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178 Cards in this Set
- Front
- Back
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How is resistance to streptomycin usually acquired?
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ribosomal mutation
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How is resistance to quinolones generally acquired?
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gyrase gene mutation
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How is resistance to rifampin usually acquired?
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RNA polymerase gene mutation
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By what mechanism is resistance passed to abx resistant strains of staph aureus?
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transduction
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For what bugs in transformation critical in the development of drug resistance?
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pneumococci and Neissera resistance to penicillin
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What chemotherapeutic agents cause ototoxicity?
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aminoglycosides, vancomycin, minocycline
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Which chemo agents cause visual tox.?
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ethambutol, isoniazid
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What chemo agents produce photosensitivity?
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tetracyclines, fluoroquinolones
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What are the characteristics of bactericidal agents?
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-they have concentration dependent killing, the rate and extent of killing is dependent upon the drug concentration
-time dependent killing-killing is not increased with increasing concentrations above MBC |
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What is the postantibiotic effect (PAE)?
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a persistent suppression of microbial growth that occurs after levels of abx have fallen below the MIC.
-determining the length of the PAE will contribute to determining the frequency of daily dosing, |
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Are most abx that inhibit bacterial cell wall synthesis bactericidal or static?
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bactericidal
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What are the natural penicillins?
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Penicillin G (these 3 are IM)
Benzathin penicillin procaine penicillin penicillin V (orally useful) |
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Describe the properties of the natural penicillins.
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-highest antibacterial activity against certain gram positive bacteria
-some gram neg. coverage, some anaerobic -readily inactivated by Beta-lactamase -NO antipseudomonal activity -eliminated by active transport in the kidney -poor CNS penetration -Penicillin V is acid resistant and therefore orally useful |
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What are the penicillinase resistant penicillins (antistaph pens)?
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nafcillin
cloxacillin oxacillin methicilin (used in testing only) |
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What are the properties of penicillinase resistant penicillins?
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-lower activity against certain gram positive bacteria
-some gram neg and anaerobe -some are acid stable and highly protein bound -DOC against penicillinase producing S. aureus -hepatic metabolism and renal excretion |
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What are the extended spectrum penicillins?
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ampicillin
amoxicillin |
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Describe the properties of extended spectrum penicillins?
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-lower gram pos. coverage, extended gram neg. coverage, anaerobic coverage with combined with penicillinase inhibitors
-no antipseudomonal activity -resistance frequently develops -acid resistant, urinary excretion |
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What are the antipseudomonal penicillins?
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carbenicillin (least activity)
ticarcillin mezlocillin piperacillin (has strongest activity against pseudomonas) |
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Describe the properties of antipseudomonal penicillins.
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-covers bacteria covered by the extended spectrum pens plus some additional enteric gram neg. bacilli but major use is pseudomonas
-acid sensitive -renal excretion |
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Describe the properties of the combo products with Beta lactamase inhibitors.
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-addition of beta lactamase inhibitors extends the spectrum of these agents
-not all beta lactamases are inhibited by these products and bacteria may develop resistance independent upon beta lactamase production -MRSAs are resistant -examples of drugs include ampicililn/sulbactam, amoxicillin/clavulanic acid, piperacillin/tazobactam, ticarcillin/clavulanic acid |
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Describe penicillin G.
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-the prototype of all ICWS
-Strep pneumo, gonorrhea, clostridia, etc are susceptible to pen G -bactericidal, inhibit the final stage (cross linking) of bacterial cell wall synthesis by binding to specific penicillin binding proteins located inside bacterial cell wall (ultimately blocks transpeptidation) -these are ONLY bactericidal if bacteria are actively growing and making cell walls |
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What are the different mechanisms of bacterial resistance to penicillins?
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-inactivation by bacterial beta-lactamase (this is clinically most important)
-decreased perm. of outer membrane of the bacterial cell to pens which prevents it from reaching PBPs -autolytic enzymes not being activated, thus forming tolerant organisms -lack of cell wall -non peptidoglycan based cell wall |
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What is the significance of giving methicillin and what does resistance signify?
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if bacteria are resistant to this drug (which is penicillinase resistant) then the resistance is not based upon penicillinase but alteration of the penicillin binding proteins (transpeptidases)
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When is oral admin of Penicillin G indicated?
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only in mild infections or those requiring prolonged tx or for prophylaxis, oral absorb. not very efficienct
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Describe the parenteral admin. of Penicillin G.
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-preferred route of admin
-IM injxns are painful and irritating to the tissue tho -when high doses required, better to use IV route -do not use intrathecally -benzathine pen G is the longest acting preparation -Pen G benzathine is recommended for the tx of mild to moderate infxns, prophylaxis and tx of rheumatic fever and management of syphilis -penicillins penetrate the BBB poorly |
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Describe the excretion of penicillins.
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-pen G is the most rapidly excreted drug by normal kidney
-most is by tubular secretion -tubular secretion can be partially blocked by probenecid (can be used to increase the levels of pen. in severe infxns) |
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Describe the toxicity of penicillins.
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other than allergy, they are probably the most non-toxic and safest drugs available
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Describe the incidence of penicillin allergy.
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-b/c of wide use, pens and cephalosporins have greatest potential for allergic rxns
-can be life-threatening -antimicrobial drugs rank second only to blood products as cause of allergic rxns in hosp. pts. -penicillins are the foremost, followed by sulfa drugs and cephalosporins, etc -all penicillins are cross allergic and cross sensitizing -all 4 types of allergic rxns can be produced by penicillins, -methicillin was the most common cause of interstitial nephritis |
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Describe the toxicities of penicillins aside from allergy.
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-tissue irritation-Pen G mostly
-excess Na, K-cardiac and renal tox -soft frothy stools and diarrhea -overgrowth of staph, pseudomonas, proteus, or yeast, superinfection with other organisms such as yeast -severe febrile rxn called Jarisch-Herxheimer rxn in syphilis or lepto |
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Describe the properties of monobactams.
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ex: aztreonam
-drugs with monocyclic beta-lactam ring -relatively resistant to beta-lactamases -active against gram neg. rods -no activity against gram pos. and anaerobes -safe in pts wtih penicillin allergy |
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Describe the properties of carbapenems.
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ex: imipenem, cilastatin, meropenem, ertapenem
-give IV and have broad spectrum activity -pseudomonas may develop resistance rapidly -imipenem can cause seizures in high levels and should be used cautiously in pts with brain lesions, etc -ertapenem is highly stable against beta-lactamases and has activity against a wide variety of orgs., IV or IM |
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Describe the beta lactamase inhibitors.
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ex: clavulanic acid, sulbactam, tazobactam
-weak antibacterial action -inhibit many but not all beta lactamases -most active against plasmid encoded lactamases |
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Describe the structure of cephalosporins.
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closely related to penicillins and have beta-lactam ring structure
-they seem to have increased resistance to b-lactam as compared to penicillins |
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Describe the properties of first gen. cephalosporins.
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AKA narrow spectrum
-have good activity against gram pos. bacteria and relatively moderate activity against gram neg. -most gram pos. cocci (with exception of enterococci, MRSA and S. epidermis) are susceptible -have good activity against E.coli, Klebsiella, and proteus mirabilis |
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What are examples of first gen. cephalosporins?
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cefazolin (DOC for surgical prophylaxis b/c very effective against bacteria on skin)
cephalexin (active orally) cephradine |
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Describe the properties of second generation cephalosporins.
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-have increased activity against gram neg organisms but are much less actie than third gen. cephalosporins
examples: cefoxitin, cefamandole, cefaclor, cefuroxime, cefotetan, cefprozil, loracarbef |
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Describe the properties of 3rd generation cephalosporins.
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AKA broad spectrum
-generally less active than 1st gen against gram pos. cocci but much more active against Enterobacteriaceae, including penicillinase producing strains -a few members are very active against pseudomonas -examples: cefotaxime sodium (CNS) cefoperazone (metab by liver, antipseudomonal) ceftazidime (antipseud) ceftriaxone (CNS penetration) cefixime |
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Describe the 4th gen. cephalosporins.
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comparable to 3rd gen but more resistant to some beta-lactamases
example is cefepime |
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Against what organisms do none of the cephalosporins have reliable acitivity?
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MRSA
enterococci listeria atypicals like chlamydia and mycoplasma |
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What is the mechanism of cephalosporins?
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similar to that of penicillins,
-interference with bacterial cell wall synthesis and an increase in autolytic enzyme that causes cell wall breakdown -bactericidal -the activity of cephalosporins rests on the integrity of the beta-lactam structure |
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Describe the protein binding of cephalosporins.
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-most have some plasma protein binding
-penetration to most tissue is adequate except eye and CNS -newer gen. cephalosporins and others that DO enter the CNS are used for meningitis caused by aerobic gram neg. organisms -most are excreted by kidney unchanged except for cefoperazone, ceftriaxone is extensively metab. by liver as well -probenecid slows the excretion rate and prolongs their half life -dosage adjustment necessary during renal insuffic. |
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Describe the clinical use of cephalosporins.
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-they are the DOC for infxns with Moraxella (second/third gen), Gonorrhea (ceftriaxone), E.coli/klebsiella/proteus-1st/2nd gen, salmonella-3rd gen, pen resis. strep pneumo-ceftriaxone
-may also be considered in gram pos infxns in pts with penicillin sensitivity, mixed infxns (cellulitis or skin ulcers), surgical prophylaxis, UTIs |
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Describe the adverse rxns and toxicity of cephalosporins.
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-fairly safe abx
-uncommon rxns include pseudomembranous colitis, super infection, disulfiram like rxn after alcohol consumption, direct and indirect positive coombs test, diarrhea, dose dependent renal tubular necrosis, synergistic nephrotoxicity with aminoglycosides (esp in elderly and dec. renal fxn pts) |
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Describe the antibacterial spectrum of cefepime.
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it is considered a 4th generation cephalosporin and covers both gram pos and neg organisms
-better against enterobacter and citrobacter spp than other cephalosporins - |
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Describe the pharmacokinetics of cefepime.
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-admin. parenterally
-penetrates CSF -primarily renally excreted -elevated liver enzymes can be seen with this drug -probenecid can competitively inhibit renal tubular secretion |
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Against what type of bacteria is vancomycin effective?
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ONLY against gram positives
-most strains of S. aureus and S. epidermidis are susceptible, as well as strep, coryne, and clostridium -particularly useful against penicillin and methicillin resistant staph infxns and gram pos in penicillin allergic pts -synergistic bactericidal effects can be achieved when combined with aminoglycosides but increases nephro and ototox. -poor penetration to CNS=not good for meningitis |
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What is the mechanism of action of vancomycin?
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-it is bactericidal and exerts its effect by binding to the precursor units of bacterial cell walls, inhibiting the elongation of the PG chain and inhibiting transpeptidation
-not absorbed orally, given IV -given orally only for tx of abx associated enterocolitis |
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What are the adverse rxns of vancomycin?
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ototoxicity and nephrotoxicity
-red man syndrome, flushing from histamine release |
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What is fosfomycin?
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-inhibits cell wall synthesis at one of the first steps in the synthesis of PG
-active against both gram pos and neg -used for uncomp lower UTI in women |
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Describe bacitracin.
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-interferes with the final dephosphorylation step in the phospholipid carrier cycle,which causes impedance of mucopeptide transfer to the growing cell wall
-active mainly against gram pos -used topically, parenteral rarely used b/c to nephrotox. -most commonly used with polymyxin B or neomycin to prevent superficial skin and eye infxn following minor injuries |
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Describe cycloserine.
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-inhibits enzymes involved in cell wall synthesis and PG synthesis, resulting in a weak cell wall and eventually cell lysis
-second line broad spectrum abx used to tx active pulmonary and extrapulmonary TB and UTIs -can be bactericidal or static -adverse effects most frequently involve the CNS |
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Which drug is associated with fatal aplastic anemia?
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chloramphenicol
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Describe the mechanism of chloramphenicol.
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inhibits bacterial protein synthesis by reversibly binding to the 50s subunit of the bacterial 70s ribosomes and prevents the attachment of the amino acid containing end of the aminoacyl-tRNA to teh acceptor site on the ribosome
-it is bacteriostatic but can be "cidal" against certain common meningeal pathogens such as H.flu, neisseria mening, strep pneumo |
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Against what organisms is chloramphenicol effective?
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it is "broad spectrum"
-not effective against entamoeba histolytica or pseudomonas |
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What contributes to bacterial resistance against chloramphenicol?
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-resistance is significant due to acetyl transferase, an enzyme made by resistant organisms which inactivates chloramphenicol
-can be passed btwn bacteria spp |
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Does chloramphenicol penetrate the CNS?
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yes
-it is distributed widely in the body, to all tissues including eyes and CNS |
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Describe the metabolism of chloramphenicol.
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metabolized in the liver where it is conjugated wtih glucuronic acid
-only 10% of active drug is excreted by glomerular filtration in the urine |
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Describe the toxicities of chloramphenicol.
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-reversible bone marrow depression and hematopoietic problems (can also inhibit mitchondrial protein synthesis in mammalian cells)
-chloramphenicol should NOT be routinely given for ordinary infections -fatal aplastic anemia (genetically determined serious complication) -allergy -"gray baby" syndrome in infants-due to inability to conjugate and excrete the drug |
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What are the therapeutic uses of chloramphenicol?
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-b/c of potential toxicity and bacterial resistance and availability of alternatives, this drug is rarely used
-typhoid fever -meningitis -eye infections as topical -infections from gram neg. organisms (do not use as DOC for staph) -rickettsia, brucellosis, RMSF, etc |
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What are the drug interactions of chloramphenicol?
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-inhibit the hepatic metabolism of tolbutamide
-warfarin -inhibits cytochrome P450-interacts with phenytoin -plasma concentrations can be reduced by use of phenobarbital (induces P450) -do not use with erythromycin |
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Describe the mechanism of action of tetracyclines.
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-inhibition of bacterial protein synthesis
-bind specifically to 30S ribosomes -bacteriostatic |
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What types of organisms do tetracyclines treat?
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"broad spectrum"
-also effective against acute intestinal amebiasis in plasmodium falciparum infections and bacillary dysentery caused by strains of shigella |
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What organisms are resistant to tetracyclines and how did they likely acquire it?
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B fragilis, proteus, pseudomonas
-plasmids or resistant mutants transport the drug out of the cell |
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Describe the absorption, metabolism, and excretion of tetracyclines.
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-chelates with Ca, Fe, Al which lowers solubility in GI tract
-distribution is wide in all tissues except CNS and joints -these like to deposit in bones and teeth -metabolized by liver and excreted primarily through urine and some through bile -long acting tetracyclines (doxy and minocycline) are slowly excreted mostly in the bile |
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What are the adverse rxns of tetracyclines?
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-GI side effects-alter enteric flora
-bone and teeth (dental discoloration)-do not give to prego or kids <8 yrs old -liver damage -renal damage (renal tubular acidosis) -photosensitization -inhib. of ADH associated with demeclocycline -allergy |
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What are the therapeutic indications of tetracyclines?
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-DOC for mycoplasma pneumoniae, chlamydiae, rickettsiae, and spirochetes
-used in combo with H. pylori -used in various gram neg and pos infxns including vibrio -DOC for chlamydia is azithromycin -used in combo with aminoglycoside in plague, tularemia, and brucellosis -sometimes used in protozoal infxns such as entamoeba histolytica or plasmodium falciparum |
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Describe minocycline.
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a tetracycline with high concentration in saliva and tears
-used in the meningococcal carrier state -long half life |
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Describe demeclocycline.
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-blocks ADH receptor fxn in collecting tubules
-used in SIADH |
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What is tigecycline?
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-a derivative of minocycline and was developed to circumvent resistance mechanisms
-IV abx for the tx of complicated skin and skin structure infxns and intra-abdominal infections -binds to 30s ribosomal subunits, is bacteriostatic -spectrum of activity similar to tetracyclines -has activity against MRSA and MRSE, penicillin resistant strep pneumo and vancomycin resistant enterococci |
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Do aminoglycosides penetrate the CSF?
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no
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Are aminoglycosides absorbed orally?
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no, none of them are
-they are more active at alkaline pH |
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Describe the mechanism of aminoglycosides.
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-all act by inhibiting protein synthesis by inhibiting 30S subunit
-bacteriostatic -in order to be effective they must first be actively transported into susceptible bacteria by a transport mechanism requiring oxygen and bind irreversibly to the bacterial 30s subunit -under aerobic conditions aminoglycosides are bactericidal |
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Against which organisms are aminoglycosides effective?
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gram negative rods -enteric bacteria
-when there is a suspicion of sepsis or endocarditis -P. aeruginosa -bacteria that acquire resistance to one aminoglycoside may exhibit cross resistance to the other aminoglycosides -in some dz such as endocarditis and bacteremia, combo tx wtih penicilin and aminoglycosides produces better results |
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How are aminoglycosides eliminated?
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renally
-they accumulate in the body in renal failure, adjustment in dose is necessary in these cases |
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How is resistance to aminoglycosides acquired?
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-one type is conferred by plasmid mediated chemical changes of enzymes that adenylate, phosphorylate or acetylate the aminoglycoside drugs
-alteration of bacterial ribosomes, etc |
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Against which organisms are aminoglycosides generally ineffective?
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strep, clostridia, bacteroides, rickettsia, fungi, and viruses
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What are the therapeutic uses of aminoglycosides?
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-they are used primarily to tx severe systemic infxns caused by susceptible gram neg organisms
-streptomycin is used for tularemia and bubonic plague, TB, and endocarditis -pre-op suppression of enteric aerobic flora -hepatic encephalopathy -intestinal amebiasis -topically in wounds or burns |
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What are the toxicities of aminoglycosides?
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nephrotoxicity
ototoxicity neuromuscular weakness |
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Describe spectinomycin.
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-an aminocyclitol abx that is produced by streptomyces, structurally related to aminoglycosides
-currently, the clinical use is in the tx of uncomplicated gonorrhea by a single IM injxn in pts who are allergic to ceftriaxone or other beta-lactam abx -do not use to tx pharyngeal gonorrhea tho |
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Are sulfa drugs bacteriostatic or cidal?
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generally bacteriostatic
-but in the tx of certain UTIs they are bactericidal |
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What is the mechanism of sulfa drugs?
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-they compete with PABA in the synthesis of bacterial folic acid (this does not affect human cells since we have to use preformed folic acid)
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Against what organisms are sulfa drugs effective?
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both gram pos and neg organisms
-E. coli, nocardia, actinomycetes, staph aureus, MRSA, chlamydia, toxoplasma gondii |
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What are the mechanisms of resistance to sulfa drugs?
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decreased sensitivity of target enzymes
-increased formation of PABA -use of exogenous folate |
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What are the therapeutic uses of sulfa drugs?
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UTI infxns
nocardiosis (DOC) toxoplasmosis, and trachoma pneumocytis carinii in kids and AIDS pts |
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How are sulfa drugs generally administered?
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most orally
-topical use causes unnecessary sensitization or allergic response (it is generally not recommended except with silver sulfadiazine for burns or wounds) |
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Do sulfa drugs penetrate the CNS?
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yes and they cross the placenta too
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How are sulfa drugs metabolized?
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primarily in the liver as acetylated products and excreted primarily through the kidney
-acetylated sulfonamides are generally insoluble esp in acidic urine and cause crystalluria so there is a potential danger of renal damage by sulfa drugs |
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What are the toxicities of sulfa drugs?
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-may cause kernicterus in the nursing infant by displacing protein bound bilirubin, CI in infants less than 2 mos old
-toxicity is often bizarre -drug sensitivity, blood dyscrasia, kidney and liver damage, peripheral nerve damage, stevens johnson syndrome, microscopic hematuria |
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Describe Co-trimoxazole (Bactrim, TMPSMX).
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combo of trimethoprim and sulfamethoxazole in a fixed 1:5 ratio
-effective in P jiroveci pneumonia, shigellosis, UTIs, prostatitis -active against both methicillin susceptible and resistant -effective against resp tract pathogens -DOC for UTIs, moraxella catarrhalis infections -second line drug for listeria |
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Describe sulfadiazine.
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-oral, intermediate duration sulfonamide abx
-used in combo with pyrimethamine for the tx of toxo -poorly soluble in urine and causes crystalluria more often than other sulfonamides -generally limited to severe infections for this reason |
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Describe trimethoprim.
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-has activity against both gram neg and pos organisms
-commonly used for the tx and prophylaxis of UTIs, traveler's diarrhea, and pneumocystis carinii when combined with sulfamethoxazole -recurrent UTIs -relatively safe in pts with impaired renal fxn or in those who cannot tolerate sulfa drugs |
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Describe trimethoprim use in prego.
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-b/c it is a folate antagonist it can inhibit purine metabolism and is teratogenic
-DO NOT give in prego |
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Describe silver sulfadiazine.
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-a topical antiinfective agent used to prevent and tx infections of wounds caused by second and third degree burns
-has activity against both bacteria and yeast -exact mechanism is unknown, does not inhibit folic acid synthesis like other sulfa drugs -damages the cell membrane and the cell wall |
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Describe pyrimethamine; sulfadoxine.
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they are used together in an oral prep to tx or prevent malaria but the combo is NO LONGER recommended for malaria prophylaxis due to the possibility of fatal toxic epidermal necrolysis
-used together b/c of their synergistic activity on folic acid production |
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What is the mechanism of action of erythromycin?
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inhibition of protein synthesis of susceptible bacteria (gram positive)
-binds reversibly to 50S ribosomal subunits and interferes with the translocation step |
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Describe the antibacterial spectrum of erythromycin.
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-similar to that of penicillin G
-most active in vitro against most gram positive bacteria including listeria, staph aureus, strep pyogenes, s pneumo, the viridans strep and S. faecalis -active against mycoplasma pneumoniae, chlamydia, legionella -majority of gram neg. organisms are resistant to this drug |
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How is resistance to erythromycin and other macrolides developed?
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-drug efflux by an active pump mechanism
-ribosomal protection by inducible or constitutive production of methylase enzymes which modify the ribosomal target and decrease drug binding -hydrolysis by esterases -chromosomal mutations that alter a 50S ribosomal protein |
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Describe the absorption, metabolism, and excretion of erythromycin.
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-gastric acids rapidly destroy erythromycin base
-passes through placenta, but does not go into CNS -there are IV forms available when large doses are necessary -mostly excreted in feces |
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Describe the toxicity and adverse rxns of erythromycin.
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-seldom causes serious adverse rxns
-GI disturbances,mild allergic rxns, elevated hepatic enzymes and cholestatic jaundice, ototoxicity -IV admin can cause phlebitis -QT prolongation, torsades de pointes |
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What are the drug interactions of erythromycin?
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-it can inhibit the hepatic metabolism of other drugs increasing their serum concentrations
-Serious QT prolongation and cardiac arrhythmias have been reported when co-admin with cisopride or pimozide, etc. |
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What are the clinical uses of erythromycin?
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-most commonly used to tx mixed infections of skin soft tissue, body cavities caused by gram pos organisms
-as an alternative to penicillin in pts allergic to it -tx pharyngitis and skin infections caused by Group A strep pyogenes -tx pneumonia caused by M. pneumoniae and chlamydia infections, legionairre's dz |
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Describe the properties of clarithromycin.
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-an oral macrolide similar to erythromycin and azithromycin
-penetrates lung tissue and macrophages to a greater degree than erythromycin -effective against MAC -approved for tx of H pylori associated duodenal ulcer and for the tx of community acquired pneumonia in kids -effective against moraxella, mycoplasma pneumoniae, legionella, chlamydia pneumoniae -mechanism is same as erythromycin-inhibition of protein synthesis -metabolized in the liver |
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What are the differences btwn azithromycin and erythromycin?
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azithromycin can be dosed once daily and produces less GI intolerance than erythromycin
-it reaches higher intracellular concentrations which increases its efficacy and duration of action |
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What is the spectrum of azithromycin?
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-usually active against organisms that are usually susceptible to erythromycin
-has increased activity against M. pneumonia, Chlamydia, haemophilus, moraxella |
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Describe the absorption and metabolism of azithromycin.
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-given orally and IV
-unlike clarithromycin, food decreases the bioavailability of azithromycin so drug should be given at least 1 hr before or 2 hrs after food -elimination mostly by the liver, bile, and transintestinal -is not metabolized by the liver and has less effect on cytochrome P450 so less drug interactions |
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Describe the clinical effectiveness of azithromycin.
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-single doses are effective for tx of STDs due to chlamydia and gonorrhea
-tx of pediatric otitis media and pharyngitis and for MAC prophylaxis -IV dosage form is also available for initial tx of CAP and PID |
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What is telithromycin?
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a broad spectrum abx and the first in a new family called ketolides
-these resemble macrolides but have greater killing capacity -spectrum good against respiratory pathogens including erythromycin and penicillin resistant pneumococci -good activity against IC and atypical bacteria -inhibits 50S subunit -given orally and metabolized by CYP3A4 -causes diarrhea, serious hepatotoxicity and drug was withdrawn |
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What is clindamycin effective in treating?
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-effective in combo with pyrimethamine in tx toxoplasmic encephalitis in pts with AIDS
-active against a wide range of aerobic gram pos cocci as well as several anaerobic gram neg and gram pos organisms -many spp of strep, and staph, most anaerobes are also susceptible |
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What is clindamycin well known to cause?
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pseudomembranous colitis
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What is the mechanism of clindamycin?
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binds to 50S ribosomal subunit which inhibits protein synthesis
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Does clindamycin penetrate the CNS?
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no but high concentrations are found in bone, bile, and urine
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What is the mechanism of action of streptogramins (dalfopristin and quinupristin)?
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they inhibit bacterial protein synthesis by irreversibly blocking ribosome functioning
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What are the CI to streptogramins?
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breastfeeding
kids hepatic dz prego HS |
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What are the drug interactions with streptogramins?
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-they inhibit cyt. p450 3A4 and will decrease the elimination of other drugs
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What is the spectrum on linezolid (in the class oxazolidinones)?
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mostly works against aerobic gram positive organisms
-indicated for tx of bacterial pneumonia, skin infxns, vancomycin resistant enterococcal infxns, MRSA |
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What is the mechanism of linezolid?
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inhibits bacterial protein synthesis by interfering with translation
-binds to 50s subunit -it is also a reversible, non-selective inhibitor of MAO! |
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What are the CI to using linezolid?
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HS
pheochromocytoma (b/c they inhibit MAO) |
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What is the spectrum of nitrofurantoin?
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-exhibits wide spectrum of antibacterial activity against gram positive and negative E coli, S. pyogenes, klebsiella, etc.
-most proteus and Pseudomonas are resistant |
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What is the mechanism of nitrofurantoin?
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-probably interference with bacterial enzymes
-its antibacterial activity is higher in acidic urine so an acidifying agent is desirable to keep urinary pH below 5.5 |
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What are the toxicities of nitrofurantoin?
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-colors the urine brown
-interstitial pulmonary fibrosis on chronic usage -neurological disorders (severe polyneuropathies and demyelination and degeneration of neurons) |
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What are the CI of nitrofurantoin?
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pregnancy and impaired renal fxn and allergy
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What are the uses of nitrofurantoin?
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-for tx UTIs
-it is effective against gram neg bacteria -also effective against gram positive bacteria in UTI |
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What is the mechanism of action of methenamine?
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-decomposes to formaldehyde and ammonia in the acid medium of the urinary tract
-formaldehyde binds to amino groups, and inactivates proteins of the bacteria resulting in bactericidal action |
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What is the spectrum of methenamine?
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-active against gram negative organisms, esp E. coli
-bacterial resistance to formaldehyde does not develop |
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What are the toxicities of methenamine?
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-it is essentially non toxic b/c little decomposition takes place in the body until it appears in the acidic urine
-bladder irritation -CI in hepatic or renal insufficiency |
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What are the uses of methenamine?
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-rather limited
-used for chronic suppressive tx esp. of the UTI caused by E.coli -may be used prophylactically prior to urinary tract instrumentation and catheterization |
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What is the mechanism of nalidixic acid?
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-inhibits DNA synthesis of many susceptible gram negative organisms but has no effect on Pseudomonas
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What are the toxicities of naldixic acid?
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-if the tx is longer than 2 wks it is better to perform liver fxn tests and blood cell counts to keep track of the toxic rxns
-produces convulsion with high doses in pt with cerebral vascular insufficiency, parkinsonism, epilepsy -erosion of cartilage of wt bearing joints in young |
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What are the drug interactions of naldixic acid?
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-nitrofurantoin antagonizes the action of this drug if they are used together
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What is the use of naldixic acid?
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-to tx UTIs caused by gram negative bacteria, esp. E. coli, proteus, klebsiella, etc
-ineffective against Pseudomonas |
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What is the first broad spectrum abx orally active against pseudomonas?
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ciprofloxacin
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Describe the antibacterial spectrum of ciprofloxacin.
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-broad spectrum abx indicated for UTI, lower resp tract infxns and infxns of the skin, bones, and joints
-highly active in vitro against a broad range of gram positive and negative organisms including pseudomonas and MRSA -somewhat less effective against gram positives -poor activity against anaerobics |
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What is the mechanism of ciprofloxacin?
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-inhibition of DNA gyrase of the susceptible bacteria
-these are potent bactericidal agents that alter the structure and fxn of bacterial DNA by interfering with the enzyme DNA gyrase (topoisomerase II) |
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What is the mechanism of resistance development against ciprofloxacin?
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-mutation of the topoisomerase enzyme (DNA gyrase)
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Describe the PHK of ciprofloxacin.
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-oral admin
-antacids containing Mg interfere with absorption -does not enter CSF readily -metabolized in the liver at moderate extent -excreted in urine |
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What are the shortcomings of ciprofloxacin?
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limited activity against S. pneumo
poor CNS penetration not effective against anaerobes |
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What should ciprofloxacin NOT be used for?
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-empiric tx of CAP
-aspiration pneumonia (due to poor activity against anaerobes) -chronic resp. fibrosis -long term outpatients tx -cystic fibrosis |
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What are the adverse rxns of ciprofloxacin?
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-GI disturbances
-all quinolones increase QT interval -transient elevations of serum transaminase, LDH, alk phos -tendon rupture -CI in pregos, kids<18 years old and nursing mothers |
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Describe norfloxacin.
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-a fluoroquinolone, similar to ciprofloxacin
-virtually all urinary tract pathogens are susceptible -also active against many of the bacterial strains that cause enteritis, but not C. dificile -anaerobic bacteria, non-aeruginosa strains of pseudomonas and acinetobacter are generally resistant |
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Describe ofloxacin.
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-bactericidal against many gram pos. and neg. organisms
-very poorly active against treponema pallidum and anaerobes -used to tx many common infxns and is similar to cipro and norfloxacin -tx UTIs, lower resp tract infxns, bronchitis, COPD, etc. |
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Describe levofloxacin.
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-fluoroquinolone antiinfective available for oral or IV admin.
-twice at potent as ofloxacin against a variety of aerobic gram positive and negative bacteria, including tubercle bacilli -unlike cipro, this drug does not interact significantly with theophylline -FDA approved to tx sinusitis, chronic bronchitis, CAP, skin infxns., complicated UTIs and acute pyelo |
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Describe trovafloxacin, alatrofloxacin.
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-active against a wide range of gram positive and negative bacteria
-no significant drug interactions with cimetidine, cyclosporine, digoxin, theophylline, or warfarin -under new regulations, use will be restricted to certain life or limb threatening infxns b/c of risk of HEPATIC DZ |
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Describe moxifloxacin.
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oral once a day broad spectrum fluoroquinolone
-FDA approved to tx acute exacerbations of chronic bronchitis, acute sinusitis, and pneumonia -good penetration into respiratory tissues, CNS -metabolized through glucuronide and sulfate conjugation -improved activity against penicillin resistant pneumococci |
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What are the CI of moxofloxacin?
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-QT prolongation
-uncorrected hypokalemia -pts receiving Class IA or III antiarrhythmic agents |
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Describe gatifloxacin.
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-similar coverage as moxifloxacin
-only topical formulation marketed for ocular infxns |
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Describe gemifloxacin.
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-once a day oral fluoroquinolone
-active against penicillin resistant S. pneumo -approved for CAP |
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Describe daptomycin.
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-it is a lipopeptide abx that is bactericidal against gram positive bacteria
-no mechanism of resistance has been identified -IV admin -primarily excreted unchanged by the kidneys |
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Describe mupirocin.
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-a lipopeptide abx
-bacteriostatic at low concentrations and bactericidal at high concentrations -bacterial protein and RNA synthesis are inhibited when mupirocin reversibly binds to bacterial isoleucyl-tRNA synthetase -admin topically to skin or nares -used in the tx of impetigo caused by S. aureus and beta hemolytic strep -intranasal application in pts who carry MRSA |
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Describe polymyxin B.
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-used mostly for gram negative infxns
-bactericidal -binds to gram negative bacterial cell membrane phospholipids which increases permeability of cell membrane -excretion through the kidney is slow -NO GI absorption (no oral use) -used for topical application to wounds, burns, (pseudomonas infxns) of the eye, for tx of UTI, septicemia, bacteremia when other abx are ineffective or CI -nephrotoxicity is a risk |
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Describe Colistimethate, colistin, polymyxin E.
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-parenteral abx
-inactive until hydrolyzed in vivo to colistin -used for the tx of gram neg infxns esp pseudomonas aeruginosa -CI is renal dz |
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What is the use for colistin sulfate, hydrocortisone acetate, neomycin sulfate, and thonzonium bromide?
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they are combined in an otic suspension to tx superficial bacterial infxns of the external auditory canal
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What are the first line agents in tx TB?
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isoniazid, rifampin, ethambutol, pyrazinamide, streptomycin
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What is the mechanism of isonicotinic acid hydrazide (isoniazid)?
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-exact mechanism is unknown
-it does inhibit the biosynthesis of mycolic acid -is able to reach intracellular bacilli unlike streptomycin -resistance to this drug develops quickly when given alone tho -always given with other drugs in tx of TB |
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Is isoniazid effective for prophylaxis?
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yes
-causes liver damage so must weight the benefits/risks esp. in pts. over 35 |
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Is isoniazid bacteriostatic or cidal?
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static at a concentration of 0.2 micrograms/mL or less and cidal at higher concentrations
-INH and rifampin combo is cidal |
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Describe the administration and excretion of isoniazid.
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oral admin
-metabolism by acetylation inactivates the drug -some are slow and some are fast acetylators of this drug |
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What are the toxicities of isoniazid?
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-CNS stimulation
-peripheral neuritis -liver damage, abnormal liver fxn tests, jaundice, multilobular necrosis, hepatitis in older persons -hemolysis is G6PD deficiency -lupus like syndrome |
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What is the mechanism of rifampin?
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-inhibits the DNA dependent RNA polymerase acitivity w/o affecting the mammalian enzyme system
-bacteriocidal -inhibits growth of most Gram pos. cocci and some gram neg. microbes |
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Describe the administration and excretion of rifampin.
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-oral admin
-passes into CSF -eliminated through bile mostly |
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What are the therapeutic uses of rifampin?
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-primarily for tx of pulmonary TB in combo with other primary antituberculotic agents (alone for latent infxn)
-also indicated for tx of asx "carriers" of N. meningitides where risk of meningitis is high -effective against leprosy |
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What are the toxicities and side effects of rifampin?
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-not serious
-induces the p450 system -harmless orange color to urine, sweat, tears, and contact lenses -decreases effectiveness of birth control |
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What is the mechanism of ethambutol?
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inhibits arabinosyl transferases involves in cell wall synthesis
-bacteriostatic |
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How does resistance to ethambutol develop?
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-in vivo via single aa mutations in the embA gene when ethambutol is given in the absence of other effective agents
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What are the adverse effects of ethambutol?
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-decrease of visual acuity and loss of green red perception suggesting retrobulbar neuritis
-allergy, GI distress, numbness, jt pain, or peripheral neuritis -renal insuff. -not recommended in kids <13 yo |
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Describe pyrazinamide.
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the only derivative of salicylic acid that has the most marked effect on tubercle bacilli
-readily absorbed from GI tract and widely distributed in the body fluids except CSF -excreted in the urine -tubercle bacilli develop resistance fairly rapidly -causes hepatic injury -given orally |
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What are the toxicities of pyrazinamide?
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-toxicity is pretty high
-hepatic -peptic ulcer -kidneys -thyroid injury |
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Describe ethionamide.
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a second line TB drug
-oral admin -poorly tolerated due to GI irritation -neurological complications -resistance develops pretty rapidly |
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Describe capreomycin.
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-a second line TB drug
-a peptide abx -causes kidney damage, 8th nerve deafness, vestibular disturbances |
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What is rifabutin?
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-an oral antimycobacterial agent
-a deriv. of rifampin -recommended as an alternative to clarithromycin or azithromycin for primary MAC prophylazis in HIV pts. -considered an alternative to rifampin for TB and TB prophylaxis in HIV pts b/c has fewer drug interactions with protease inhibitors |
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What is the mechanism of rifabutin?
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-inhibits DNA dependent RNA polymerase
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What is the spectrum of rifabutin?
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-MAC, some strains of M. TB, leprosy, some Gram neg and gram pos similar to rifampin
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What are the adverse rxns of rifabutin?
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-rash, GI upset, neutropenia
-urine discoloration -thrombocytopenia |
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What is dapsone?`
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-the most widely used and least expensive drug in the tx of leprosy
-similar mechanism to sulfonamides (PABA antagonist) |
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What is clofazimine?
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-a phenazine dye used as an antimycobacterial and antiinflammatory agent
-bactericidal against TB and M. marinum and slowly bactericidal against leprosy -binds preferentially to mycobacterial DNA and inhibits reproduction and growth -insoluble in water and is incompletely absorbed from GI tract -steady state not reached until after 30 days of tx |
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What are the adverse rxns of clofazimine?
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-GI
-hepatitis -crystalline deposits of the drug |
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What is the mechanism of thalidomide?
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-not completely understood
-studies suggest that it selectively reduces levels of TNF-alpha by accelerating the degeneration of TNF-alpha mRNA encoding protein |
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What is thalidomide recommended for?
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-the DOC for moderate to severe erythema nodosum leprosum in men and women of non childbearing potential
-increases lean body mass in pts with AIDS associated wasting syndrome -most heavily regulated drug in the US |
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What are the adverse rxns of thalidomide?
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human teratogenesis
-DO NOT GIVE DURING PREGO -drowsiness and somnolence -peripheral neuropathy -constipation -rash and HS in HIV pts. |
