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43 Cards in this Set
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Vancomycin: po/iv Description
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Glycopeptide inhibitor of cell wall synthesis
Directly binds to the D-ala-D-ala end terminus of peptidoglycans Resistance: change to D-ala-D-lac end terminus. Bactericidal activity varies from strain to strain Slower killing than beta-lactams |
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Vancomycin Spectrum of Activity
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Spectrum of Activity:
Gram-positives: streptococci, staphylococci, enterococci Vancomycin resistance is ~20-40% in enterococci from hospitals Decreased susceptibility/resistance now emerging in Staphylococci |
NOTE: VANCOMYCIN USE ON THE RISE
Anaerobes: Clostridium difficile (antibiotic-associated colitis…a.k.a C-diff colitis) There's an epidemic due to more virulent strains so there's more Vanco. |
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Current uses of Vanco
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Current Uses:
MRSA infections (SSTIs, pneumonia, bloodstream infections, endocarditis) Clostridium difficile colitis Main adverse effects: Rash “Red-man syndrome”-related to histamine release during drug administration Drug is not absorbed when administered orally (used only for colitis) Only trough concentrations should be monitored: T arget troughs: 10-20 mg/L |
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Daptomycin (Cubicin®): IV
MOA SOA Clinical Considerations |
Mechanism of action:
Lipopeptide antibiotic that directly disrupts cell membrane / cell wall integrity Spectrum of activity: Gram-positive organisms: Streptococci, Staphylococci, Enterococci MRSA, VRE, strains with decreased vancomycin activity/resistance |
DO NOT use for pneumonia (inferior to standard therapies) !!
May cause myositis/rhabdomyelitis (muscle toxicity) Monitor creatine phosphokinase levels |
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Fluoroquinolones (FQs)
Mechanism of action |
Disrupt normal bacterial DNA synthesis by inhibiting the functions of DNA gyrase and topoisomerase IV
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Fluoroquinolones (FQs)
Properties Mechanism of resistnace |
Rapidly Bactericidal
Concentration-dependent Mechanism of Resistance: Mutations in DNA gyrase and topoisomerase IV (altered proteins) Gram (+) and Gram (-) organisms Overproduction of multidrug efflux pumps (“Acr” or “Mex” pumps) Gram (-) organisms |
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Fluoroquinolones (FQs)
Agents |
1st Generation
Ciprofloxacin (Cipro®, Ciloxan®): po/iv/topical Ofloxacin (Floxin®, Ocuflox®): po/iv/topical Norfloxacin (Noroxin®): po 2nd Gen... Gemifloxacin (Factive®): po Levofloxacin (Levaquin®): po/iv Moxifloxacin (Avelox®): po/iv |
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Fluoroquinolones
SOA |
Gram negatives: active against nearly all
Cipro, Levo are most active FQs against Pseudomonas Gram-positives: Newer agents (gemi-, levo-, moxi-) more active than older agents (cipro, norflox, oflox) Streptococci, Staphylococci, Enterococci (+/-), Bacillus anthracis Limited activity vs. MRSA Anaerobes (esp. newer FQs) Atypical bacteria (including Legionella spp.) Mycobacteria (including tuberculosis) |
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Fluoroquinolones:Current Uses
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RTIs, sinusitis (newer agents preferred)
SSTIs (but not if MRSA suspected/document) UTIs (1st line therapy) exception: moxifloxacin (minimal urine concentrations) Pseudomonas infections Use in combination if systemic infection!!! (resistance risks with monotherapy) Bacterial gastroenteritis (Salmonella) Cutaneous/Inhalation Anthrax (1st line for bioterrorism-associated) Ocular infections / otitis externa (topical) |
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Are nearly all MRSAs floroquinolones resistant?
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Yes
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Fluoroquinolones:Clinical Considerations
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All FQs need dose reductions in patients with moderate-severe renal dysfunction except moxifloxacin (hepatic elimination)
Adverse effects: May cause photosensitivity / rash Gemifloxacin: rash more common in younger females (up to 25%) Musculoskeletal: tendon rupture Hypo- and/or hyperglycemia: Especially if concurrent oral hypoglycemic agents More common with gatifloxacin in elderly patients Generally avoid in pregnancy / pediatrics (though quinolones are used in CF patients) Chelated by divalent cations – careful when using P.O. !!!! |
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Rifampin
MOA MOR SOA |
Mechanism of action:
Inhibition of bacterial RNA polymerase Usually bactericidal Mechanism of resistance: Altered RNA polymerase enzyme Spectrum of Activity Gram-positives: Staphylococci, Streptococci Gram-negatives: Neisseria meningitidis, Haemophilus Some atypical antibacterial activity Mycobacterium tuberculosis, other mycobacteria |
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Rifampin - Current Uses
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First line agent for tuberculosis treatment
Synergistic/additive antibacterial activity in combination with other drugs against gram-positive organisms to treat: endocarditis, osteomyelitis, meningitis, infections related to prosthetic materials (e.g., hip infection, heart valves) Potent against biofilm, slow growing bacteria Prevention of meningitis due to streptococci and/or Haemophilus for contacts of a meningitis patient |
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Rifampin: Clinical Considerations
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Should never be used alone to treat any infection
rapid development of resistance! Drug turns all bodily fluids red-orange tint Potent inducer of all CYP450 isoenzymes…many drug interactions!!! |
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Metronidazole: po/iv/topical
MOA SOA |
Mechanism of Activity:
reduced by low-redox-potential electron transport proteins; directly disrupts DNA and inhibits nucleic acid synthesis Bactericidal, amoebicidal, and trichomonicidal concentration-dependent Spectrum of Activity Nearly all clinically significant anaerobic bacteria (e.g., Bacteriodes, Clostridium) Amoebic microorganisms Trichomonas vaginalis Helicobacter pylori |
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Macrolides
MOA MOR |
Mechanism of Activity:
Protein synthesis inhibition via binding to 23S ribosomal RNA at the peptidyl transferase cavity of the 50s ribosomal subunit Primary Mechanism of Resistance : Alteration of macrolide ribosome binding sites via methylations |
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Examples of Macrolides
Give three Hint: Begins with C and A and E |
Clarithromycin
Azithromycin Erythromycin |
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Azithromycin structural properties
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- N-methyl group is inserted between
carbons 9 and 10 of erythromycin more stable to acid degradation longer half life attributed to greater and longer tissue penetration |
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Clarithromycin structural properties
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-Methyl ether gives better absorption;
more stable for oral administration with [relatively] less gastric upset. -Greater lipophilicity so less frequent dosage required |
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Antibacterial Activity of Macrolides
Cidal or Static? |
Bacteriostatic
Spectrum of activity: Gram positives: Streptococci, Staphylococci, Enterococci (+/-) Gram negatives: Primarily typical respiratory pathogens (Haemophilus, Moraxella spp.) Anaerobes: primarily oral anaerobes Atypical bacteria Proprionobacteria (acne vulgaris) Helicobacter pylori Mycobacteria |
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Macrolides:Current Clinical Uses
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RTIs, sinusitis (esp. azithromycin, clarithromycin)
SSTIs (if PCN/Ceph allergic) Acne vulgaris (PO and/or topical tx) Treatment of H. pylori infection (ulcers) Treatment/prevention of Mycobacterial infections in HIV-Infected patients (azithromycin, clarithromycin) STDs: Chlymydia, Syphilis treatment (in PCN-allergic patient) |
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What is the most common side effect of Macrolides?
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GI Upset is most common adverse effect!!!
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2nd Gen Macrolides
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Used for Com Acquired Pneunmo
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Linezolid (Zyvox)
MOA |
Binds to A site and prevents tRNA from coming in
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Linezolid (Zyvox)
MOA |
Mechanism of Action:
Oxazolidinone Ribosomal protein synthesis inhibitor (different mechanism/binding site than macrolides, tetracyclines, aminoglycosides) Inhibits initiation of protein synthesis by selectively binding to 23S ribosomal RNA of the 50S subunit Prevention of tRNA binding to “A” site |
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Linezolid (Zyvox)
Clinical Considerations |
Reversible MAO Inhibitor:
May cause hypertension if given with tyramine-containing foods, decongestants, … Fatal/Life-threatening serotonin syndrome has occurred rarely w/ concomitant antidepressant therapy 100% bioavailable (po/iv interchangeable) Adverse effects: well-tolerated, but: anemia, thrombocytopenia, rarely neuropathies with longer (>2 week) tx courses |
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Linezolid (Zyvox®): po/iv
SOA |
Gram-positives:
Streptococci Staphylococci (including MRSA and S. aureus strains with reduced vancomycin susceptibility) Enterococci (including strains with vancomycin resistance (VRE)) Gram negatives: primarily respiratory pathogens Bacteriostatic against Staphylococci, Enterococci Bactericidal versus Streptococci |
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Clindamycin: po/iv/topical
MOA SOA MLS B Class Antibotic Macrolid Lincosamides = Clindamycin Strepogramins |
Mechanism of action:
Inhibition of protein synthesis by binding to the 50S subunit of the bacterial ribosome [“MLSB” class] Spectrum of Activity Gram-positives: Streptococci, Staphylococci (including some MRSA), Enterococci (+/-) Most anaerobes (oral anaerobes, Bacteroides) Minimal activity against Gram-negatives and atypicals. |
Usually bacteriostatic
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Quinupristin/Dalfopristin (Synercid®)):
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Streptogramin antibiotic
[macrolide/lincosamide/streptogramin (“MLSB”) family] Mechanism of Action: Both drugs synergistically inhibit bacterial protein synthesis They do not have activity when they are by themselves |
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Quinupristin/Dalfopristin (Synercid®
SOA |
Bacteriostatic / Bacteriocidal:
resistance to macrolides and clindamycin usually predicts bacteriostatic activity Spectrum of Activity Gram-positives: Streptococci Staphylococci (including MRSA and strains with reduced vancomycin susceptibility) Enterococci (including vancomycin-resistant strains) NO ACTIVITY against Enterococcus faecalis !!!Does have activity againt E. Faecium – Good since 90% that live in gut are Faecium species Gram-negatives: limited to respiratory pathogens Some activity against anaerobes and atypical bacteria |
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Tetracyclines
MOA MOR |
Mechanism of Action:
Protein synthesis inhibition via binding to the 30s ribosomal subunit Prevents binding of aminoacyl tRNA to the mRNA-ribosomal complex. Mechanisms of resistance: Production of efflux proteins (tetA) Production of ribosomal protection proteins (tetM) |
Available Agents
Tetracycline: po Doxycycline: po/iv Minocycline: po |
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Tetracyclines
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Bacteriostatic
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Spectrum of activity:
Gram positive: Streptococci, Staphylococci (including some MRSA), enterococci (+/-), Bacillus anthracis Gram negative: common respiratory pathogens Oral anaerobes, Proprionobacteria (acne vulgaris), atypical bacteria Helicobacter pylori Borrelia burgdorferi, Rickettsia (tick-borne bacteria) |
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A Glycylcycline drug...
Uses: Intra-abdominal infections, SSTIs |
Tigecycline (Tygacil)
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IV only “Broad spectrum” tetracycline Gram (+), gram (-), anaerobes, tetracycline-resistant orgs. Uses: Intra-abdominal infections, SSTIs Clinical Considerations: Similar to other tetracyclines, but also: High frequency of nausea/vomiting (~20%) |
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Aminoglycosides (Drug class)
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Mechanism of Action:
Bind to the 30s ribsomal subunit; inhibit initiation of protein synthesis and also causes misreading of the genetic code (i.e. mutant proteins) Glycosidacally linked amino sugar molecules; contain at least one aminohexose and a highly substituted 1,3-diaminocyclohexane Most commonly used: amikacin, gentamicin, streptomycin, tobramycin |
Theset he ONLY CIDAL drugs
of the protein synthesis inhibition class |
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Aminoglycosides
MOR |
Primary: Enzymatic deactivation by acetylation, phosphorylation, or adenylation of key amino and/or hydroxyl groups
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Occurs easily when drug is byitself - similar to the mechanism for Rifamycin
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Aminoglycosides
SOA |
Rapidly Bactericidal
Concentration-dependent Spectrum of Activity: Gram negatives: active against nearly all (including Pseudomonas) Gram-positives: less active, but synergistic when combined with beta-lactams against streptococci, staphylcocci, enterococci Mycobacterium tuberculosis (streptomycin) NO anaerobic/atypical antibacterial activity |
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Aminoglycosides:Clinical Uses
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Goal prevent resistance
In combination with beta-lactams and other antibiotics against streptococci, staphyolcocci, enterococci: In combination with other gram-negative antibiotics for infections due to hospital-acquired pathogens Tuberculosis (streptomycin): 2nd/3rd line agent used in multi-drug resistant TB infections Inhaled (TOBI®): lung infections in cystic fibrosis patients Topical: ocular infections, otitis externa |
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Aminoglycosides:Clinical Uses 2
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Monotherapy with aminoglycosides results in rapid emergence of resistance
Monitor peak & trough concentrations: Monitor peak since the conc goes up with dose rate Peak 10x than MIC is ideal Peaks (6-10 mg/L with usual doses) correlate with efficacy Troughs (< 2 mg/L with usual doses): correlate with nephrotoxicity |
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Chloramphenicol
(brought up for historic purposes) Now there are safer drugs |
Used to be good for menigitis. (Penetrates the CNS well)
Protein synthesis inhibition via binding to the 50s ribosomal subunit First therapeutically important antibiotic to be produced by a totally synthetic route Excellent CNS penetration historical drug of choice for meningitis & other CNS infections SE: Slowly developing anemia. Aplastic anemia (1:200,000) Need to monitor serum concentrations. |
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Folate Synthesis Inhibitors
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Sulfonamides / Trimethoprim:
1. S inhibits Dihydropteroatesynthetase 2. T inhibits DihydrofolateReductase |
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Folate Synthesis Inhibitors
SOA |
Spectrum of Activity:
Gram-positives: Streptococci (+/-), Staphylococci (including some MRSA), but NOT enterococci Gram-negatives: limited to respiratory pathogens and select other organisms (e.g., E. coli, Enterobacter, Proteus) Pneumocystis jirovici (“PCP”) Poor against anaerobes and atypical bacteria |
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Sulfonamides:Current Clinical Uses
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Outpatient treatment of S. aureus infections
Including MRSA, w/ confirmed susceptibility P. jirovici pneumonia treatment/prophylaxis in HIV-infected patients RTIs, sinusitis, UTIs: emergence of resistance currently limits use in these settings Should not be used for pharyngitis (less effective than PCNs/Cephs) |
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Sulfonamides:Clinical Considerations
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Cross-allergenicity exists amongst various sulfas
Trimethoprim may be used for UTI treatment/prevention Photosensitivity Hyperkalemia especially with IV doses, in patients with renal dysfunction, and/or with potassium supplementation Bone marrow suppression Drug Interactions: Protein binding competition/inhibition of metabolism: Warfarin, glyburide |
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