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88 Cards in this Set
- Front
- Back
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Quinolone history
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Synthetic compound
Nalidixic acid - limited activity (UTI) - low blood concentration Quinolones are bicyclic |
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Fluoroquinolone structure
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Quinolone with fluorine added to 6' position
Enhanced antimicrobial activity compared to nalidixic acid |
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Naphthyridone nucleus
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Similar to quinolones but has nitrogen at 8' position
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Quinolones still actively used (4)
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Ciprofloxacin
Levofloxacin Moxifloxacin Gemifloxacin |
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Quinolones active against pneumococcal infections (3)
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Levofloxacin- most able to get to site of infection in vivo
Moxifloxacin Gemifloxacin- lowest MIC in vitro |
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Quinolone mode of action
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Inhibiting DNA synthesis at DNA gyrase (topoisomerase II) and topoisomerase IV
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DNA gyrase (topoisomerase II) function
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Introduce supercoiling into DNA
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Topoisomerase IV function
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Separate replicated DNA molecule
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Mechanism of quinolone resistance
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Most common mechanism: Chromosomal mutations causing alterations in drug targets (DNA gyrase more common than topoisomerase IV)
Chromosomal mutation causing change in drug permeation - reduced porin channels - increased efflux |
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Quinolones are bactericidal or bacteriostatic?
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Bactericidal
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Bacterial targets of quinolones
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Broad spectrum--
Gram negative organisms, mostly aerobic. Somewhat effective for Pseudomonas (cipro is best) Newer fluoroquinolones good for Strep pneumo and MSSA (not MRSA) MRSA and Enterococcus usually resistant. Anaerobes usually resistant except to trovafloxacin, moxifloxacin and levofloxacin. Gonococci gaining resistance. Mycobacteria variable. |
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Quinolones are concentration or time-dependent killing
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Concentration dependent killing
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Bioavailability of oral quinolones
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High bioavailabilty of oral quinolones
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Where quinolones are metabolized
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Metabolized in kidney or liver
Cipro = both Levo = renal Moxi = hepatic Gemi = hepatic |
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Tissue and IC levels of quinolones?
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Tissue and intracellular levels of quinolones exceed serum (high Vd)
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T1/2 of quinolones
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Long (new FQ's can be given daily)
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Quinolones contraindicated in pregnancy because
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Cartilage toxicity in children
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Side effects of quinolones
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Fairly well tolerated:
N/V, diarrhea, headaches Cartilage toxicity Tendonitis (rare) Phototoxicity (halogen at 8') Prolonged QTc/arrhythmias Glucose homeostasis problems: hypo- or hyperglycemia (gatifloxacin) Mild macular rash |
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Quinolone drug interactions
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Xanthine (caffeine, theophylline): some FQ (cipro) --> decreased xanthine metabolism
Antacids or Iron Zinc: divalent cations chelate with FQ and FQ isn't absorbed |
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Clinical uses of quinolones
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UTI
STD: Chlamydia, Gonorrhea (gaining resistance) Skin (esp GN infections) Osteomyelitis Respiratory: sinusitis, CA-pneumonia, nosocomial pneumonia Infectious diarrhea |
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Concentration-dependent killing agents
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Fluoroquinolones
Aminoglycosides Metronidazole (anaerobes) Works best WAY above MIC Some have post-antibiotics effect (PAE) |
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Time-dependent killing agents
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Penicillins
Cephalosporins Aztreonam Macrolides/azalides Clindamycin Time above MIC is important (usually 4x MIC) |
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Examples of aminoglycosides
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Streptomycin
Kanamycin Gentamicin Tobramycin Neomycin Amikacin Netilmicin Paromomycin |
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Aminoglycoside structure
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Amino sugar bound by glycosidic linkage to a central hexose nucleus
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Aminoglycoside mechanism of action
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Binds 30S ribosome to block initiation of bacterial protein synthesis and cause misreading
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Are aminoglycosides bactericidal or bacteriostatic?
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Bactericidal
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Resistance to aminoglycosides
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Change in 30s ribosome conformation
Cell wall permeability change alters transport Enzymatically inhibits drug - if gentamicin-resistant, usually tobramicin-resistant and vice versa - Amikacin affected least |
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Antimicrobial activity of aminoglycosides
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Enterobacteriaceae:
E coli Klebsiella Enterobacter Proteus Morganella Citrobacter Serratia Pseudomonas (tobra) Y pestis (strepto) F tularensis (strepto) M tuberculosis (strepto) Atypical mycobacteria (Amik) Amoebiasis, Cryptosporidium (paramo) NOT: Strep, anaerobes, alone for Staph |
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How aminoglycosides are administered
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Usually IV or IM (good peak concentrations)
Also intraperitoneal, intrapleural |
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Distribution of aminoglycosides
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Poor (low Vd)
Urine is 25-100x plasma level Poor distribution to eye, CNS, bile, prostate, saliva |
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Metabolism and excretion of aminoglycosides
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No metabolism
Excreted in kidney |
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T1/2 of aminoglycosides
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Short (hours)
Renal failure greatly increases T1/2 |
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Side effects of aminoglycoside use
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Nephrotoxicity
Ototoxicity (often irreversible) Neuromuscular block (assoc w/ MS) Rash Drug fever |
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Aminoglycoside interactions
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Nephrotoxicity increased by other nephrotoxins
Intracellular transport blocked by Ca2+, Mg2+, chloramphenicol Mutual inactivation if taken with beta-lactams. |
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When to use aminoglycosides
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Severe infections (facultative/aerobic GNR)
Empiric therapy for sepsis (esp in immune compromised, Pseudomonas) |
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Spectinomycin MOA
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Binds bacterial 30s ribosome to inhibit protein synthesis
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Spectinomycin uses
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Given IM for gonorrhea
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Tetracyclines are bactericidal or bacteriostatic?
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Bacteriostatic
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Tetracycline MOA
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Binds bacterial 30s ribosome to block tRNA binding and prevent elongation of the peptide
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Uses of tetracyclines
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Broad spectrum:
GP, GN, aerobes, anaerobes, spirochetes, Mycoplasma, Rickettsia, Chlamydia |
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Tetracycline resistance
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Decreased influx, increased efflux
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Tetracycline excretion
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Renal or hepatic
Hepatically excreted tetracyclines (doxycycline) have higher availabilities and longer half-lives. |
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Tetracycline toxicity
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Skin hypersensitivity
Bone/teeth in fetus/child: depress growth, discolored teeth GI: nausea, vomiting, diarrhea Superinfectin: Candida, C diff Liver: fatty liver and liver necrosis Renal: azotemia, diabetes insipidus Neuro: vertigo |
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Tetracycline drug interactions
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Decreased absorption with divalent cations
Anticonvulsants increase metabolism Methoxyflurane can increase nephrotoxicity Diuretics elevate BUN Can increase contraceptive metabolism Can potentiate coumadin |
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Tetracycline indications
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CA- and atypical pneumonia
Genital Chlamydia/PID Granuloma inguinale Rickettsia Lyme disease Brucella Ehrlichiosis Relapsing fever Vibrio MRSA/MRSE Tularemia Leptospirosis Acne Malaria Syphilis Helicobacter Other zoonoses |
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Quinupristin/Dalfopristin bactericidal or bacteriostatic
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Bacteriostatic
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Quinupristin/Dalfopristin MOA
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Binds 50s ribosome and inhibits protein synthesis
Quinupristin: peptide chain elongation Dalfopristin: peptidyl transferase |
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Quinupristin/Dalfopristin resistance
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Plasmid-mediated methylation of target site
Drug modifying enzymes Efflux |
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Antimicrobial activity of Quinupristin/Dalfopristin
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E faecium- VSE and VRE but NOT E faecalis
MSSA, MRSA Coagulase negative Staph (NOT S aureus) Strep pneumo GPs Atypical respiratory pathogens |
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Quinupristin/Dalfopristin metabolism and excretion
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Hepatic metabolism
Biliary excretion No dose change for renal failure |
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Distribution of Quinupristin/Dalfopristin
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Widely distributed
Doesn't cross placenta Concentrates in macrophages |
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Toxicity of Quinupristin/Dalfopristin
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Inflammation, thrombophlebitis, pain at infusion site
N/V, diarrhea (C diff) Arthralgia, myalgia, pain Increase in bilirubin, liver enzymes, creatinine, anemia, thrombocytopenia |
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Quinupristin/Dalfopristin drug interactions
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Inhibits CYP-450 3A4
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Linezolid is bactericidal or bacteriostatic?
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Bacteriostatic
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Linezolid MOA
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Binds 50s ribosome to inhibit protein synthesis
Prevents 30S-70S initiation complex |
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Linezolid antimicrobial activity
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VSE, VRE (E faecium and faecalis)
Methicillin-resistant S aureus and epidermidis Pneumococci S pyogenes GPs |
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Linezolid metabolism and excretion
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Mostly metabolized by oxidation (use in renal failure)
Urinary excretion |
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Linezolid toxicity
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N/V, diarrhea (C diff)
Headache Rash Thrombocytopenia, leukopenia, anemia (>2w use) |
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Linezolid drug interactions
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Absorbed well with food
MAO inhibitors and SSRI Avoid food with tyramine |
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Linezolid indications
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VRE
GP infections Ca- and nosocomial pneumonia (MSSA, MRSA, Strep pneumo) Complicated skin and skin structure infections (diabetic foot) |
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Daptomycin derivation
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From Streptomyces roseoporus
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Daptomycin MAO
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Disrupt bacterial membrane through formation of transmembrane channels --> leakage of intracellular ions --> depolarize cell membrane and inhibit macromolecular synthesis
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Daptomycin bactericidal or bacteriostatic?
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Bactericidal
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Daptomycin concentration or time-dependent killing?
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Concentration dependent killing with PAE
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Antibacterial activity of Daptomycin
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GP organisms only
- Staph, Strep, Enterococci Anaerobic organisms: - Clostridium, Peptostreptococcus, Corynebacterium jeikeium, Leuconostoc, Lactobacillus |
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Administration of Daptomycin
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Only available as IV
Highly protein bound |
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Daptomycin excretion
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Renally excreted
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Daptomycin drug interactions and toxins
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HMB-CoA reductase inhibitors (statins)
Myopathies (muscle pain, weakness, CPK elevation) |
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Macrolide structure and derivation
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14 member "Large ring"
From Streptomyces erythreus 15 member ring = Azalide |
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Examples of macrolides (4)
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Erythromycin
Clarithryomycin Azithromycin Dirithromycin |
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Macrolide MOA
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Inhibit protein synthesis by binding to 23S rRNA of 50S ribosome (domain V) and inhibit tRNA translocation.
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Antimicrobial activity of Erythromycin
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S aureus
Strep Mycoplasma Bordetella Chlamydia Legionella Campylobacter Clostridium Peptococcus Peptostreptococcus |
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Antimicrobial activity of clarithromycin
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Same as erythromycin
+ increased Chlamydia, MSSA, and Strep activity + coverage for H flu, Moraxella, Mycobacterium avium |
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Antimicrobial activity of azithromycin
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Less active against S aureus and Strep than erythromycin
More active against H flu and Moraxella |
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Resistance to macrolides
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Alter 23S rRNA by methylation
(erm gene) Change in permeability and active drug efflux (mef gene) Macrolide inactivating enzymes Phosphotransferase Esterase |
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Erythromycin metabolism and excretion
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Concentrated by liver, excreted by bile
Persists in tissues longer than serum Concentrates in PMNs and macrophages |
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Clarithromycin bioavailability, metabolism and excretion
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50% bioavailability
Active metabolism Excreted by bile/urine - adjust for renal failure |
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Clarithromycin pharmacokinetics
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Levels in tissue > serum
Concentrates in neutrophils |
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Azithromycin pharmacokinetics, metabolism and elimination
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High tissue penetration
Concentrates in phagocytes T1/2 of 24 days Hepatic elimination No adjustment for renal/hepatic failure No CYP-450 induction |
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Clarithromycin and Erythromycin drug interactions
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Warfarin
Carbamazepine Cyclosporine Digoxin Theophylline Valproate |
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Macrolide side effects
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Well-tolerated
GI Cholestatic hepatitis (estolate- rare) Ototoxicity (rare, reversible) QT prolongation Pyloric stenosis (children <6w) |
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Macrolide indications
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Mycoplasma pneumonia
Legionella Diphtheria Pertussis Chlamydia Campylobacter gastroenteritis Mycobacterium avium complex |
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Ketolide example
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Telithromycin
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Ketolide structure
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Macrolide by substitute 14 member ring with ketone group
- more acid stable - enhanced antimicrobial activity |
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Ketolide MOA
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Similar to macrolides but binds 2 domains at 23S rRNA (II, V)
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Ketolide side effects
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Exacerbates myasthenia gravis
Interferes with CYP-450 Resistance with increased use |
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Reversal reaction symptoms (2)
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1. Erythema of skin plaques
2. Peripheral nerve swelling with loss of sensation |
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Erythema nodosum leprosum symptoms (6)
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1. Subcutaneous red nodules
2. Arthalgias/arthritis 3. Fever 4. Nephritis 5. Leukocytosis with left shift 6. Uveitis |
