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91 Cards in this Set
- Front
- Back
Antibiotic:
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*A chemical substance, produced by microorganisms, which has the capacity to inhibit the growth and even to destroy bacteria and other microorganisms, in dilute solutions.
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bacteriostatic:
bacteriocidal: |
*inhibits growth, but doesn't kill them.
*kills the bacteria. |
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Peak drug concentration is most important in:
Time above MIC is most important in: AUC is most important in: |
*Aminoglycoside, Fluoroquinolones
*Penicillin, ß-lactams *Vancomycin |
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Describe the peak effect:
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-The higher amount of drug you give, the more killing you get.
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Describe the "time above MIC" effect. Compare to the peak effect.
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left-peak effect
right-no peak effect |
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What does "time above MIC" mean?
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% of time in the dosing interval that the drug concentration is above the MIC
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What does MIC mean?
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*Minimal Inhibitory Concentration.
*Lowest concentration of an antibiotic that will inhibit bacterial growth. |
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What's the MIC here?
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2µg/mL
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∆ b/t pharmacokinetics and pharmacodynamics?
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What is SPA?
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*A framework for treatment with antibiotics.
Source: history, physical, laboratory Pathogen(s): based upon the source (Gram stain: rapid method to identify a pathogen) Antibiotic: based upon the likely pathogen(s) |
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General timeline of initiating antibiotic treatment?
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*Presentation (history, physical, lab)
-Antibiotics are started *Culture results/Susceptibility results (usually 2 days later) -Antibiotics are re-evaluated |
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Tgts in antibacterial agents:
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*Cell wall, cell membrane
*Intracellular targets -Ribosome (protein synthesis) -Metabolism -DNA synthesis |
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ß-lactams:
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*Penicillins
*Cephalosporins *Monobactams *Carbapenems *ß-lactamase inhibitors (fights bacteria's efforts to become resistant) |
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Penicillins:
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*Penicillins
*Penicillinase resistant penicillins *Aminopenicillins *Anti-pseudomonal penicillins |
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Chemical features of Penicillins:
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*Beta-lactam ring common to all beta-lactams
*Penicillin 5 sided ring with S at top *Cephalosporins 6 sided S at top *Carbapenems 5 with C at top, trans side chain *Monobactams no side ring, side chains *Side chains confer specific properties (absorption, etc.) |
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What is necessary for ß-lactams to work?
How can that be inactivated? What effects can side chains have? |
*Intact ß-lactam ring necessary for anti-bacterial activity
*Enzymes (beta-lactamases) inactivate *Side chains effect spectrum of activity and other properties such as half-life and acid stability |
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How to ß-lactams work?
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*Inhibits cell wall synthesis.
*Synthesis of peptidoglycan requires about 30 enzymes *Penicillins are dipeptides (alanine and ß-dimethylcysteine) that competively inhibit cross-linkage (transpeptidase) of cell. *Look like D-alanyl-D-alanine. *Covalently bind to their target; IRREVERSIBLE. |
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Significance of peptidoglycan in the action of ß-lactams:
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-Cross linking of NAM and NAG with Transpeptidase and D-alanyl-D-alanine.
-Antibiotics weaken the cross-linking and make bacteria EXPLODE. |
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Significance of antibiotic side chains in acting against gram neg bacteria?
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-Side chains make antibiotics more or less likely to get through porins in a gram neg bacteria.
-There are many types of porins. |
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Significance of PBPs:
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*Penicillin binds to PBP (penicillin binding proteins)
*Transpeptidase is a PBP *Other PBPs for example in E. coli are necessary for maintaining rod like shape and for septum formation during division |
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Spectrum of Activity of Penicillin:
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*Natural Penicillin: penicillin G
*Streptococci, enterococci, T. pallidum, B. burgdorferi, N. meningitidis, actinomyces *Procaine PenG short-acting. Streptococci, mouth anaerobes, meningococcus, listeria *Benzathine long acting: T. pallidum, rheumatic fever prophylaxis *Penicillin V potassium: oral |
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How well does penicillin work against meningitis?
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*Poor penetration into uninflamed meninges; drug gets in better when it's infected
*Some ~5% of serum concentration found in the CSF when the meninges are inflamed. Hence, able to use penicillin to treat meningitis when caused by susceptible bacteria. |
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How many units is a mg of penicillin?
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*1 international unit of crystalline penicillin G sodium = 0.6 µg
*1 mg of penicillin G sodium = 1667 units |
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Penicillinase-Resistant Penicillins:
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*IV: nafcillin, oxacillin, (methicillin)
*p.o. dicloxacillin *Anti-staphylococcal; not hydrolyzed by penicillinase produced by staph. *Less active than penicillin G *Adverse effects: leukopenia, renal *Nafcillin: biliary excretion (all others are renally cleared) |
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What are the aminopenicillins?
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*Ampicillin, amoxicillin
*Some Gram negative activity |
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What are the Anti-pseudomonal Penicillins?
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*Carboxypenicillins: carbenicillin, ticarcillin
*Ureidopenicillins: piperacillin: more active than ticarcillin against P. aeruginosa; some gram negative rods and Bacteroides; they are inactivated by some of the common beta-lactamases |
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What types of adverse effects can we get from penicillins?
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*Hypersensitivity
*Anaphylaxis *Granulocytopenia *Seizures |
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Describe the first generation cephalosporins:
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*Cephalothin, cefazolin t1/2 2 hr, cephalexin
*Staph, strep, some gram negative, not pseudomonas; poor anaerobe activity *Not active against enterococci |
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Describe the 2nd generation cephalosporins:
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*Cefoxitin, cefotetan (cefamycins: methoxy at position 7) more active against gram negative and anaerobes (B.fragilis)
*Cefuroxime active against ampicillin resistant H. flu; penetrates into CSF *Oral: cefuroxime axetil, cefaclor, cefprozil, loracarbef |
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What are some adverse reactions due to Cephalosporin side chains?
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MTT (methyl-tetrazole-thiomethyl) at position 3: cefamandole, cefotetan, moxolactam, associated with disulfiram-like reactions, hypoprothrombinemia, inhibition of vitamin K activation. Associated with bleeding.
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Describe the 3rd generation cephalosporins:
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*Ceftazidime, cefoperazone (MTT): good activity against gram negatives including Pseudomonas aeruginosa
*Less active against gram positives *Penetrates CSF *Cefotaxime, ceftriaxone: good gram negative activity, not P. aeruginosa, moderate gram positive activity *Cefotaxime t1/2 1.1 hour *Ceftriaxone t1/2 8 hours: home IV, gonorrhea; ceftriaxone gallstones *Oral agents: cefixime, cefpodoxime |
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CSF Concentrations of Third-generation Cephalosporins:
Which ones get to the CSF better? |
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Describe the 4th generation cephalosporins:
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*Cefepime t1/2 2.0 hours
*Active against gram negatives including P. aeruginosa and gram positives |
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What do cephalosporins NOT work against?
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No cephalosporins are active against enterococci, listeria, legionella. Until recently, MRSA.
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What is the new advanced generation of cephalosporins?
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Ceftaroline: active against MRSA
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Describe Monobactams:
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*Aztreonam: monocyclic ß-lactam ring
*Active against gram negative rods including P. aeruginosa *No activity against gram positives or anaerobes |
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Describe Carbapenems:
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*Imipenem: hydroxyethyl side chain in trans orientation
*Imipenem is metabolized by a renal enzyme (dihydropeptidase) *Cilastatin inhibits dihydropeptidase *Meropenem hydroxyethyl side chain in cis orientation *Different side chain on the side ring *Not hydrolyzed by renal dihydropeptidase *Ertapenem: long half-life 4.0 hours |
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Describe the activity of carbapenems; what are they effective against?
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*Broad gram negative coverage
*Imipenem and Meropenem are active against *Pseudomonas aeruginosa *Ertapenem is not active against P. aeruginosa *S. aureus (methicillin susceptible) and streptococci *Anaerobes *Meropenem has increased gram negative activity and somewhat less gram positive compared to imipenem |
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Describe adverse effects from carbapenems:
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Adverse effects: imipenem seizures
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What are ß-lactamase Inhibitors?
examples? |
*Drugs that block a bacterial enzyme that produces β-lactam resistance
*Clavulanic acid, sulbactam, tazobactam inhibit ß-lactamases. They are used in combination with a beta-lactam antibiotic *They are not antibacterial agents |
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Describe uses and dosages of Clavulanate:
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*Amoxicillin/clavulanate (augmentin); clavulanate diarrhea
*A/C 250 = amox 250 mg and clav 125 mg *A/C 500 = amox 500 mg and clav 125 mg *A/C 875 = amox 875 mg and clav 125 mg *Amoxicillin/clavulanic acid *Augmentin XR™ (2 tablets twice a day) *each tablet contains amoxicillin trihydrate and amoxicillin sodium 1000 mg and clavulanate 62.5 mg |
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What are other ß-lactamase inhibitors besides Clavulanate?
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*Ampicillin + sulbactam (Unasyn)
*Ticarcillin + clavulanate (Timentin) *Piperacillin + tazobactam (Zosyn) *Pip/tazo 3.375 gm q 6 hr (pip 3 gm, tazo 0.3) *For P. aeruginosa 4.5 gm q 6 hr (16 gm pip per day) or 3.375 gm q 4 hr (18 gm pip per day) |
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Half life of common ß-lactam antibiotics?
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Antibacterial Agent t1/2 (hours)
Penicillin G 0.5 Clavulanate 0.9 Ampicillin 1.0 Imipenem 1.0 Cefotaxime 1.1 Aztreonam 1.7 Cefazolin 2.0 Cefepime 2.0 Cefotetan 3.3 Ertapenem 4.0 Ceftriaxone 8.0 |
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Describe glycopeptide antibiotics:
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*Vancomycin, poorly absorbed orally
*Mechanism: bactericidal *Inhibits cell wall synthesis; bind to D-alanyl-D-alanine |
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Describe Vancomycin:
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*Most gram positive bacteria; not gram negatives or anaerobes
*Less efficacious against S. aureus when compared to anti-staphylococcal ß-lactams (less rapidly bactericidal and clinically less efficacious) *New problem: VISA and VRSA (Vancomycin Intermediate S. aureus / Vancomycin Resistant S. aureus) |
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Adverse effects from Vancomycin?
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*Nephrotoxicity was a problem in the past
*Nephrotoxicity seen when used in combination with an aminoglycoside *Red-neck (red-man) syndrome (histamine) *Ototoxicity, rash |
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Describe Fosfomycin:
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*Interferes with an early step in peptidoglycan synthesis
*Active against gram positive and gram negative bacteria *Use: Oral agent used to treat uncomplicated urinary tract infections |
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Describe polypeptide antibiotics:
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*Polymyxin is a polypeptide
*Polymyxin B and polymyxin E = colistin *Poor diffusibility *Polymyxin are cationic detergents that disrupt the cell membrane causing an increase in permeability *Bactericidal |
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Uses and side effects of polymyxins?
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*Spectrum of activity: P. aeruginosa and other gram negatives except Proteus, Serratia, Providencia, Neisseria
*Nephrotoxic, hence they are rarely used systemically *Resurgence in use in hospitals where there are multi-drug resistant gram negative organisms |
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Describe Lipopeptide antibiotics:
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*Daptomycin: cyclic lipopeptide
*Binds to bacterial membranes and causes rapid depolarization of the membrane potential *Bactericidal |
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What is Daptomycin useful against?
What is it not useful for? Side effects? |
*Active against Staphylococci, streptococci and enterococci including vancomycin resistant strains
*Does not penetrate well into the lung (daptomycin is not indicated for the treatment of pneumonia) *Adverse effects: myopathy |
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What are antibacterial agents with Intracellular targets?
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*Target: Ribosome
-aminoglycosides -MLS (K) -tetracyclines -chloramphenicol -oxazolidinones *Metabolism *DNA |
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Describe aminoglycoside antibiotics:
examples? |
*Two or more amino sugars joined in a glycosidic linkage to hexose. Highly water soluble.
*Gentamicin, tobramycin, amikacin *Streptomycin (TB, enterococcus: synergy with penicillin) *Neomycin B (topical) |
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How do aminoglycoside antibiotics work?
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*Bactericidal; concentration dependent killing
*Uptake into bacterial cell dependent on electrochemical gradient of inner membrane; this gradient is generated by aerobic metabolism *Hence, these drugs are inactive in an anaerobic environment such as an abscess *Block protein synthesis by binding to 30S ribosome and blocks initiation of protein synthesis, misreading of genetic code, premature termination of translation |
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What bugs are aminoglycosides effective against?
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*Active against aerobic gram negative rods
*Often synergistic with ß-lactams *Inhibit staph *Tularemia, plague *Streptomycin Mycobacterium tuberculosis |
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Side effects of aminoglycosides?
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*Nephrotoxic and ototoxic (auditory and vestibular) (neomycin severe nephrotoxicity precludes use as a parenteral agent)
*Need to monitor levels *Streptomycin is more ototoxic *Neuromuscular blockade |
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What are the MLS antibiotics?
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*Macrolides
Ketolides *Lincosamides *Streptogramins |
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What are important chemical features of Macrolides?
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*14-membered carbon ring with an aminosugar and a neutral sugar (cladinose)
*Erythromycin in an aqueous environment at a low pH undergoes internal rearrangements and forms inactive compounds *Newer macrolides are more acid stable |
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How do macrolides work?
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*Inhibits protein synthesis: binds to 50S subunit of the ribosome
*Usually bacteriostatic |
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What bugs do macrolides work against?
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*Streptococci, staph, enterococci is variable
*C. diphtheriae, mycoplasma, chlamydia, legionella, Moraxella catarrhalis *New macrolides activity against H. flu *Helicobacter pylori clarithromycin in combination with other antimicrobial agent *New macrolides active against atypical mycobacteria such as MAI (mycobacterium avium intracellulare) resistance may develop on monotherapy. |
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Adverse effects of Macrolides?
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*Adverse effects mainly GI: nausea, vomiting
*Cardiac arrhythmia *Clarithromycin metallic taste *Erythromycin estolate: cholestatic hepatitis |
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Describe Lincosamides:
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*Lincomycin and Clindamycin
*An amino acid derivative attached to a sulfur containing sugar *Mechanism of action: same as a macrolide *Active against most strep and staph *Most anaerobes including Bacteroides fragilis *Good for aspiration pneumonia *Adverse effects: diarrhea; C. difficile |
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Describe streptogramins:
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*Streptogramins are naturally occurring compounds found in combinations
*They are macrocyclic lactone peptolides *Quinupristin (streptogramin B) and dalfopristin (streptogramin A) [synercid®] |
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How do Streptogramins work?
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*Inhibit protein synthesis
*Streptogramin B (SgB) binds to ribosome at a site that overlaps with macrolides and lincosamides *Streptogramin A (SgA) binds to ribosome at a nearby site *SgA and SgB are synergistic |
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What are streptogramins effective against?
what are they NOT good against? side effects? |
*Streptococci, staphylococci
*Enterococcus faecium (bacteriostatic) *Not active against E. faecalis *Adverse effects: arthralgias, myalgias, phlebitis |
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Describe the structure of Ketolides:
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14-membered macrolide ring with cladinose at position 3 replaced by keto and 11,12 carbamate bridge
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How do ketolides work?
What are they effective against? side effects? |
*Binds to ribosome near where macrolides bind (domain V) and also binds to domain II of the 23S rRNA
*Strep, staph, H. flu. Additionally, active against macrolide resistant Streptococcus pneumoniae *Adverse events: visual |
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How do tetracyclines work?
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*Inhibits protein synthesis by binding to ribosomes (bacteriostatic)
*Staph, strep, gram negatives, anaerobes *Rickettsia, ehrlichia, mycoplasma, borrelia, pasteurella, brucella, yersinia, francisella, Vibrio cholera, chlamydia, bacillus, plasmodium (malaria) |
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SEs of tetracyclines:
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*Adverse effects: GI upset
*Minocycline vertigo *Demeclocycline photosensitivity *Deposited in bone and teeth, discolored teeth *Antagonizes penicillin when treating pneumococcal meningitis |
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Special considerations for tetracyclines:
outdated- absorption- |
*Fanconi syndrome from outdated (expired) tetracycline. Tetracycline degrades over time.
*Absorption decreased by divalent and trivalent cations (calcium, magnesium, iron, aluminum, etc) |
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Describe the Glycylcyclines:
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*Tigecycline
*Derivative of tetracycline *Same mechanism of action as tetracycline *Increased spectrum of activity: active against many tetracycline resistant gram positive bacteria (MRSA, streptococci, enterococci), gram negative bacteria and anaerobes *Adverse effects: nausea, vomiting |
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Describe Chloramphenicol:
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*Bactericidal/bacteriostatic
*Binds to 50S ribosome (also binds to mitochondrial ribosome) *Not commonly used in US. *Gram positives, gram negatives, B. fragilis, rickettsiae, chlamydia, mycoplasma *Adverse effects: bone marrow; Aplastic anemia 1:24,500 to 1:40,800, higher rate of leukemias in those that recover *Grey baby syndrome: lower conjugation, lower excretion |
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Describe Oxazolidinones:
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*Linezolid: a synthetic compound!
*Inhibits protein synthesis bacteriostatic: S. aureus, enterococci bactericidal: S. pneumoniae *Adverse effect: thrombocytopenia |
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Describe Sulfonamides:
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*Similar in structure to para-aminobenzoic acid (PABA) that is used in the synthesis of folate
*Susceptible organisms are those that must synthesize their own folate *Bacteria and humans that use preformed folate are not affected *Substitutions at the amide result in compounds that are more active and may affect absorption, solubility, GI tolerance *Bacteriostatic *Competitively inhibit incorporation of PABA into dihydro-folic acid; microbial enzyme: dihydropteroate synthetase |
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What are sulfonamides good against?
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*Gram positive and gram negative bacteria, nocardia; However, many bacteria have developed resistance
*Sulfadiazine plus pyrimethamine to treat toxoplasmosis *Silver sulfadiazine (topical) treat infected burns |
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SEs of sulfonamides:
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*Adverse effects: GI upset, WBC abnormalities, thrombocytopenia, rash, hypersensitivity, death
*Newborns: kernicterus (sulfa displaces bilirubin from albumin) |
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Describe Trimethoprim:
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*Dihydrofolate reductase (DHFR) inhibitor
*Potentiates sulfonamides *20 to 100 more potent than sulfa *Penetrates into prostate *Used in combination with sulfa to treat Pneumocystis jiroveci (formerly: Pneumocystis carinii), Stenotrophomonas, Tropheryma whippelii *Adverse effects: megaloblastic anemia, leukopenia, granulocytopenia |
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Bactrim:
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*Sulfamethoxazole to TMP 800 mg to 160 mg (5:1)
*TMP/SMX should not be used to treat Group A streptococcal pharyngitis since it does not eradicate the streptococcus |
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Describe Quinolones:
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*Derivatives of nalidixic acid
*Newer quinolones have a fluorine at position 6 *Inhibit DNA synthesis *Gram negatives: primary target is topoisomerase II (aka DNA gyrase) (introduces negative supercoils into DNA) *Gram positives: primary target is topoisomerase IV *Bactericidal |
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What are the quinolones good against?
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*Nalidixic acid gram neg. however rapid development of resistance
*Ciprofloxacin, norfloxacin, ofloxacin mainly gram negative *P. aeruginosa ciprofloxacin however increasing resistance *Moxifloxacin improved gram positive activity, e.g. Strep pneumoniae *Levofloxacin: in vitro more active than ciprofloxacin less active than gati/moxi against Strep. pneumoniae *Quinolones active against intracellular bacteria such as chlamydia, mycoplasma, legionella, brucella |
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SEs from quinolones:
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*Adverse effects
-seizures -rash -tendon rupture*** *Hypoglycemia: gatifloxacin *Arthropathy in immature animals. Hence, not given to children.*** |
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Absorption considerations in quinolones:
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Absorption decreased by divalent cations (calcium, magnesium, iron, etc)
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Describe rifamycins:
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*Rifampin and rifabutin
*Macrocyclic compounds that are soluble in organic solvents. Hence, they diffuse through lipids. *Inhibit bacterial DNA dependent RNA polymerase *Active against mycobacteria, most gram positive and many gram negative *Mutational resistance rapidly develops; hence it must be used in combination with other antibacterial agents *Rifabutin: MAI *Rifampin: M. tuberculosis |
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SEs from rifamycins:
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*Adverse effects: turns body fluids (urine, saliva, tears, sweat) orange-red
*Rash, hepatotoxicity |
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Describe metronidazole:
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*Alters cell membrane electrochemical potential
*Anaerobic bacteria: Bacteroides fragilis, Clostridium difficile *Protozoa: Trichomonas, giardia *Disulfiram-like reaction |
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Describe Nitrofurantoin:
adverse effects? |
*Damages DNA
*Active against E. coli, enterococci *NOT for treatment of pyelonephritis or prostatitis *Adverse effects *Hypersensitivity, rash, fever chills, leukopenia, granulocytopenia, hemolytic anemia, cholestatic jaundice, hepatocellular damage, acute pneumonitis *Long term use can lead to interstitial pulmonary fibrosis |
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Describe Methenamine:
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*Urinary tract antiseptic
*Releases formaldehyde at an acidic pH *Nearly all bacteria are susceptible *Proteus and other urea splitting bacteria raise urinary pH |
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When to use a Bactericidal Antibacterial Agent: 3
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*Meningitis
*Osteomyelitis *Endovascular infection (e.g. endocarditis) |
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What kinds of interactions can different antibiotics have with each other?
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synergy, antagonism, indifference
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Preferred treatment for endocarditis:
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Penicillin plus an aminoglycoside.
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Give an example of an antagonistic antibiotic interaction:
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