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AntibacterialDrugs
lecture 17-18,24-25 goodman
| Question | Answer |
|---|---|
| mechanism of action of sulfonamides | pABA analogs/competitive inhibitors of the dihydropteroic acid synthase that brings together dihydropteridine and pABA in the first step of folic acid synthesis |
| 3 moieties which make up folic acid | dihydropteridine, pABA and glutamic acid |
| Why not use sulfonamides for tx of abscesses? | pus and tissue breakdown products provide purines, pyrimidines and AA for bacteria to use and thus they won't use the folic acid synthesis pathway |
| trimethoprim mechanism of action | inhibits bacterial dihydrofolate reductase, the last step in folic acid synthesis (reducing dihydro to tetrahydrofolate) |
| sulfonamides are bacteriostatic and prone to resistance | |
| mechanism of resistance of sulfonamides | those isolates that are resistant contain increased [pABA] and flood out sulfa drugs that are competitive antagonists OR have altered dihydropteroic acid synthase with lesser affinity for sulfonamides |
| G6PD deficiency and sulfa drugs | G6PD deficient pts shouldn't take sulfa drugs, increases their risk for hemolytic anemia |
| uses for sulfonamide monotherapy | nocardiosis, minor UTIs caused by GN bacteria or chlamydia |
| fluoroquinolones | inhibit replication and transcription by binding to prokaryotic DNA gyrase/topoisomerase complex and inactivating the enzymes (topo - GP target, gyrase - GN target) |
| sulfisoxazole | most popular drug for sulfonamide monotherapy, very few adverse effects, freely soluble |
| fluroquinolone absorption from the gut is inhibited by _______ | cations, avoid milk, antacids, etc. |
| fluoroquinolone adverse effects | cartilage weaking in children (avoid giving to preg mothers), significant phototoxicity, rest are non-specific |
| fluoroquinolones - mechanism of resistance | altered topoismerase enzymes OR increased efflux/decreased influx of drug across membranes |
| fluoroquinolones are used against these organism | Legionella, Pseudomonas, Mycobacterium, Chlamydia only works on aerobes can replace aminoglycosides for serious GN infections |
| ciprofloxacin (Cipro) | first generation fluoroquinolone, best used on GN, has weak GP coverage. |
| levofloxacin (Levaquin) | newer fluoroquinolone, active against Streptococcus pneumoniae, Staph and many GP & GN infections |
| nitrofurantoin (Macrobid, Furadantin, Macrodantin) | is reduced in bacteria then oxidizes to generate toxic intermediate that damages DNA; used for UTIs (works best at pH 5.5), good against E. coli, bacteriostatic AND bactericidal, caution preg women and GP6D deficient pts |
| rifamycins | bind DNA-directed RNA polymerase and stop transcription, bactericidal, excellent selectivity for prokaryotic machinery, resistance due to mutation causing decreased affinity for drug substrate |
| rifampin or rifampicin | major use is against TB; also prophylaxis of meningococcal meningitis, good against Legionella, tx for leprosy in dapsone-resistant pts |
| rifabutin | a rifamycin drug, good against TB and Mac |
| transpeptidase | enzyme that cleaves off a terminal D-ala and links it to an L-lysine to form crosslinks in the bacterial cell wall |
| beta-lactam abx - mechanism of action | pseudosubstrates that bind to the transpeptidase enzyme (aka PCN-binding protein) in bacteria and irreversibly inactivate it, ending cell wall biosynthesis |
| How are beta-lactams bacteriocidal? | bacteriostatic - work best when an organism is growing by inhibiting wall synthesis bactericidal - cause cell lysis by the action of autolysins that are activated when cell wall balance is thrown off |
| beta-lactam resistance mechanisms | 1) changing porin structure in membrane 2) altering transpeptidase = less avid binding of PCNs 3) acquisition of beta-lactamases through plasmids or chromosomal transfers |
| beta-lactam pharmacokinetics | acid-labile, best given IV x pen V, amoxicillin, cephalosporins very short half-life ~ 30 min eliminated by organic acid pump in kidney, which is blocked by probenecid |
| type of bacteria most susceptible to beta-lactams | GP organisms (+ N. gonorrhoeae) and spirochetes, especially those which are rapidly growing GN organisms don't allow beta-lactam entry through their porins |
| beta-lactam allergic reactions | caused by very antigenic PCN-oylated proteins or AA in the blood. test for hypersensitivity using penicilloyl-lysine about 20% cross-reactivity with cephalosporins |
| syphilis tx | Pen G always |
| pen G-benzathine (Bicillin L-A) | 1/2 life of 1-2 wks, only parenteral b/c acid-labile, benzathine is local anesthetic, good for GP and primary syphilis (almost all N. gonorrhoeae and Staph now resistant) |
| nafcillin (Unipen) | beta-lactam, used especially for serious MRSA infections, given IV |
| oxacillin (Dynapen) | acid-stable beta-lactam that can be given orally or IV for MRSA infections |
| ampicillin, amoxicillin | extended spectrum aminoPCNs, acid-stable and thus oral, have better activity against GN bacteria like Proteus, E. coli and H. influenzae |
| ticarcillin (Ticar) | antipseudomonal carboxyPCN, big gun, can be mixed with clavulanate (Timentin) |
| piperacillin (Pipracil, with tazobactam = Zosyn) | broadest spectrum PCN, useful for a variety of GN & GP infections |
| advantages to cephalosporins over PCNs | less sensitive to beta-lactamases in many cases, some 2nd-4th generations show excellent penetration into CSF, works well typically for PCN-allergic pts |
| first generation cephalosporins, narrow spectrum = decent GP coverage but hardly any GN | cephalexin (Keflex), cefazolin (Ancef) still useful against PCNase-making Staph |
| second generation cephalosporins, moderate spectrum = decent GP coverage with extension to GN rods and some anaerobes | cefuroxime (Ceftin), cefoxitin (Mefoxin) is good for anaerobes |
| third generation cephalosporins, broad spectrum = good GP coverage and GN especially when mixed with aminoglycosides | Ceftriaxone (Rocephin) - long half-life (8 hrs), first line for gonorrhea now Ceftazidine (Fortaz) - important antipseudomonal Cefotaxime (Claforan) - resistant to beta-lactamases, good for meningitis |
| fourth generation cephalosporins, resemble 3rd except greater resistance to beta-lactamases | Cefepime (Maxipime) |
| carbopenems (Imipinem, meropenem, etc) | extremely broad-spectrum, activity against GN, GP, aerobes and anaerobes |
| imipinem/cilastatin (Primaxin) | beta-lactam carbopenem in combo with a drug that inactivates the enzymes that degrade it in the renal tubules = increased half-life. decent GN coverage also, give with aminoglycosides |
| clavulanic acid & tazobactam | beta-lactamase inhibitors, typically used in combination with beta-lactams for max effect (Augmentin & Zosyn) |
| vancomycin mechanism of action | glycopeptide that binds to D-ala-D-ala and keeps transpeptidase from cleaving the terminal one and establishing crosslinks |
| vanc resistance | VRE and some MRSA now, acquisition of enzyme that substitutes lactate for last D-ala so vanc can't bind anymore |
| vanc adverse effects | rapid IV push leads to histamine release and "red-neck syndrome," ototoxic & (maybe) nephrotoxic especially when combined with an aminoglycoside |
| target organisms of aminoglycosides | great for GN organisms just like PCN is the mainstay for GP |
| mechanism of action of aminoglycosides | multi-sugar molecule block initiation and elongation; cause mRNA misreading and incorporation of mutated proteins into the PM, causing leakage of ions and eventual lysis |
| aminoglycosides don't work in which situations? | against anaerobes (need O2-dependent pump to bring it in cells), in low pH |
| mechanism of resistance for aminoglycosides | proteins add various moieties onto the sugars and stop their binding to ribosome sites |
| why aminoglycosides are sequestered in the EC space | they are polycationic and very polar = very low GI absorption |
| adverse effects of aminoglycosides | ototoxic and nephrotoxic, can block the neuromuscular junction especially in susceptible pts like those with MG |
| aminoglycoside used for enterococcal and/or viridans endocarditis, tularemia and bubonic plague | streptomycin |
| 2 mainline aminoglycosides | gentamicin and tobramycin |
| 1st choice that is resistant against transferase enzymes that inactivate aminoglycosides | amikacin |
| neomycin | aminoglycoside, too toxic for parenteral use, used to "prep the bowel" pre-surg |
| mechanism of action of tetracyclines | binds 30S ribosomal subunit and prohibits tRNA binding, thus stopping protein elongation |
| mechanism of resistance of tetracyclines | bacteria have acquired a gene that is turned on after tetracycline has been noted to enter cell through its specific transporter. DNA encodes for an ATP-dependent pump that kicks tetracycline out |
| tetracycline is amphipathic and has short half-life | |
| unique absorption/excretion features of doxycycline and minocycline | Both are very lipophilic, longer half-life in fat ppl doxy - virtually no renal excretion, 20 hr half-life and safe to give to anephric pt minocycline - elimintated in bile and by kidneys |
| volume of distribution with tetracyclines | very large b/c they home to bone and fat (doxy/mino more to fat than tetra) |
| adverse effects of tetracyclines | discolor teeth in children under 12 y/o, photooxidize when exposed to UV radiation and generate ROS |
| mechanism of action of MLSK family | bind 50S ribosomal subunits and prevents peptide addition to proteins (via peptidyl transferase inhibition) |
| azithromycin (unique feature) | avidly binds tissues and is released over the course of weeks |
| macrolides specifically bind _____ | 23S RNA in the 50S subunit and stop peptide export channel |
| erythromycin | prototypic and first macrolide, concentrates in cells |
| clarithromycin therapeutic uses | used for tx of MAC, especially in AIDS pts |
| clindamycin uses | can be used for most GP infections as second line, but mostly used for anaerobes in mixed infections |
| quinupristin-dalfopristin | bacteriocidal in combination, under class called streptogramins, bind 50S subunit and cause release of incomplete protein chains, approved for VRE and MRSA |
| biggest adverse effect of quinupristin-dalfopristin | strongly inhibits P450 |
| chloramphenicol | broad-specturm bacteriostatic against aerobes and anaerobes, excellent penetration across BBB, inhibits peptidyl transferase, causes erythroid suppression, brain abscesses and meningitis |
| linezolid | bacteriostatic but -cidal for strep, binds 23s rRNA, mild MAOI, used for multi-drug resistant GP organisms like VRE, MRSA, etc |
| daptomycin | effective against MRSA and VRE, binds to bacterial membranes and depolarizes them (some crossreactivity with human PMs), several untoward effects, reserve for life-threatening situations. |
| metronidazole | mainline drug for killing anerobes, also works on protozoa like treponemia, giardia and entamoeba, has disulfiram-like effect therefore avoid EtOH. |
| bactitracin | topical use for GN/GP infections like infected dermal ulcers or eczema, good for C. diff - give orally |
| tx for leprosy | dapsone combined with rifampin |
Created by:
sirprakes
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