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Antimicrobial Therapy

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Question
Answer
Gram positive aerobes cocci cluster   staphylococci  
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Gram + aerobe cocci pairs   S. pneumoniae  
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Gram + aerobe cocci chains   group and viridans streptococci  
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Gram + aerobe cocci pairs & chains   Enterococcus sp.  
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Gram + aerobe bacilli   bacillus sp. coryneobacterium sp, listeria monocytogenes, nocardia sp.  
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Gram - aerobe cocci   moraxella catarhalis, neisseria gonorrhoeae, neisseria meningitidis, haemophilus influenza  
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Gram - aerobe bacilli   E. coli, Enterobacter sp, citrobacter, Klebsiella sp, Proteus sp, Serratia, Salmonella, Shegella,Acintobacter, Helicobacter, Psuedomonas aeruginosa  
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Anaerobes above diaphram   peptococcus sp, petostreptococcus sp, prevotella, veillonella, actinomyces  
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Anaerobes below diaphram   clostridium perfringes, tetani, difficile bacteroides fragilis, disastonis, ovatus, thetaiotamicron, fusobacterium  
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atypical bacteria   legionella pneumophila, mycoplasma pneumonia/hominus, chlamydia pneumoniae/trachomatis  
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Spirochetes   treponema pallidum(syphilus), borrelia burgdorferi (Lyme)  
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bacteria in mouth   peptococcus, peptostreptococcus, actinomyces  
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bacteria of skin/soft tissue   S. aureus, S. pyogenes, S. epidermidis, Pasturella  
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bacteria in bone/joints   S. aureus, S. epidermidis, Streptococcus, N. gonorrhoeae, Gram-neg rods  
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bacteria in abdomen   E. coli, proteus, klebsiella, enterococcus, bateroides  
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bacteria in urinary tract   E. coli, Proteus, Klebsiella, enterococcus, Staph saphrophyticus  
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bacteria in upper respiratory   S. pneumoniae, H. influenza, M. catarrhalis, S. pyrogenes  
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bacteria in lower respiratory tract   S. pneumoniae, H influenza, K pneumonia, legionella pneumonophilia, mycoplasma, chlamydia  
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hospital acquired lower respiratory tract   K. pneumoniae, P. aeroginosa, Enterobacter sp, Serratia sp., S. aureus  
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Meningitis   S. pneumoniae, N. meningitidis, H. influenza, Group B strep, E. coli, Listeria  
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MIC   minimum inhibitory concentration, lowest concentration of antibiotic that inhibits growth of bacteria, antibiotic conc. in body fluid must be greater than MIC  
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bacteriostatic   stops growth of bacteria, limits spread of infection while immune system attacks pathogen  
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bacteriocidal   kills bacteria  
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factors improve antibiotic cross BBB   lipid soluble, small size, low protein binding, inflammation of BBB open passage of BBB to allow antibiotic to pass  
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Concentration dependent killing antibiotic   aminoglycosides (gentamycin, tobramycin, amikacin); Fluoroquinolones (Cipro, levofloxin, moxifloxin)Once a day dose. also have post-antibiotic effect.  
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Time-dependent killing antibiotic   B-lactams (PCN, cephalosporin), glycopeptides, macrolides, clindamycin; must doses to maintain dose above MIC  
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beta-lactamase   reside in perplasmic space of bacteria; deactivates beta lactam ring of penicillin; only nafcillin is resistant  
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Which penicillin has greatest activity against gram + organisms, gram - cocci, and non-beta lactamase anaerobes?   Penicillin G, Pen VK  
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Antibiotic resistant to staphylcoccal beta lactamase and active against staphylcocci, streptococci only?   Nafcillin, Oxacillin, Methicillin; Nafcillin is IV only; Give po med 1 hr before or after food. Mostly used for staph infections, except MRSA, obviously.  
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Extended spectrum penicillin, with improved gram - activity, but susceptible to beta lactamase?   Ampicillin, Amoxicillin. Amoxicillin is best po aminopenicillin inactivated by beta-lactamase  
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PBP   penicillin binding protein thatreside in bacteria cytoplasmic membrane and cross link peptidoglycan layer (which is part of cell wall); binding site of PCN that stops bacterial cell wall growth and kills bacteria  
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Staphylococci   Gram + aerobe cocci, causes infection in skin/soft tissue, bone/joint, hospital acquired pneumonia. Killed by beta-lactam compounds, and vancomycin  
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beta-lactam compounds   penicillins, cephalosporins, monobactams, carbapenems, B-lactamase inhibitors  
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PCN that are acid-stable; can be given po?   Penicillin V, dicloxacillin, amoxicillin  
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S. pneumoniae   Gram positive aerobe cocci in pairs; URI,community acquired pneumonia, meningitis  
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What is the difference between gram + and gram - bacteria?   peptidoglycan layer (unique to bacteria)is thicher in Gram + bacteria. Gram - bacteria have a lipid bilayer not present in gram + bacteria.  
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What is the mechanism of methicillin resisitance?   Altered PBP (penicillin-binding protein); found in staph, pneumococci, enterococci  
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Enterococcus species   Gram positive aerobe cocci in pairs/chains; cause UTI, abd infections  
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What type of PCN are formulated for delayed absorption?   benzathine and procaine pcn. IM injection for B-hemolytics strep (10 day conc.) Benzathine PenG treat strep throat(1.2 million), syphilis (2-4 million weekly x 3)  
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What is preferred oral PCN?   Amoxicillin (amino-pcn;best bioavailability) Penicillin V is oral form but should not be give with food & has narrow spectrum (QID.)  
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List Penicillinase-resistant penicillin   methicillin, nafcillin,oxacillin Gram +: methicillin susceptible S. aureus, group streptococci, viridans strep.  
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List Aminopenicillins   Ampicillin, Amoxicillin; Increase to Gram negative (Proteus mirabilis, Salmonella, Shigella, some E. coli, BL-H. influenza)  
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What penicillin class is only active against resistant gram-negative aerobes   Carboxypencillins (Carbenicillin, ticarcillin)  
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Ureidopenicillins   piperacillin, azlocillin; good activity with anaerobes,Kleibsiella pneumoniae, combo with pseudomonas aerugionosa outside of urinary tract  
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What is the purpose of combination therapy   Beta lactamase inhibitors (clavulanic acid, sulbactam, tazobactam) extends penicillin. Ex: Unasyn, Zosyn, augmentin, timentin  
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What cephamycins are active against anaerobes   2nd generation cephamycins; cefoxitin, cefotetan, cefmetazole (anaerobe: Bacteroides fragilis)  
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What is the most common first generation cephalosporin?   Cefazolin; commonly used in surgical prophylaxis  
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What is 1st generation cephalosporin?   cefazolin, cephalexin  
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what is included with 2nd generation cephalosporin?   cephamycins, carbaphems, cefuroxime Cephamycins: cefoxitin, cefotetan, cefmetazole  
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What is 1st generation cephalosporin active against?   Gram +: meth-susc S. aureus, pcn-susc S. pneumoniae, group/viridans strep, E. coli, K. pneumoniae, P. mirabilis  
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What is 2nd generation cephalosporin active against?   Gram +:meth-susc S. aureus, pcn-susc. S. pneumoniae, group/viridans streptococci Gram - : E. coli, K. pneumoniae, P. mirabilis, H. influenza, M catarrhalis, Neisseria sp. ANAEROBES: Bacteroides fragilis  
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What has the best activity against gram + aerobes including S. pneumoniae?   Ceftriaxone, cefotaxime  
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What is significant for 3rd generation cephalosporin?   expanded gram-negative activity; work against resistance organisms  
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What 3rd gen cephalosporin is active against pseudomonas aeruginosa?   ceftazidime, cefoperazone  
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What bacteria produce beta-lactamase   H. influenza, K. pneumoniae, some species of E. coli, staph. aureus & neisseria, Enterobacter sp  
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List 3rd generation cephalosporins   cefdinir, cefixime, cefoperazone, cefotaxime, ceftazidime, ceftibuten, ceftriaxone  
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What generation of cephalosporin pass the BBB?   3rd gen, (ceftriaxone, cefotaxime) ROCEPHIN (ceftriaxone) is a 3rd generation cephalosporin. Means it can be used to treat meningitis.  
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Significance of 4th generation cephalosporin   extended spectrum activity, same as Gram + 3rd generation & pseudomonas aeruginos, enterobacter sp. (mix of ceftriaxone and ceftazidime)  
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Example of 4th generation cephalosporin   cefipime  
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Why choose cefipime over ceftazidime?   cefipime covers pcn-rst strep, enterobacter  
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What percentage of pt have cross-allergy to cephalosporin from pcn   5-10% (if allergy to pcn shouldn't receive cephalosporin.)  
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Monobactam   Aztreonam; NO activity against gram + or anaerobes. Can receive aztreonam pneumonia, sepsis, meningitis if allergic to pcn  
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What does Carbapenems NOT cover   Carbapenems do not cover MRSA, VRE, coagulase-negative staph, C. diff, S. maltophilia, Nocardia  
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MECHANISMS OF RESISTANCE FOR BETA-LACTAMS   1. beta-lactamase enzymes 2. alteration in PBPs cause < binding 3. alteration of outer cell membrane < penetration  
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MECHANISM OF ACTION FOR BETA-LACTAMS   1. interfer with cell wall synthesis by binding to PBP 2. inhibit of PBP inhibit peptidoglycan synthesis BACTERIOCIDAL TIME-DEPENDENT KILLING  
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PHARMACOKINETICS OF B-LACTAMS   1. food usually affects absorption 2. Wide distribution 3. usually eliminated by kidney 4. usually short half-life (except ceftriaxone)  
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What is the best orally absorbed b-lactams   Pen VK > Pen G amoxicillin > ampicillin  
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What Beta-lactam passes BBB   3rd & 4th gen Cephalosporins meropenem aztreonam  
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What b-lactams are eliminated by liver   Nafcillin oxacillin ceftriaxone cefoperazone  
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What is the mechanism of hypersensitivity to Beta-lactams?   antibodies to penicillin or metabolic by-products  
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What Beta-lactams does not display cross sensitivity?   aztreonam  
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Adverse effects of Beta-lactams   neuro: irritable, jerking, confusion, seizures (esp in > dose w renal insufficiency) Leukopenia, neutropenia, thrombocytopenia with therepy > 2 wks. GI (N/V/D, > LFTs, C. diff) Interstitial Nephritis (nafcillin, methicillin) phlebitis, hypokalemia,  
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Cephalosporin specific adverse effects   MTT side chain: cefamandole, cefotetan, cefmetazole, cefoperazone, molalactam) Hypoprothrombinemia (< Vit K bacteria in gut) Ethanol intolerance  
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Mechanism of action: Vancomycin   inhibit cell wall synthesis-at site different than b-lactams Binds to D-ala-D-ala portion of cell wall precursor BACTERICIDAL (except Enterococcus) TIME DEPENDENT KILLING  
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What does Vanco not work against?   Gram Negative aerobes or anaerobes  
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when is Vancomycin given PO?   only po for c. diff colitis  
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How dose Vancomycin?   TBW instead of IBW Wide distribution (variable CSF) Renal dosing necessary-kidney elimination  
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Mechanism of resistance for Vancomycin?   Modification of D-alaD-ala binding site to D-lactate Plasmid-mediated change in permeability of drug  
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Adverse effects of Vancomycin?   Red-man syndrome nephro/ototoxic neutropenia, thrombocytopenia thrombophlebitis  
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Inhibitors of cell wall synthesis   B-lactams: pcn, cephalosporin, monbactams, carbapenems Vancomycin  
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Inhibitors of protein synthesis   tetracycline, aminoglycosides, macrolides, clindamycin, streptogrammins, oxazolidinones, glycylcyclines  
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Inhibitors of nucleic acid function or synthesis   Fluoroquinolones  
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Inhibitors of metabolism   Sulfonamides, Trimethoprim  
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Tetracyclines   demeclocyclines doxycycline minocycline tetracycline  
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Mechanism of action for Tetracycline   Inhibit protein synthesis by reversibly binding to 30S ribosome (inhibit binding of t-RNA to acceptor (A) site on mRNA) BACTERIOSTATIC  
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SPECTRUM OF ACTIVITY : TETRACYCLINE   Broad Spectrum: Gram + aerobes (s. aureus-MSSA) S. pneumoniae (PSSP), some group/veridan strep, bacillus sp, listeria sp, nocardia sp. Gram - aerobes: H. influnzae, H. ducreye, C. jejuni, H. pylori. Anaerobes (mouth). Misc bacterial  
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Pharmacokenitics of Tetracycline   TIME-DEPENDENT Doxycycline/minocycline-best F (90%) Interact with Mg/Ca (di-trivalent cations) Widely distributed-not CSF  
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What tetracycline does not need renal dose adjustments?   Doxyclycline, Minocycline  
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What tetracycline is available in IV and PO form   Doxycycline  
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What tetracycline is excreted unchanged in urine   demeclocycline tetracycline (also the F = 60-80%)  
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Mechanism of resistance for tetracycline   1. decreased permeability 2. efflux 3. ribosomal protective proteins 4. enzymatic inactivation  
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What tetracycline does not exhibit cross resistance?   Minocycline  
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Adverse effects of tetracycline   GI: n/v/d, p. colitis hypersensitivity photosensitivity hepatotoxicity deposit on bone/teeth-not for children < 8, or pregnant women  
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Who should not receive tetracycline?   children < 8 and pregnant women (due to deposits on bone/teeth)  
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Aminoglycosides   Gentamycin, tobramycine, amikacin, streptomycin  
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Mechanism of action: Aminoglycosides   inhibit protein synthesis (30S ribosome) Bacteriocidal Post-antibiotic effect  
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Spectrum of activity Aminoglycosides   G +: most S. auerus, coagulase - staph viridans strep, enterococcus G-: E. coli, K. pneumo, proteus, morganella, providencia, serratia, salmonella, shigella, p. aeruginosa. Mycobacteria: tuberculosis, atypical  
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How is aminoglycosides used to treat endocarditis   Use aminoglycoside with other agent for Gram+ coverage-amino. has little gram + coverage  
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What aminoglycoside has better coverage for pseudomonas aeruginosa   Amikacin > tobramycin > gentamycin  
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What aminoglycoside treats tuberculosis   streptomycin  
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What aminoglycoside is used for atypical bacterial infections.   streptomycin or amikacin  
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Pharmacokinetics of Aminoglycosides:   CONCENTRATION dependent killing Poor PO absorption Distribute in ECF-not CSF. Dose on IBW half-life dependent on renal function  
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How does renal function affect aminoglycosides?   normal renal function 2/5-4hrs. prolonged in impaired renal function  
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Mechanism of resistance- Aminoglycosides   1. alt. in uptake-< penetration 2. modifying enzymes, -poor binding to ribosome 3. alt in ribosome binding site  
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Adverse effects of aminoglycosides?   nephrotoxicity-reversible ototoxicity-irreversible  
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Compare difference of ototoxicity among different aminoglycosides?   vestibular-dizziness, vertigo, ataxia: Streptomycin, gentamycin, tobramycin Auditory: tinnitus, < hearing: amikacin, netilmicin, gentamycin  
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Macrolides   erythromycin, clarithromycin,azithromycin  
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mechanism of action of macrolides   inhibit protein synthesis (50S) BACTERIOSTATIC -except at high doses may be bacteriocidal to susceptible organisms  
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Macrolide spectrum of activity   gram + aerobes: MSSA, PSSP, group/viridans strep, bacillus sp., corynebacterium sp. Gram - aerobes: h. influenza, M. cattahalis, neisseria sp upper airway anaerobes ATYPICAL BACTERIA!  
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What does macrolides not work against?   No enterobacteriaceae activity  
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What macrolides has best activity against Gram + aerobes?   erythromycin, clarithromycin  
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What macrolide does not work against H. influenzae?   Erythromycin does not work against H. influenzae  
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Pharmacokinetics of macrolides   erythromycin require EC for oral absorption; ester (salts) improve Erythomycin absorption clarithromycin absorb regardless of food azithromycin-food affects absorption Hepatically eliminated cross-sensitivity among all macrolides  
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What macrolide required dose adjustment for kidney function?   Clarithromycin  
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What are the half-lives of Macrolides   1.4 hrs for Erythromycin, 3-7 hrs for clarithromycin, 68 hrs for azithromycin  
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Mechanism of resistance for macrolides   1. active efflux 2. altered taget sites  
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Adverse effects of Macrolides   GI: n/v/d, dyspepsia-most common w/erythro. cholestatic hepatitis (> 1-2 wk of erythromycin) thrombophlebitis-IV erythro, azithro ototoxicity, prolonged QT, allergy  
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Ketolides   Telithromycin  
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Mechanism of action of telithromycin   Inhibits protein synthesis by binding to 2 sites on 50S CONCENTRATION DEPENDENT BACTERIOCIAL (S. pneumoniae)  
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Spectrum of activity of telithromycin   Gram + aerobe: S. pneumoniae!!, MSSA, group/viridan strep, listeria Gram -: N. meningitis, moraxella, H. influenzan, aeromonas, e. coli Atypical: chlamydia, mycoplasma, legionella  
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Pharmacokinetics of telithromycin (ketolide class)   absorp:rapid, incomplete, food no effect distributtion-lungs eliminate-hepatic-no renal dosage necessary  
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Adverse effects of telithromycin   n/v/d, abd pain hepatotoxicity-why not used much CNS (ha, insomnia, visual dist. transient loc) prolong QT Resp. Failure esp. w Myasthenia Gravis  
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Clindamycin mechanism of action   inhibit protein synthesis-50S bind in close proximity to macolides-competitive inhibition bacteriostatic; bacteriocidal in high doses w susceptible organism  
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Spectrum of activity-clindamycin   MSSA PSSP group/viridan strep anaerobes ABOVE the diaprham pneumocystis carinii, toxopasmosis gondii, malaria  
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Pharmacokinetics of clindamycin   F=90%, food minimal affect Tissue and bone distribution time dependent dosing-half life 2/5-3 hr  
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Clindamycin Mechanism of resisitance   1. altered target site 2. active efflux?  
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erm gene   alters binding site on ribosome creates resistance to macrolides, clindamycin, Synercid  
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mef gene   encodes efflux pump pumps out macrolides  
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Adverse effect of clindamycin   GI:n/v/d, dyspepsia C. diff-worst offender-require tx w metronidazole hepatotoxicity-rare, elevated trasaminase rare allergy  
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Streptogramins   quinupristin/dalfopristin 30:70 ratio (Synercid) only one available active against gram - VRE  
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Mechanism of action-Synercid   Inhibit protein synthesis-50S (early & late stages) BACTERIOSTATIC (cidal-to some)  
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Spectrum of activity   mostly Gram + (MSSA, MRSA, coag - staph, PRSP, strep, enterococcus faecium only,corynebacterium, bacillus, listeria, actinomyce clostridium (x c. diff), pepto/peptostreptococcus Limited gram- aerobes-neisseria, moraxella atypical-mycoplasma, legionella  
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Pharmacokinetics of Synercid   Time-dependent activity IV route only distribute-lungs, gallbladder, bile > blood low CSF Liver metabolized-bile elimination No renal dosing required  
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Mechanisms of resistance Synercid   alt. ribosome binding site enzymatic inactivation  
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Synercid adverse effects   venous irritation-central line preferred GI: n/v/d myalgia, arthralgia rash hyperbilirubinemia  
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BLACK BOX WARNING OF TELITHROMYCIN   RESPIRATORY FAILURE IN MYASTHENIA GRAVIS  
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Oxazolidinones mechanism of activity   Linezolid Inhibit protein synthesis: 50S, near surface interface of 30S which causes inhibition of 70S BACTERIOSTATIC  
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Spectrum of activity of oxazolidinones   MRSA, VRE, coag-staph, s. pneumo (PRSP) strep, enterococcus faecium/faecalis, bacillus, listeria, clostridium (ex c. diff), p. acnes, peptostreptococcus not much gram - atypical: mycoplasma, chlamydia, legionella  
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Oxazolidinones (linezolid) phamacokinetics   time dependent 100 % bioavailable, IV/PO 30% CSF, renal/nonrenal elimination, no RI adjustment needed  
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Mechanism of resistance for oxazolidinones   alt in ribosome binding-rare cross resistance to other protein synthesis inhibitors unlikely  
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Adverse effects of linezolid   GI-n/v/d headache thrombocytopenia-therapy > 2 wks, rtn to nml when therapy stopped  
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Glycylcyclines (tigecycline) mechanism of activity   inhibits protein TRANSLATION by binding to 30S and blocking tRNA into A site of ribosome BACTERIOSTATIC  
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Spectrum of activity of tegecycline   BROADEST Spectrum (except no pseudomonas) Gram +, Gram-, anaerobes  
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Tigecycline pharmacokinetics   TIME DEPENDENT activity IV only 71-89% protein binding lung, skin, gallbladder penetration no extensively metabolized 33% kidney excretion/ 59% biliary/fecal excretion  
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Tigecycline resistance   none to date  
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Tigecycline adverse effects   diarrhea nausea vomiting acute pancreatitis-rare  
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FLUOROQUINOLONES mech. of action   inhibit bacterial topoisomerase (need for DNA synthesis (DNA gyrase, Topoisomerase IV) BACTERIOCIDAL/ POST ANTIBIOTIC EFFECTS.  
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DNA gyrase   removes excess positive supercoiling in DNA helix Gram neg target for fluoroquinolones  
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Topoisomerase IV   essential for seperation of interlinking daughter DNA molecules Gram + target for fluoroquinolones  
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Spectrum of activity for fluoroquinolones   Excellent Gram - aerobes, & atypical bacteria limited gram + aerobes, no anaerobe resistance develop against p. aeruginosa other bacteria: mycobacterium tuberculosis, bacillus anthracis  
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Pharmacokinetics of fluoroquinolones   CONCENTRATION DEPENDENT KILLING Good bioavail p oral, food can delay peak extensive distribution, min CSF renal/hepatic elimination  
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Range of distribution for fluoroquinolones   prostate, liver, lung, skin/soft tissue, bone urinary tract cipro> levofloxacin > gatifloxacin  
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Fluoroquinolones Mechanism of resistance   1. alt target sites-chomosomal mutations in genes that encode DNA gyrase/topoisomerase IV 2. alt cell wall permeability-< porin expression 3. efflux 4. cross-resistance between FQs  
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Adverse effects fo fluoroquinolones   GI: n/v/d, dyspepsia CNS: ha, agitation, insomnia, dizziness, rare hallucination/seizures hepatotoxicity-> LFTs QT prolongation  
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Metronidazole mechanism of action   inhibit DNA synthesis by prodrug, toxicity against anaerobic bacteria, ferredoxin cause cell death BACTERIOCIDAL  
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Metronidazole spectrum of activity   anaerobe bacteria:bacteroides, fusobacterium, prevotella, clostridium, h. pylori anaerobic protozoa: trich, entamoeba, giardia, gardnerella vaginalis  
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Pharmacokinetic of Metronidazole   IV/PO F=90%, food not interfer does penetrate CNS metabolize by liver  
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Resistance to metronidazole   documented, but uncommon impaired oxygen scavenging ability-oxygen impairs activation of met. altered ferrodoxin levels-< transcription of ferrodoxin gene  
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Adverse effects of metronidazole   n/v, stomatitis, metallic taste peripheral neuropathy, seizure, encaphalopathy-caution w preexisting CNS disulfiram reaction with ETOH ingestion  
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TMP-SMX   trimethoprim-sulfamethoxazole (Bactrim or Septra) INhibitor of metabolism  
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Machanism of action TMP-SMX   inhibit folinic acid sythesis which is necessar for microbial production of DNA Sulfamethoxazole: inhibit dihydropteraoate synthesis (inhibit PABA into folic acid) Trimethoprim: inhibit dihydrofolate reductase- ALONE-bacteriostatic. TOGETHER-bacterioci  
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TMP-SMX spectrum of activity   gram+: s. pneumoniae, s. aureus, s. pyogenes, nocardia. NO ANAEROBE activity. Lots of Gram-: acinobacter, enterobacter, e coli, k. pneumoniae, proteus, salmonella, shigella, haemophilus sp., N. gonorrhea, stenotrophomonas maltophilia. TX of choice for PCP  
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Pharmacokinetic of TMP-SMX   TIME DEPENDENT ACTIVITY F=90%, IV/PO Distribute urine, prostate, CSF renal adjustment required renal/hepatic elimination  
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TMP-SMX resistance   point mutation in dihydropteroate synthase and/or altered production/sensitivity of dihydrofolate reductase slow progression b/c combo drug E. coli, Klebsiella, proteus, H. influenzae  
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Adverse reaction TMP-SMX   GI: n/v, glossitis hematologic-leukopenia, thrombocytopenia, eosinophilia may require d/c of med Steve-Johnson's syndrome hypersensitivity CNS: h/a, aseptic meningitis, seizures crystalluria  
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Nitrofurantoin   Urinary antiseptic bacteriostatic, bacteriocidal Alt. when E. coli resistant to TMP-SMX and FQs  
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Pharmacokenitics of nitrofurantoin   well absorped PO, metabolized and excreted quickly-no systemic action. Contraindicated for significant renal insufficiency. Urinary pH affect drug activity  
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Side effects of nitrofurantoin   anorexia, n/v neuropathy, hemolytic anemia w/glucose-5 phosphate dehydrogenase deficiency  
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