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Antimicrobia
UVa med pharmacology block 4
| Question | Answer |
|---|---|
| What are the bactericidal agents? | all B-lactams aminoglycosides fluroquinolones vancomycin rifampin metronidazole isonazid |
| When is an organsim "succeptible" to anitmicrobial therapy? | when enough antimicrobial can be added to "tip" the balance in favor of host defenses while causing minimal toxicity |
| Name the penicillinase resistant penicillins, their route of administration, and their specific usage? | Methicillin, Naficillin, Oxacillin (IV) Dicloxacillin (oral) - narrow spectrum drugs used only for penicillinase producing staph spp (which is most of them) |
| What are the aminopenicillins, what are their route of administration, what would be an inappropriate use? | Ampicillin (oral or parenteral), amoxicillin (oral) |
| What are the three desired characteristics of a chemotherapeutic agent? | - High toxicity against microbes coupled with a low propensity to select for resistant strains - favorable pharmacokinetics - low toxicity for the patient |
| What kind of rare toxicity is often seen with Methicillin? | interstitial nephritis (autoimmune), thus obviating its use |
| How does Vancomycin affect cell wall synthesis? | - It binds to the ultimate (last) and penultimate (second to last) D-alanine residues and "somehow" hinders the transfer of cell wall subunits from the lipid carrier to the peptidoglycan |
| Other than synergism, what are some indications for using combinations of antibiotics? | - mixed infections - unknown etiology - enhance therapy - to prevent resistance - to treat infections at different anatomical sites |
| What is peculiar about the structure of the bacterial cell wall? What is the repeating (Park) subunit, and why is it important in anitmicrobial therapy? | - repeating heteropolymer of N-acetylglucosamine (NAG), and N-acetylmuranic acid (NAM) polymers are cross-linked at the NAM subunit - D-alanine-D-alanine is the repeating (Park) subunit ** penicillin molecule mimics this dipeptide |
| What are the only two cephalosporins useful for meningitis? | Cefuroxime, other 3rd generations, and Cefepime |
| What is special about Meropenem and Aztreotam? What is speciabl about each? | - newer antibiotics, highly resistant to wide variety of b-lactamases - Meropenem: wide spectrum, particularly valuable against mixed and nosocomial infections *** excellent against anaerobes, pseudomonas, acinetobacter |
| What are the bacteriostatic agents? | Macrolides Tetracyclines Chloamphenicol Clindamycin Sulfonamides Ethambutol |
| What should be the only TRUE broadspectrum antibiotics? Why? | Agents that works against more than one class of organism (ie. bacteria and rickettsia), like tetracyclines ***NOTE: in clinical practice broad spectrum refers to agents that act against gram positive and gram negative bacteria |
| What drug interferes with Penicillin excretion in urine? | Probenecid (a uricosuric agent), competes for the transporter in the kidney leading to higher, longer lasting doses of penicillin |
| How does the process of transpeptidation work? How do B-lactams inhibit this step? | - terminal D-ala-D-ala bond is cleaved and another repeating unit from another polymer in linked to the remaining D-alanine |
| Why is inactivation of PBP's by B-lactams "trivial" in a sense? | Because cell death only occurs if autloysins are ALSO present, in addition to the PBP's being inhibited. ***That is, inhibiting cell wall growth only matters if the cell wall is also being broken down at the other end |
| What is the 2nd generation cephalosporin we need to know? What is its special preperation? How do they differ? What is the difference between first and second generation cephalos? | - Cefuroxime --> useful againt H. influenza and pseudomonas *** penetrates CNS and useful against H. influenza meningitis - Cefuroxime axetil --> orally active form - Second generation are broader spectrum and less active against Gram + |
| What are the third generation cephalosoprins? What is special about each? | - Cefotaxime and Ceftizoxime similar, pen CNS, poor against bacteriodes - Ceftriaxone: longest T1/2, good CNS pen (use: meningits, pneum, sepsis) - Ceftazidime: LESS potent against Gram - more potent against pseudomonas |
| How do third gen cephalisporins differ from previous generations? | - Third gen have Gram - spectrum - they are resistant to most b-lactamases produced by Gm - |
| What two main "classes" of antibiotics inhibt cell wall synthesis? | - beta lactams - vancomycin |
| What are four mechanisms of B-lactam resistance? | - autolytic enzyme deficiency (tolerance) - altered PBP's (most important for staph aureus) - b-lactamases (responsible for MOST resitance in clinical isolates) - failure to penetrate outer membrane |
| Untoward effects of Meropenem and Aztreotam? Why sholud one be careful with these? | Meropenem: nausea, vomiting, local phlebiti, hypersensitivity Aztreotam: nausea, vomiting, local phlebitis, rash **Very broad spectrum can lead to resistant strains if overused. also very expensive. |
| What are the B-lactamase inhibitors? What is the combination we need to know? | Sublactam, Tazobactam, Calvulanic acid Calvulanate + Amoxicillin = AUGMENTIN |
| What antimicrobial group are ALL antipseudomonal drugs synergistic with? | Aminoglycosides |
| What are B-lactamases? When are they produced? Which type of bacteria make penicillinases, which make both penicillinases and cephalosporinases? | - homologues of PBP's whose synthesis is induced by antibiotics - Gram + make only penicillinases, Gram - produce both |
| What are the two First generation cephalosporins (from need to know list)? How do they differ? What is their usage? | Cefazolin --> preferred parenteral form, less irritating on injection, longer half life Cephalexin --> can be used orally |
| Describe the distribution, metabolism, and excretion of B-lactams | - widely distributed, byt CNS, eye and prostate levels are low without inflammation - NOT metabolized - excreted by rapid renal clearance by glomerular filtration and tubular secretion |
| T or F: Most antibiotic are natural products of microbial secondary metabolism, and antibiotics are produced by a wide range of microbes | FALSE - Antibiotics are synthetic derivatives of products of microbial metabolism - Only a small subset of microbes make most antibiotics |
| When is Vancomycin used? What drugs is it synergistic with? Some untoward effects? Mechanism of resistance? | - severe staph/strep infections in penicillin allergic patients, MRSA (IV) - C. Difficile (oral) |
| What are some "difficult sites" in terms on antimicrobial access? | CNS, eye, prostate, intracellular |
| What is the source of hypersensitivity to penicillins? | Ab's directed against penicillonoic acid (produced by action of b-lactamases on penicillins) |
| How are Penicillin G and V absorbed? What are the salts of G and what is special about them? | G --> absorbed poorly from gut, IV **procaine and benzathine salts are longer acting and relased from IM depot |
| What are the antipseudomonal antibiotics? What other bug can they kill? Which form is good for UTI? | - Carbenicillin and Ticarcillin --> can kill pseudomonas and proteus - Indanyl Carbenicillin is used to treat UTI ** rapidly excreted by kidneys |
| What is the fourth generation cephalosporin? What is special about it? | Cefepime --> very resistant to b-lactamases, cleared by kiendy, excellent CNS penetration ** combines Gram + and antipseudomonal acitivity of best 3rd generations, hold in reserve ** not active against MRSA, M.Tb, Bacteriodes |
| What is the broad spectrum penicillin? What bugs is it active against? | Piperacillin increased activity against enterobacteria and pseudomonas |
| What kind of rare toxicity is often seen with Ampicillin? What condition and what drug increased its incidence? | Maculopapular rash of late onset ** 90% in those with mononucleosis ** 20% in those taking allopurinol |
| What kind of rare toxicity is often seen with Oxacillin? | hepatotoxicity |
| What is the major untoward effect of penicillins? What are the top three most common, and top three most serious reactions? | Allergic responses are by far the most prominent Top three common: skin rash, fever, bronchospasm Top three serious: anaphylaxis, erythema mulitforme (stevens johnson), exfoliative dermatits Allergy to ONE penicillin = allergic to all |
| What organisms is Penicillin G the drug of choice for? | Group A B-hemolytic strep (pyogenes) Strep viridans Menigococcus Treponema pallidum (syphillis) |
| What penicillin is excreted in bile, and thus clearance in independent of renal failure? | Naficillin |
| What are some situations when bactericidal agents are MANDATED? | - Meningitis, endocarditis, and infections in the immunocompromised |
| What kind of rare toxicity is often seen with Naficillin? | reversible bone marrow suppresion |
| What patients fare less well on weekly Isonazid treatment? Explain. | - "fast acetylators" fare less well - Isonazid is acetylated, becomes ineffective against the mycobacteria and appears in urine - Rate of acetylation is genetically determined, and fast acetylators have a shorter half life of drug |
| In what four pharmacokinetic areas are Fluoroquinolones "stellar"? | absorption, distribution, metabolism, excretion ***This means that they are readily absorbed orally, have excellent tissue penetration, and have differing methods of metabolism and excretion |
| What are some important isonazid toxicities? | - Neurotoxicity of peripheral neuropathy in 1% of patients that is more common in slow acetylators, seizures - competitive inhibitor of phenytoin metabolism, so increased toxicity - SLE- like syndrome, pellagra-like syndrome, pyridoxine deficiency |
| What bugs are second generation fluoroquinolones effective against? Third generation? | Second --> excellent activity against gram negative rods Third --> increase gram positive efficacy, ie pneumococcus |
| When is erythromycin used as prophylaxis? What is an important side effect with a common medication that some of these patients take? | - COPD patients to prophylax for pneumonia - Asthma patients are sometimes on theophylline, and erythormycin increases theophylline's concentration |
| What drugs can be an alternative to penicilins for streptococcal infection? What drug can be alternative for staphyloccal infection? | Strep alternative --> Macrolides Staph alternative --> Clindamycin |
| How is erythromycin taken? What is special about when it should be taken? | - taken orally - it is acid labile, so should be taken on an empty stomach SOME preparations have acid-resistant coating |
| What are the uses of Erythomycin? | - Mycoplasma pneumoniae - Alternative to penicillins in treating streptococcal and pneumococcal infections (if allergics to b-lactams) - FIRST CHOICE for C. diphtheriae |
| Rifampin Toxicities? | - NOTORIOUS inducer of MANY p450 enzymes - hepatotoxic -> reversible elevation of bilirubin (more likely in alcoholics and liver disease) - red/orange tears, saliva, urine, sweat, feces |
| What are the four R's of rifampin | RNA polymerase inihibitor Reves up p450 Red/orange body fluids Rapid resistance if used alone |
| What is Metronidazole used for? | - Effective against all ANAEROBIC gram -, including bacteriodes - Also effective against Giardia, Entamoeba, and Trichomonas - Alternative to clindamycin, b-lactams, and CAM - DOC for: bacterial vaginosis and pseudomembranous colitis |
| What is the mechanism of Metronidazole? static or cidal? | - interrupts normal electron transport process by accepting electrons from ferroxidins - CIDAL |
| In what patients must Rifampin be used with caution? Why? | - Patients with compromised hepatic function because it is deacytelated in the liver and involved in enterohepatic circulation |
| What is the protocol of use for Rifampin? | - ALWAYS use with another drug due to fast emergence of resistance - Used from H. influenzae prophylaxis - Used for Meningococcal prophylaxis |
| What are some toxicities of erythromycin? | - GI upset most common - Cholestatic hepatitis seen with esolate preparation avoid giving to patients wtih impaired liver function - Potentiates effects of theophyllines, carbamazepine, cyclosporine, digoxin, warfarin (CYP450) |
| What is Clindamycin's role in therapy? What is an important complication? | - alternative to penicillins for STAPH in hypersensitive individuals - also good for bacteriodes fragilis (not in CNS) good anaerobic coverage below the diaphragm - PSEUDOMEMBRANOUS COLITIS is important complication |
| What bugs is Rifampin active against? | Mycobacteria, Gram positives and Nisseria spp. |
| What is the mechanism of Ethambutol? Use? Static or cidal? Principla toxicity? | - UNKNOWN mechanism - effective only against mycobateria and always in combination with other drugs - Principla side effect is retocular neuritis, reversible - STATIC |
| When does erythromycin penetrate the meninges? | When there is inflammation |
| What is special about Azithromycin? | - accumulates in acidic vesicles in phagocytic cells - administered only once every 3 to 5 days |
| In what patients should Metronidazole dosage be reduced? | Patients with liver disease since the reduced form of metronidazole is mutagenic (carcinogenic) |
| Metronidazole toxicities? How serious are they? | - They are rarely serious enough to discontinue treatment - disulfuram-like effects, headache, nausea, METALLIC TASTE - furry tounge, glossitis, dizziness, vertigo, ataxia, convulsions, encephaolpathy |
| What is the mechanism of action of the Macrolides? Static or Cidal? What feature do they share with chloroamphenicol? | Bind to 50s ribosomal subunit and inhibits protein synthesis, STATIC Like CAM, they inhibit MAMMALIAN mitochondrial protein synthesis but not cytoplasmic ribosomal protein synthesis |
| How toxic are Fluoroquinolones? Some examples? | Generally well tolerated nausea, vomiting, diarrhea, rare CNS effects, headaches, drowsiness, photosensitivity, arthropathy |
| Mechanism and use of Pyrazinamide? cidal or static? | UNKNOWN, but kills tubercle bacillus; used in short term therapy (6 months) and with other drugs because resistance develops |
| What is the salient difference between Erythromycin and the newer macrolides (azithromycin and clarthromycin)? | newer macrolides are more effective against H. influenzae |
| What patients is Metronidazole contraindicated in? | Patients with active CNS disease ***b/c it penetrates the CNS |
| What is the mechanism of resistance against Fluoroquinolones? | Mutations in DNA gyrase Increased efflux |
| What is the use and mechanism of Isonazid? static or cidal? | - Used for M. Tb - Prevents synthesis of mycolic acids, a unique component of mycobacterial cell wall -CIDAL |
| What drug is the DOC for Meningococcus prophylaxis? | Ciprofloxicin |
| Pyrazinamde toxicities? | - Heptatotoxicity, monitor function of liver when used, should not be given when liver disease - Hyperuricemia --> inhibits excretion of urate in nearly ALL PATIENTS |
| Why are macrolides ineffective against Gram - organisms? | They do not pass throught the outer membrane |
| What are the levels of fluoroquinolones in CSF? In brain parenchyma? | They have low CSF levels with HIGH level in the brain parenchyma |
| What should be co-administered with Isonazid? Why? | - Co-administer Vitamin B6 (pyridoxine) to prevent neurotoxicity |
| What is the mechanism of Rifampin? static or cidal? | binds to bacterial RNA polymerase CIDAL |
| Which fluoroquinolone is virtually excreted unchanged in the urine? | Levofloxacin |
| What is the mechanism of action of Clindamycin? static or cidal? | Same as macrolides, binds ribosomal 50s subunit STATIC |
| What is the only anti-tb drug that is used by itself and in what setting? | Isonazid is used alone BUT ONLY FOR PROPHYLAXIS **treatment is always a combo |
| What is the mechanism of action of Fluoroquinolones? | They inhibit DNA gyrase |
| Hepatic/Renal?: Pyrazinamide | Renal |
| Hepatic/Renal?: Isoniazid | Met. Liver Exc. Kidney |
| Hepatic/Renal?: Tetracycline | Renal |
| Hepatic/Renal?: Macrolides | Hepatic, except Clarithro- is Mixed |
| All Beta Lactams are excreted by ______, except _____ which is excreted by _____ | All are excreted by the Kidneys, EXCEPT Nafcillin which is excreted by the liver. |
| Hepatic/Renal?: Ethambutol | Renal |
| Hepatic/Renal?: Doxycycline | Hepatic (Bile) |
| Hepatic/Renal?: Aminoglycosides | Renal |
| Hepatic/Renal?: Metronidazole | Met. Liver Exc. Kidney |
| Hepatic/Renal?: Sulfamethoxazole | Met. Liver Excreted Kidney |
| Hepatic/Renal?: Vancomycin | Renal |
| Hepatic/Renal?: Fluoroquinolones | Levoflox: Kidney Others: Mixed |
| Hepatic/Renal?: Rifampin | Hepatic |
| Tobramycin, Amikacin, Gentamicin. Put them in order for most/least susceptible to bacterial enzymes, and then put them in order for Gram - spectrum strength. | Most susceptible: Genta > Tobra > Amikacin Gram - Spectrum: Amikacin > Tobra > Genta |
| What is the drug of choice for treating Leprosy? | Dapsone (a sulfone) |
| How does Trimethoprim work? | Structural analog of folic acid and competes with dihydrofolic acid for binding to dihydrofolate reductase. |
| How do you differentiate Antibiotics associated Colitis, from normal side effects caused by Tetracyclines? | Antibiotic-associated Colitis will show blood/leukocytes in the stool. You can also assay for C. difficile in the stool |
| What is the proper procedure for dosage adjustment when using Aminoglycosides? | Loading dose + Maintenance dose --> Assay peak/Trough --> Adjust dose Calculate the drug clearance and tailor maintenance dosage. |
| Why was Sulfamethoxazole chosen to be paired with Trimethoprim instead of another Sulfonamide? | It has a similar T 1/2. |
| When is Trimethoprim used as a solo therapy? | Never. It is only used with Sulfamethoxazole |
| If an organism is resistant to Sulfonamides, can you still use the Sulfamethoxazole/Trimethoprim combination? | Yes. It is still usually efficacious. |
| What is co-trimoxazole? | A combination of Sulfamethoxazole and Trimethoprim (highly synergistic) |
| Which Aminoglycoside is by far the most ototoxic? | Amikacin (even though it mainly effects hearing, it is the most toxic) |
| How do Tetracyclines affect Gram -'s? | Gram -'s are virtually resistant to Tetracyclines |
| Which types of foods and dietary supplements should you avoid while taking Tetracyclines? Why? | Avoid dairy products, iron supplements, and antacids, because they will cause Tetracycline to form insoluble complexes (Tetracycline chelates di/tri-valent cations). |
| Sulfonamides: Cidal or Static? Is there an exception? | Generally Static. If there is no thymine present, bacteria are killed ("Thymineless death") |
| What is the mechanism of Aminoglycosides? | They block translation by "freezing" the initiation complex on the 30S subunit. *Tetracyclines also act on the 30S, but they stop elongation. |
| What is the only drug class within the protein-synthesis inhibitors that is Bacteriocidal? | Aminoglycosides |
| What are the two Tetracyclines on our need to know list? | Tetracycline Doxycycline |
| Why are the factors that influence serum concentration so important with Aminoglycosides? | They have a narrow therapeutic window, and can cause ototoxicity and nephrotoxicity. |
| What is the primary clinical application for Sulfonamides? | Lower UTIs Variety of indication if combined with Trimethoprim |
| Aminoglycosides are cationic at physiological pH. What effects does this cause on their ability as a drug? | They have poor oral availability Poor penetration of eye, CNS, tissue secretions Nearly complete renal excretion |
| How is the resistance to Sulfonamides in general? | There is wide-spread resistance. They are rarely used by themselves. |
| What is the main use for Trimethoprim/Sulfamethoxazole? | Urinary Tract Infections |
| What is the most common mechanism of Aminoglycoside resistance? | Modifying enzymes. These enzymes phosphorylate, acetylate, and adenylate hydroxyl groups of Aminoglycosides. |
| Which Aminoglycoside mainly affects hearing with its ototoxic effects? Which Aminoglysides affect both hearing/balance? | Hearing: Amikacin Both: Genta/Tobra |
| Why are aminoglycosides poorly absorbed orally? | They are cationic at physiological pH |
| What is the mechanism of action for Sulfonamides? | They inhibit Folic Acid synthesis in two ways: 1. Compete with PABA for incorporation into Folate 2. Incorporation into a "false folate" |
| When is Amikacin the Aminoglycoside of choice? | When there is resistance to Genta or Tobramycin |
| What is the mechanism of action of Tetracyclines? How do they enter bacteria? | They inhibit tRNA from binding to the 30S ribosomal subunit (Translation) They enter bacteria by an "energy dependent process". |
| How are the levels of sulfamethoxazole in the urine compared to blood? | 3x more in urine than blood. |
| How well does Tetracycline penetrate the CNS as compared to the level in plasma? | CNS concentrations are about 1/4 that of plasma. |
| What are some toxicities of Tetracyclines? | GI Distress (Must be differentiated from C. Difficile) Pain on IM injection Phototoxic Hepatic Toxicity (ass. w/pregnancy and renal disease) Metabolic Wasting Retard of bone growth in fetus Permanent staining of teeth in children < 8yrs old |
| How are Tetracyclines excreted? | Both urine and feces (enterohepatic cycline) |
| Why are Trimethoprim and Sulfamethoxazole synergistic? | Sulfonamides lower FAH2 (which competes with Trimethoprim), thus enhances Trimethoprim action. |
| What are factors that affect serum concentration of Aminoglycosides? | Anything that affects ECV (Edema, dehydration) Glomerular Filtration Rate (Fever increases GFR, Renal Function, Burns) |
| Which Tetracycline is used to treat Lyme Disease (Borrelia)? | Doxycycline |
| How well do Sulfonamides penetrate the CNS? | They penetrate the CNS well. |
| Which is more orally effective between Tetracycline and Doxycycline? | Doxycycline (100% vs. 30%) |
| Which Aminoglycoside is commonly used for serious nosocomial infections caused by Enterobacericeae or Pseudomonas? If used in combination, with what? | Gentamicin Often in combination with Beta-Lactams |
| How are Aminoglycosides excreted? How can this be exploited for therapy? | Glomerular filtration --> High concentrations in urine. Can treat cystitis with low doses. |
| When do you measure Peak and Trough values of Aminoglycosides? Why is this important? | Peak: 45-60mins after IM, 15mins after IV Trough: 1hr prior to next injection Importance: Serum assay is important for determining dosage. |
| Why are Tetracyclines contraindicated in pregnant women and for children? | - Can cause acute fatal fatty necrosis of the liver in a pregnant woman - Disrupt bone growth in fetus - Permanently stain teeth in children < 8yrs old |
| Which Tetracycline is the preferred choice for patients with impaired renal function? Why? | Doxycycline. It's mainly metabolized by the liver. |
| Because Tetracyclines are such broad spectrum antibiotics, what superinfections might you expect as a complication? | Fungal infections (Mainly Candida) C. Difficile Colitis |
| As a class, Aminoglycosides are very active against which organisms? | AEROBIC Gram - Enterobacter E. Coli Klebsiella Proteus Serratia Pseudomonas |
| Why are Sulfonamides avoided in pregnant women? | They can displace bilirubin from serum proteins, which can pass into the CNS and cause kernicterus. |
| What are some toxicities of Aminoglycosides? | Neurotoxicity: High levels produce neuromuscular blockade. Ototoxicity: Hearing and balance functions Nephrotoxicity: Acute Tubular Necrosis (1wk after therapy usually reversible.) |
| What is a commonly used combination including an Aminoglycoside for bowel surgery prophylaxis? | Erythromycin + Drug effective against anaerobes |
| What are the therapeutic indications of Tetracyclines? | Gram + Mycoplasma Rickettsiae Chlamydia Spirochetes Gram -'s are essentially resistant to Tetracyclines |
| What is the spectrum of organisms covered by Trimethoprim/Sulfamethoxazole? | E. coli Proteus, Klebsiella, Enterobacter, Salmonella, Shigella, Serratia DRUG OF CHOICE for Pneumocystis Carinii |
| What are some toxicities for Sulfonamides? | Allergic reactions (rashes, fever, photosens.) Kernicterus Renal damage (from crystals, toxic nephrosis, or allergic nephritis) Hemolysis in G6PD-deficient patients Stevens-Johnson (rare) |
| Which organisms are Sulfonamides active against? | Nocardia Chlamydia (tetracycline is first choice) Toxoplasmosis Several Protozoa: P. falciparum, Toxoplasma Gondii, Pneumocystis carinii |
| What can prevent the transportation of Aminoglycosides into bacteria? | Low pH, Hyperosmolarity, divalent cations, and anaerobiasis. |
| Tetracycline is the drug of choice (usually Doxycycline) for: | Chancroid (Hemophilus ducreyi) Brucellosis Cholera Relapsing fever (Borrelia recurrentis) |
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sam.mrosenfeld
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