneumo (URI, otitis media) - listeria |
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What are therapeutic uses of ticarcillin, pipericillin, and mezlocillin?
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"difficult to treat gram(-) bacteria"
- proteus mirabilis - pseudomonas aeruginosa - serratia marcescens - klebsiella pneumoniae |
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What are the broadest spectrum beta-lactams? (2)
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"carbapenems"
- imipenem - meropenem |
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What are the therapeutic uses of imipenem and meropenem?
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- serious infections of unknown origin
- mixed infections |
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What drug is combined with imipenem and why?
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- cilistatin (renal dipeptidase inhibitor)
- imipenem is hydrolyzed and inactivated by a renal dipeptidase |
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What is cilistatin and what is it's use with antibiotics?
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- renal dipeptidase inhibitor
- used with imipenem which is normally hydrolyzed by imipenem |
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What are two beta-lactamase inhibitors?
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- clavulanic acid
- sulbactam |
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What are clavulanic acid and sulbactam?
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beta-lactamase inhibitors
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What two drugs combine a beta-lactam with beta-lactamase inhibitors?
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- Augmentin (amoxicillin + clavulanate)
- Unasyn (Ampicillin + sulbactam) |
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What drugs make up Augmentin?
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amoxicillin and clavulanate
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What drugs make up Unasyn?
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ampicillin and sulbactam
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What is MOA of beta-lactamase inhibitors?
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- they are beta-lactams
- react with beta-lactamase to form acyl-enzyme complex and inhibit the enzyme |
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What is the 1st generation cephalosporin and what is its therapeutic use?
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- cephalexin
- mostly gram(+) coverage - treats community-acquired skin infections |
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What is 2nd generation cephalosporin and what is it's therapeutic use?
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- cefuroxime
- increased gram(-) coverage - treats community-acquired pneumonia caused by H. influenzae or Klebsiella pneumonia |
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What is cephalexin and what does it treat?
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- 1st generation cephalosporin
- mostly gram(+) coverage - treats community-acquired skin infections |
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What is cefuroxime and what does it treat?
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- 2nd generation cephalosporin
- increased gram(-) coverage - treats community-acquired pneumonia caused by H. influenzae or Klebsiella pneumonia |
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What are two 3rd generation cephalosporins and what do they treat?
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- ceftriaxone and cefotaxime
- penetrate CNS, useful for meningitis by gram(-) - also treatment of choice for gonorrhea |
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What is treatment of choice for gonorrhea?
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- ceftriaxone (3rd generation cephalosporin)
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What is ceftriaxone and cefotaxime and what do they treat?
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- 3rd generation cephalosporins
- penetrate CNS, useful for meningitis by gram(-) - also treatment of choice for gonorrhea |
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What are two important properties about beta-lactams regarding how they are processed by the body?
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- not metabolized
- excreted in urine |
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How are most beta-lactams processed and what are the exceptions?
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- excreted in the urine (not metabolized)
- nafcillin and cefoperazone are excreted in bile |
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How fast are most beta-lactams eliminated and what is the exception?
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- rapidly eliminated (30-120 mins) by glomerular filtration
- exception is ceftriaxone which has 8 hr half life |
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What is most common side effect of penicillins?
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- hypersensitivity (rash, fever, bronchospasm, anaphylaxis)
- least toxic antibiotics bc humans have no cell wall |
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Which penicillin can be used if a patient has had a previous allergic reaction?
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- aztreonam (a monobactam)
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What are three main concerns with cephalosporins?
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- hypersensitivity
- intense local pain upon IM injection - some cause bleeding disorders |
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What is a unique potential toxicity of cefotetan, cefoperazone, and cefamandole)?
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- bleeding disorders
- side chain interferes with prothrombin formation |
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What cephalosporins can cause bleeding disorders as well as disulfiram-like reaction when used with alcohol? (3)
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- cefotetan
- cefoperazone - cefamandole |
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Which cephalosporins carry a high risk of superinfections?
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2nd and 3rd generation
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What is a unique risk with 2nd and 3rd generation cephalosporins?
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superinfections
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What are therapeutic uses for vancomycin?
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"bactericidal for gram(+) - doesn't penetrate outer membrane of gram(-)"
- infections caused by MRSA, Enterococcus faecium/faecalis, and penicillin-resistant-strep pneumo - pseudomembraneous colitis caused by C. diff |
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What drug is used to treat pseudomembraneous colitis caused by Clostridium difficile and what property makes this work?
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- oral vanvomycin
- not absorbed from GI tract |
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How is vancomycin normally given and what is the exception?
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- parenterally bc it isn't absorbed by GI tract
- exception is oral vancomycin in pseudomembraneous colitis due to C. diff |
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What is MOA of vancomycin?
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- binds tightly to acyl-D-ala-D-ala C terminus of peptide chain to prevent glycan polymerization and crosslinking of the peptide
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In what organism is vancomycin resistance often observed?
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Enterococci faecium
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What are 2 key observations of vancomycin resistance?
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- plasmid-mediated
- induced directly by vancomycin |
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What 3 enzymes mediate vancomycin resistance?
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- VanX
- VanH - VanA |
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What is the mechanism of vancomycin resistance? (i.e. what is the product of VanX, VanH, and VanA)
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- D-ala-D-lac instead of D-ala-D-ala
- vancomycin does not bind to acyl-D-ala-d-lac with high affinity, but cell wall cross-linking is not affected by substitution of D-ala for D-lac |
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What enzyme is assocatiated with VRSA and how does it occur?
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- vanA
- obtained genese by horizontal transfer of a transposon |
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When is VISA seen?
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after prolonged exposure to vancomycin (25 days to 18 weeks)
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What 2 drugs make up the bactericidal protein synthesis inhibitors?
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- aminoglycosides (except spectinomycin)
- streptogramins |
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What 5 drugs make up the bacteriostatic protein synthesis inhibitors?
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- tetracyclines
- chloramphenicol - macrolides - clindamycin - linezolid |
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How do aminoglycosides and linezolid inhibit protein synthesis?
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- block formation of the initiation complex
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Which drugs inhibit protein synthesis by blocking formation of the initiation complex? (2)
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- aminoglycosides
- linezolid |
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How do chloramphenicol, tetracycline, and clindamycin inhibit protein synthesis?
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- block aminoacyl-tRNA binding
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Which drugs inhibit protein synthesis by blocking aminoacyl-tRNA binding? (3)
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- chloramphenicol
- tetracycline - clindamycin |
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Which drugs block protein synthesis by blocking translocation of the new peptidyl-tRNA back to the P site? (2)
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- macrolides
- spectinomycin |
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How do macrolides and spectinomycin inhibit protein synthesis?
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- block translocation of the new peptidyl-tRNA back to the P site
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What are aminoglycosides active against as single agents?
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- only gram(-) bacteria (except staphylococci)
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What inhibits penetration of aminoglycosides through porins and binding to sites on cytoplasmic membrane?
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- divalent cations (Ca2+ and Mg2+)
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What drug is inhibited by divalent cations (Ca2+ and Mg2+)?
|
aminoglycosides
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What is necessary for aminoglycosides to reach binding sites in gram(+) bacteria?
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- beta-lactams
|
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What is important to remember about oxygen and aminoglycosides?
|
- uptake of drug requires oxygen
- thus, aminoglycosides are ineffective against strict anearobes |
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What is an example of synergism with aminoglycosides?
|
addition of a beta-lactam
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What is an example of synergism with beta-lactams?
|
addition of aminoglycoside
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What are therapeutic uses of aminoglycosides?
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- moderate to severe aerobic gram(-) infections
- almost always combined with a beta-lactam |
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What is a precaution of using aminoglycosides and beta-lactams?
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- premixing the two drugs inactivates them (forms a complex)
|
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What are main toxicities of aminoglycosides and how bad is it? (2)
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- ototoxicity
- neprotoxicity **severe; limits their use |
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How are aminoglycosides administered and what are their distribution limits?
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- parenteral admin (usually IM)
- excluded from CNS and ocular fluids |
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What most often causes resistance to aminoglycosides and how is this resistance mediated?
|
- modification of the antibiotics by enzymes (adenylation, acetylation, phosphorylation)
- plasmid-mediated and thus transmissable |
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Which aminoglycoside is least susceptible to enzymatic inactivation?
|
amikacin
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What are the therapeutic uses of tetracyclines? (4)
|
- Rocky mtn spotted fever (Rickettsia)
- cholera (vibrio choerae) - lyme disease (Borrelia) - brucellosis (Brucella) |
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Which 4 bacteria can be targeted by tetracyclines?
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- rickettsia
- vibrio cholerae - borrelia - brucella |
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Which 4 diseases can be treated with tetracyclines?
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- rocky mtn spotted fever
- cholera - lyme disease - brucellosis |
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Which 3 drugs are tetracylines and what is their specturm?
|
- tetracycline, doxycycline, minocycline
- "broad-spectrum" but rarely used d/t resistance and toxicities |
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How are tetracyclines administered and what is their distribution?
|
- oral or IV
- distribute well except CNS |
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What are main toxicities of tetracyclines?
|
- GI irriatation (oral admin)
- phototoxicity (rashes on skin in sun) - hepatic tox - renal tox - deposition in bones and teeth - fanconi syndrome |
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What drug is associated with Fanconi syndrome and what are its effects?
|
- caused by ingestion of outdated tetracycline
- nausea, vomiting, polyuria, proteinuria |
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What antibiotics are contraindicated in pregnancy?
|
- fluoroquinolones
- tetracyclines |
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In what patients are tetracyclines contraindicated?
|
- pregnant women and children < 8 yrs
- causes deposition in bone and teeth |
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What is a newer tetracycline which has expanded their use and spectrum of action?
|
tigecycline
|
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What are therapeutic uses of tigecycline?
|
- MRSA
- penicilin-resistant strep pneumoniae - many gram(-) bacteria (Citrobacter, Klebsiella, Shigella) - many anaerobes (Bacteroides) |
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What are the mechanisms of resistance to tetracyclines?
|
- **production of an efflux pump
- production of TetM protein that protects ribosome from inhibition by tetracycline - mutations in ribosomal structural proteins |
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What is spectrum and general use of chloramphenicol?
|
- "broad spectrum" but toxicities limit use
- reserved for treatment of serious infections when other drugs are contraindicated |
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What are therapeutic uses of chloramphenicol? (2)
|
- bacterial meningitis (H. influenzae or N. meningitidis) in patients with penicilin allergy
- Rocky mtn spotted fever (Rickettsia) when tetracycline is contraindicated |
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What are major toxicities of chloramphenicol? (3)
|
- aplastic anemia (irreversible and fatal)
- dose-related, reversible bone marrow depression - gray-baby syndrome (circulatory collapse) |
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What is main resistance mechanism to chloramphenicol and how is it mediated?
|
- inactivated by acetyl transferase
- this enzyme is often found of multi-drug resistant plasmids |
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What drugs end in "cycline"?
|
tetracyclines
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What drugs end in "thromycin"?
|
macrolides
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What drugs have antagonistic effects with macrolides? (2)
|
- chloramphenicol
- clindamycin |
|
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What 3 drugs are macrolides?
|
- erythromicin
- clarithromycin - azithromycin |
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What are therapeutic uses of macrolides? (4)
|
- Legionnaire's disease (Legionnella)
- mycoplasma pneumoniae - chlamydia trachomatis - whooping cough (Bordetella pertussis) |
|
|
How are azithromycin adn clarithromycin distributed?
|
- accumulate in phagocytes and are released at site of infection
|
|
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What are main toxicities of macrolides?
|
- generally well-tolerated
- GI distress and hepatotoxicity can occur |
|
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What are major drug interactions of macrolides?
|
- erythromycin and clarithromycin potentiate effects of corticosteroids, cyclosporins, digoxin, and warfarin
|
|
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Which macrolides potentiate effects of corticosteroids, cyclosporine, digoxin, and warfarin?
|
- erythromycin and clarithromycin
- NOT azithromycin |
|
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Which macrolide does not inhibit P450 enzymes?
|
- azithromycin
|
|
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What are 4 mechanisms of resistance to macrolides?
|
- decrease in permeability
- efflux pump - modification of ribosome target site - hydrolysis by an esterase |
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|
What are therapeutic uses of clindamycin?
|
- severe anaerobic infections caused by Bacteroides fragilis
- alternative for toxoplasmosis and PCP |
|
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What drug is given with clindamycin to treat toxoplasmosis?
|
- pyrimethamine
|
|
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What drug is given with clindamycin to treat PCP?
|
- primaquine
|
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How has use of clindamycin changed recently?
|
- use was limited due to toxicities, but now expanding to treat opportunisitic infections associated with AIDS
|
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What are main toxicities with clindamycin? (4)
|
- GI distress (found in feces up to 2 weeks)
- skin rashes - hepatotoxicity - superinfection by C. diff (--> pseudomembraneous colitis) |
|
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What drugs can be used to treat C. diff? (2)
|
- metronidazole
- oral vancomycin |
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|
What are 3 mechanisms of resistance to clindamycin?
|
- **production of methylase that modifies binding site
- direct inactivation of drug - decreased permeability |
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What drugs end in "pristin"?
|
streptogramins
- dalfopristin - quinupristin |
|
|
What are the streptogramins?
|
- dalfopristin
- quinupristin **always used together (synergistic) |
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What is the MOA of streptogramins?
|
bind the 50S subunit and cause comformational change which blocks peptide elongation
|
|
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What are the therapeutic uses of streptogramins? (3)
|
- vancomycin-resistant Enterococci faecium (but NOT E. faecalis)
- penicillin-resistant Strep. pneumoniae - MRSA |
|
|
What are the main 2 toxicities of streptogramins?
|
- pain at injection site / phlebitis
- myalgias / arthralgias |
|
|
What are important drug interactions of streptogramins?
|
- inhibit P450 enzymes
- increase concentration of cyclosporine and Ca channel blockers |
|
|
What are the 2 mechanisms of resistance to streptogramins?
|
- methylase that blocks binding of rRNA
- acetyltransferase that inactivates antibiotic |
|
|
What is MOA of linezolid?
|
- binds 50S subunit and prevents formation of 70S initiation complex
|
|
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What are therapeutic uses of linezolid? (4)
|
- VRE
- pen-resistant Strep pneumo - MRSA - group A and B strep |
|
|
What is main resistance mechanism to linezolid?
|
- mutations in rRNA that decrease affinity of drug
|
|
|
What are main toxicities related to linezolid?
|
- bradycardia with concurrent use of beta-blocker
- thrombocytopenia - superinfections |
|
|
What are important drug interactions with linezolid?
|
- a reversible MAOI
- avoid food high in tyramine and can NOT be given with MAOIs, bupropion, tricyclic antidepressants, SSRIs, or St. John's Wort |
|
|
In what kind of organisms can metronidazole be used and what is its MOA?
|
- taken up only in anaerobic bacteria and parasites
- converted to active metabolite that disrupts DNA |
|
|
What are the therapeutic uses of metronidazole? (3)
|
- pseudomembraneous colitis from C. diff
- bacteroides fragilis - parasitic infections (trichomoniasis, giardia, amebiasis) |
|
|
Which antibiotic can be used to treat anaerobic bacteria and parasites?
|
metronidazole
|
|
|
What are main toxicities associated with metronidazole?
|
- nausea, headache
- disulfram-like reaction with EtOH - not recommended in pregnant women |
|
|
What is main resistance mechanism of metronidazole?
|
- decrease or loss of enzymes involved in activation of antibiotic
|
|
|
What are therapeutic uses of daptomycin? (4)
|
- MRSA
- VISA - VRSA - VRE |
|
|
What happens to daptomycin if used for respiratory infections?
|
- inactivated by pulmonary surfactant
|
|
|
Which drug is inactivated by pulmonary surfactants?
|
daptomycin - therefore not used for respiratory infections
|
|
|
What is MOA of daptomycin?
|
- binds to cell membrane of gram(+) bacteria to cause membrane depolarizaiton, loss of membrane potential, and cell death
|
|
|
What are main 2 toxicities of daptomycin?
|
- skeletal muscle damage
- peripheral neuropathy at high concentration |
|
|
What is primary mechanism of resistance to daptomycin?
|
- remodeling of the phospholipid membrane and diversion from division of septum where it exerts its effects
|
|
|
What 3 characteristics of tuberculosis make it difficult to treat?
|
- mycobacteria are often intracellular (in macrophages)
- very slow growing organism - tubercular nodules are poorly perfused |
|
|
What defines MDR-TB?
|
- resistance to two of the first-line drugs: isoniazid and rifampin
|
|
|
What defines XDR-TB?
|
- resistance to two first line drugs: isoniazid and rifampin
- PLUS, resistance to any fluoroquinolones - PLUS, at least 1 of 3 second line aminoglycosides (amikacin, kanamycin, capreomycin) |
|
|
What are 3 injectable second-line aminoglycosides for TB treatment?
|
- amikacin
- kanamycin - capreomycin |
|
|
What are the 4 first line TB drugs?
|
- isoniazid
- rifampin - pyrazinamide - ethambutol |
|
|
What are the 5 second line TB drugs?
|
- streptomycin
- d-cycloserine - ethionamide - ciprofloxacin - amikacin |
|
|
What is MOA of isoniazid?
|
- prodrug activated by KatG
- active form inhibits InhA which is required for synthesis of mycolic acid, a critical component of mycobacterial cell wall |
|
|
What is a special feature of isoniazid which makes it a mainstay in the TB regimen?
|
- penetrates cells and is active against intracellular organisms
|
|
|
How is isoniazid metabolized?
|
- acetylation
|
|
|
What 2 situations can cause increased toxicity to isoniazid?
|
- slow acetylation
- renal insufficiency |
|
|
What are the 2 main toxicities in isoniazid?
|
- **hepatotoxicity (can be fatal)
- peripheral and CNS neuropathy |
|
|
What are important drug interactions of isoniazid?
|
- inhibits CYP3A4 (a P450)
- decreases metabolism of phenytoin and diazepam |
|
|
What are the 2 primary mechanisms of resistance to isoniazid and what level of resistance do they confer?
|
- overproduction of the InhA gene product (low resistance)
- mutation or deletion of KatG gene (high resistance) |
|
|
What is MOA of rifampin?
|
- inhibits DNA-dependent RNA plymerase
|
|
|
What are therapeutic uses of rifampin? (2)
|
- **first-line TB drug
- meningitis prophylaxis from exposure to N. meningitidis and H. influenzae |
|
|
What is main toxicity associated with rifampin?
|
hepatotoxicity
|
|
|
What are main drug interactions of rifampin?
|
- induces 4 of 7 P450 enzymes
- this increases elimination of other drugs - can cancel contraceptive effects of oral steroids |
|
|
What is MOA of ethambutol?
|
inhibits the synthesis of arabinogalactan, an essential component of mycobacterial cell walls
|
|
|
What is therapeutic use of ehtambutol?
|
- first-line TB drug
|
|
|
What is main toxicity associated with ethambutol?
|
- optic neuritis with red-green discrimination (resolves with removal of drug)
|
|
|
What are main 2 mechanisms of resistance to ethambutol?
|
- overexpression of enzyme that synthesizes arabinogalactan
- mutations that lower affinity of enzyme for ethambutol |
|
|
What is therapeutic use of pyrazinamide?
|
- first-line TB drug
|
|
|
What is MOA of pyrazinamide?
|
- converted to pyrazinoic acid (active form)
- inhibits fatty acid syntase 1 |
|
|
What are main 2 toxicities associated with pyrazinamide?
|
- hepatotoxicity
- hyperuricemia --> gout |
|
|
What is main mechanism of resistance to pyrazinamide and how fast does it occur?
|
- mutations in pyrazinamidase that blocks conversion to active form
- develops rapidly during single therapy |
|
|
What is treatment for mycobacterium avium complex (MAC)?
|
- ehtambutol + azithromycin or clarithromycin
|
|
|
What is used for prophylaxis against MAC in AIDS patients with low T-cell counts?
|
rifabutin
|
|
|
What are 4 general types of antifungals?
|
- amphotericin B
- flucytosine - triazoles - caspofungin |
|
|
Which two antifungals are used synergistically?
|
- amphotericin B (AMB)
- flucytosine |
|
|
Which antifungals are useful with less side effects than AMB and what 3 drugs are in this class?
|
"triazoles"
- fluconazole - itraconazole - voriconazole |
|
|
What is a new antifungal useful for treatment of invasive aspergillosis and candidiasis?
|
caspofungin
|
|
|
What is caspofungin used for?
|
- invasive aspergillosis
- candidiasis |
|
|
What is MOA of amphotericin B?
|
- forms a transmembrane pore by forming complex with ergosterol (component of fungal membranes)
- leakage of ions and metabolites leads to cell death |
|
|
What are challenges that arise from MOA of amphotericin B?
|
- also forms complex with cholesterol in mammalian cells
- has 10-fold selectivity for ergosterol but still has low therapeutic index |
|
|
What are therapeutic uses of amphotericin B? (3)
|
- Cryptococcus meningitis
- Candida infections - Coccidioides meningitis (intrathecal) |
|
|
How is amphotericin B packaged to decrease toxicity?
|
in a liposomal preparation
|
|
|
What are main toxicities with amphotericin B? (3)
|
"one of most toxic agents in use"
- **potent nephrotoxin - hypokalemia and hypomagnesemia - hypersensitiviy |
|
|
What drugs must be used cautiously with amphotericin B?
|
- other nephrotoxic drugs
- aminoglycosides and cyclosporin) |
|
|
What is important about pharmacokinetics of amphotericin B?
|
- given by slow IV infusion
- rapid sequesteration in tissues, slowly released - long half-life (15 days) |
|
|
What is main mechanism of resistance to amphotericin B and how often does it occur?
|
- decreased levels of ergosterol or alteration of its structure
- development of resistance during therapy is rare |
|
|
What is MOA of flycytosine (5-fluorocystosine)?
|
- taken up by fungal cell and converted to FdUMP
- FdUMP forms complex that blocks DNA synthesis |
|
|
When is flucytosine used?
|
- combined with AMB to treat Candida and Cryptococcus meningitis
|
|
|
What are main toxicities of flucytosine? (4)
|
- bone marrow depression
- hair loss - GI distress - hepatotoxicity |
|
|
What is main mechanism of resistance to flycytosine?
|
- mutations in cytosine permease or cytosine deaminase
|
|
|
What is the MOA of triazoles?
|
- block ergosterol synthesis by inhibiting 14-demethylase, an enzyme necessary for fungal cell wall synthesis
|
|
|
What are therapeutic uses for triazoles? (4)
|
- blastomycosis
- histoplasmosis - candidiasis - aspergillosis |
|
|
What is an alternative to AMB + flucytosine for treating coccidiodal and cryptococcal meningitis?
|
fluconazole (a triazole)
|
|
|
Which triazole can penetrate the CNS?
|
fluconazole
|
|
|
What are main toxicities of triazoles?
|
- vomiting, diarrhea, rashes
- impaired hepatic function - teratogenic |
|
|
In what patients are triazoles contraindicated?
|
pregnant women (they are teratogenic)
|
|
|
What are important drug interactions of triazoles?
|
- inhibit P450
- potentiate warfarin, cyclosporine, digoxin |
|
|
What are main 2 mechanisms of resistance to triazoles?
|
- overproduction or alteration of 14-demethylase
- expression of multidrug efflux pump |
|
|
What is MOA of caspofungin?
|
- inhibits synthesis of glucans (essential part of fungal cell wall) by blocking glucan synthase
|
|
|
What are therapeutic uses of caspofungin?
|
- invasive candidiasis and aspergillosis
|
|
|
What are main toxicities of caspofungin? (2)
|
- phlebitis at injection site
- embryotoxic (contraindicated in pregnant women) |
|
|
What antifungals are contraindicated in pregnant women?
|
- triazoles
- caspofungin |
|
|
What antifungals are safe to give in pregnant women?
|
- AMB
- flucytosine |
|
|
What antivirals are used to treat HSV and VZV? (3)
|
- acyclovir
- valcyclovier - famcyclovir |
|
|
What are acyclovir, valcyclover, and famcyclovir used to treat?
|
- HSV
- VZV |
|
|
What antivirals are used to treat cytomegalovirus? (2)
|
- ganciclovir
- valganciclovir |
|
|
What are ganciclovir and valganciclovir used to treat?
|
- cytomegalovirus
|
|
|
What are 4 drug types used to treat HIV and other retroviruses?
|
- nucleoside/tide reverse transcriptase inhibitors (NRTIs)
- non-NRTIs - protease inhibitors - fusion inhibitors |
|
|
What 3 drugs are used to treat influenza virus?
|
- zanamivir
- oseltamivir - adamantadine |
|
|
What are zanamivir, oseltamivir, and adamantadine used to treat?
|
- influenza virus
|
|
|
What is a key difference in RNA viruses after attachment to host membrane?
|
- RNA viruses internalize into endosomes which then become acidified
|
|
|
How does acyclovir and valacyclovir select for viruses?
|
- catalyzed by viral thymidine kinase but not host cell Tkase (100-fold selectivity)
|
|
|
What is general MOA of acyclovir, valacyclovir, ganciclovir, and valganciclovir?
|
- nucleoside analogues that inhibit viral DNA polymerase
|
|
|
What is therapeutic use of oral acyclovir and valacyclovir? (1)
|
- genital herpes
|
|
|
What is use of IV acyclovir and valacyclovir? (3)
|
- herpes simplex encephalitis
- neonatal HSV - serious HSV and VZV infections |
|
|
What is primary mechanism of resistance to acyclovir and valacyclovir?
|
- alteration in viral tyrosine kinase or viral DNA polymerase
|
|
|
Who is at risk for complicated CMV infections? (2)
|
- unborn babies
- immunocompromised patients |
|
|
In immunocompromised patients, reactivation of latent infection can cause what? (5)
|
- CMV retinitis
- colitis - CNS disease - esophagitis - pneumonia |
|
|
What are therapeutic uses of ganciclovir and valganciclovir?
|
- CMV retinitis
- CMV prophylaxis in transplant patients |
|
|
Which of the two agents used to treat CMV is preferred?
|
- valganciclovir over ganciclovir
- it has 100x greater activity |
|
|
What are side effects of ganciclovir and valganciclovir?
|
- myelosuppression
- nausea, diarrhea, fever, rash, headache |
|
|
What are 2 mechanisms of resistance to ganciclovir and valganciclovir?
|
- decrease in formation of triphosphate form
- mutations in DNA polymerase |
|
|
How are the "ciclovirs" activated?
|
- must be phosphorylated to the active triphosphate form
|
|
|
What is general MOA of foscarnet and its therapeutic use?
|
- inhibits viral DNA polymerase at different site than ciclovirs
- treats CMV infections |
|
|
What is main way foscarnet is different than the ciclovirs?
|
does not require phosphorylation or activation
|
|
|
What are main 2 therapeutic uses of foscarnet?
|
- CMV retinitis
- acyclovir-resistant HSV and VZV |
|
|
What are 3 main toxicities of foscarnet?
|
- nephrotoxicity
- electrolyte imbalances - HA, seizures, hallucinations |
|
|
What is main mechanism of resistance to foscarnet?
|
- point mutation in viral DNA polymerase
|
|
|
What is MOA of amantadine?
|
- blocks M2 proton channel that acidifies the virus and promotes uncoating of viral RNA
|
|
|
What is therapeutic effect of amantadine, zanamivir, and oseltamivir?
|
- prevents 70-90% of illness when initiated before exposure
- reduces symptoms by 1-2 days if initiated after onset of illness |
|
|
What are side effects of amantadine?
|
- GI distress
- CNS effects |
|
|
What is main resistance mechanism of amantadine and how common is it?
|
- point mutation in M2 proton channel
- fairly widespread |
|
|
What is MOA of zanamivir and oseltamivir?
|
- sialic acid derivatives that act as neuramidase inhibitors
- block release of progeny influenza virus |
|
|
How are zanamivir and oseltamivir administered?
|
zan: inhalation
osel: orally |
|
|
What strains show resistance to oseltamivir and where is mutation?
|
- H5N1 (avian)
- H1N1 (swine) - single mutation in neuramidase |
|
|
What is HAART and what are the 4 classes of drugs used?
|
"highly active anti-retroviral therapy"
- NRTIs (nucloetide/side reverse transcriptase inhibitors) - NNRTIs (non-NRTIs) - INSTIs (integrase strand transfer inhibitors) - PIs (protease inhibitors) |
|
|
What is enfuviritide and what does it treat?
|
- fusion inhibitor
- treats HIV |
|
|
What is Maraviroc and what does it treat?
|
- CCR5 antagonist that binds to co-receptor and blocks viral binding to host cell
- treats HIV |
|
|
What are tenofovir, emtricitabine, and efavirenz and what do they treat?
|
- NRTIs and NNRTIs
- block viral reverse transcriptase - treat HIV |
|
|
What is raltegravir and what does it treat?
|
- integrase inhibitor; inhibits integration into host DNA
- treats HIV |
|
|
What are atazanavir, darunavir, and ritonzvir and what do they treat?
|
- protease inhibitors; block processing of long peptide product produced by translation
- treats HIV |
|
|
What are the NRTIs and their MOA?
|
- tenofovir and emtricitabine
- competitively inhibit HIV reverse transcriptase and cauase chain termination when incorporated into viral DNA |
|
|
What is an NNRTI and its MOA?
|
- efavirenz
- inhibits HIV reverse transcriptase |
|
|
What are 3 protease inhibitors and their MOA?
|
- atazanavir, darunavir, ritonavir
- block cleavage which results in immature, non-infectious particles |
|
|
What is a integrase inhibitor and its MOA?
|
- raltegravir
- targets integrase that integrates viral DNA into genome (only used incombination with other drugs) |
|
|
What is a fusion inhibitor and its MOA?
|
- enfuviritide
- prevents conformational changes required for fusion with host membrane |
|
|
What is CCR5 antagonist and how is its MOA unique?
|
- maraviroc
- by targeting a cellular protein instead of a viral protein, resistance would be minimized |
