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56 Cards in this Set
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Name the sub groups of bacterial protein synthesis inhibitors
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*Streptogramins and Oxazolidinones
*Macrolides *Lincosamides *Aminoglycosides *Tetracyclines *Chloramphenicol |
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Bacterial Protein Synthesis Inhibitors: Streptogramins and Oxazolidinones
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Streptogramin-Quinupristin and Dalfopristin- Formulated and used in combination, Q/D (Synercid).
Linezolid (Zyvox) is an oxazoladinone derivative |
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MOA of bacterial protein synthesis inhibitors
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Inhibit bacterial protein synthesis. Bind to the 23S RNA of 50S ribosomal subunit of bacte
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MOA of Quinupristin / Dalfopristin
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inhibits peptidyl transferase, thereby blocking the elongation of the peptide chain. Dalfopristin acts at the early phase of protein synthesis, quinupristin acts at the late phase.
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MOA of Linezolid
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binds to the 23S RNA on the 50S subunit and inhibits the formation of ribosome complex and initiation of protein synthesis.
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Antimicrobial activity of bacterial protein synthesis inhibitors
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Narrow-spectrum: active against gram-(+), some gram-(-) bacteria, anaerobes, and chlamydiae
Q/D: also active against Vancomycin-resistant Enterococcus (VRE) faecium, Methicillin-resistant Staphylococcus Aureus (MRSA), Penicillin-resistant Streptococcus Pneumoniae (PRSP), & S Pyogenes Bactericidal: when Linezolid & Q/D are combined. Bacteriostatic: Q/D |
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Antimicrobial activity of linezolid
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Linezolid represents a new class of antimicrobials, highly active
against susceptible and resistant gram-(+) bacteria, including: VRE, MRSA, Penicillin-Resistant Streptococcus Pneumoniae (PRSP), & Streptococcus Pyogenes. Primarily bacteriostatic agent except for streptococci, for which is bactericidal Not useful against gram-(-) species. |
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Pharmokinetics and adverse effects of linezolid and D/Q
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D/Q present poor oral absorption; mostly metabolized in the liver and
eliminated in feces. Causes pain and frequent thrombophlebitis at injection site; may produce arthralgia and myalgia. Linezolid: good oral absorption, also used IV, oxidized (metabolized by non-P450 enzymes), excreted in urine and feces. GI distress: diarrhea, nausea, vomiting, thrombocytopenia (chronic use), inhibits monoamine oxidase activity |
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Drug interactions with linezolid and D/Q
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Q/D increases the levels of warfarin, diazepam, non-nucleoside. reverse transcriptase inhibitors, and cyclosporine. Linezolid augments the action of SSRI, other antidepressants, as well as increases action of pseudoephedrine &
phenylpropanolamine CNS psychotic effects at higher doses |
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Name the Bacterial Protein Synthesis Inhibitors: Macrolides
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Erythromycin
Clarithromycin Azithromycin Also the KETOLIDES |
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MOA of macrolides (bacterial protein synthesis inhibitors)
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MA: Bind to the 50S ribosomal subunit and block the aminoacyl translocation and formation of translation complex.
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Antimicrobial activity of macrolides
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Bacteriostatic, but bactericidal at high doses; Limited
coverage for gram-(+) and (-) bacteria, & anaerobes. Also: Chlamydia, Mycoplasma pneumoniae, Mycobacterium Hospital / community-acquired pneumonia. Mycobacterium avium complex (MAC) pneumonia Legionnaire’s disease Alternative to penicillins (patients allergic to penicillin) |
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PK of macrolides
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Good oral absorption (except erythromycin-acid sensitive).
Extensive distribution (except the brain) Erythromycin, clarithromycin: liver metabolized Azithromycin is eliminated unchanged via kidney & feces GI distress: particularly by erythromycin Cholestatic hepatitis with erythromycin estolate (causing failure of bile flow) |
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Drug interactions with macrolides
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Erythromycin and clarithromycin increase serum levels of:
Theophylline (bronchodilator) Warfarin (oral anticoagulant) Cyclosporine (immunosuppressive agent) Statins (cholesterol synthesis inhibitors) Astemizole (histamine H1 receptor inhibitor) Various anticonvulsants Methylation or mutation of binding site leads to Macrolide-Lincosamide-Streptogramin B resistance Reduced access to cells Hydrolyzed by esterases |
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Telithromycin
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Telithromycin. Effective against many traditional
macrolide-resistant strains. Structural modification makes them poor substrates for efflux pump-mediated resistance. Bind to ribosomes of some bacterial species with higher affinity than macrolides Taken orally, good tissue and intracellular penetration Use for respiratory tract infection, including community- acquired bacterial pneumonia and S pharyngitis Reversible inhibits CYP3A4 enzyme system, may slightly prolong QTc interval. Rare cases of hepatitis reported |
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Name Bacterial Protein Synthesis Inhibitors: Lincosamides
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clindamyacin
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MOA of clinda
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Bind to the 23S RNA of 50S ribosomal subunit and inhibit the aminoacyl translocation and formation of initiation complex (similar to streptogramins/oxazolidenones and macrolides)
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Clinical uses of clinda
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Narrow spectrum: active against some gram-(+), most anaerobes, and some chlamydia, but not gram-(-) bacteria. Bacteriostatic. Treatment of penicillin-resistant gram-(+) infections and in patients allergic to penicillins.
Streptococci, staphylococci, and pneumococci are inhibited by clindamycin Anaerobic infections. Polymicrobial peritoneal infections. Hospital-acquired pneumonia (combined with G3 or G4 cephalosporins). |
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PK, adverse reactions, and drug interactions with clinda
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Methylation or mutation of the binding site causes MLS-type B resistance. Reduced drug access to bacteria. Good oral absorption.
Extensive distribution (except into the brain). Metabolized in the liver, eliminated in feces and bv kidneys. GI distress, Rash, Superinfections, Hepatotoxicity, Neutropenia Respiratory paralysis could be induced with use of muscle relaxants: baclofen, diazepam, atracurium |
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MOA of aminoglycosides
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Aminoglycosides have two (or more) aminosugars linked to an hexose ring (or aminocyclitol) via glycosidic links. Bind 16S RNA of the 30S ribosomal subunit and inhibit protein synthesis
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Name aminoglycosides
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Streptomycin: the 1st to be isolated, derived from
Streptomyces griseus, Neomycin, Gentamicin, Tobramycin, Kanamycin, Amikacin |
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Clinical uses of aminoglycosides
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Narrow-spectrum, mostly Bactericidal
Active against gram-(-) and limited gram-(+); Some are effective against Pseudomonas aeruginosa. Not effective against anaerobes Infective bacterial endocarditis Septicemia, Hospital-acquired pneumonia Chronic urinary tract infections |
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Resistance and PK of aminoglycosides
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Mutation at the ribosome binding site. Enzymatic Inactivation: by acetylation, adenylation or Poor oral absorption.
Variable distribution in body; do not enter the brain Reduced activity in low pH, hyperosmolarity, & anaerobiosis. Unmetabolized and eliminated by the kidneys. |
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Adverse reactions and drug interactions with aminoglycosides
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Ototoxicity, Nephrotoxicity, Neuromuscular blockade
Increased ototoxicity with loop diuretics, vancomycin Increased nephrotoxicity with vancomycin, cyclosporin, NSAIDs, radiographic contrast (iodine-based) agents. Respiratory depression with neuromuscular blockers. In vitro mixing with penicillins reduces the activity of both |
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Name some tetracyclines
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Tetracycline, Doxycycline, Minocycline
Tigecycline (Glycycycline) Some isolated from certain species of Streptomyces. Others are semisynthetic. |
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MOA of tetracyclines
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Bind 16S to the 30S ribosomal subunit and block the docking of tRNA on the ribosomes (similar to aminoglycosides)
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Clinical uses of tetracyclines
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Broad-spectrum, Bacteriostatic
Effective against many gram-(+) and -(-) bacteria, including, anaerobes, chlamydia, mycoplasmas, some protozoa Use doxycycline unless otherwise noted: Chlamydial infections with gonorrhea, Mycoplasma pneumoniae Alternatives for (partial list): Hospital-acquired pneumonia Ulcers, Bronchitis, Syphilis, Cholera, Tularemia, Plague & anthrax. |
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Tigecycline
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Tetracycline derivative, the first glycylcycline
New IV broad spectrum antibiotic with activity against many drug-resistant organisms. Approved for treatment of complicated skin/skin-structure infections and intra-abdominal infections with resistant organisms (but not Pseudomonas), particularly in patients who cannot tolerate other drugs |
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Resistance and PK of tetracyclines
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Enzymatic inactivation by phosphorylation, adenylation or acetylation. Reduced permeability into the cells. Ribosome protecting proteins mutation. Efflux pumping
Variable oral absorption, reduced by food, dairy, aluminum hydroxide gels, cations, and alkaline medium Extensive distribution in the body except the brain Metabolized in the liver Eliminated by the kidneys (doxy~ is eliminated in feces). |
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Tetracyclines
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Incorporates into teeth and bones (not given to children ≤8)-yellowish color
Phototoxicity, GI distress, oto-, hepato-, and nephrotoxicity. Superinfections. Serum levels of doxycycline is reduced by some anticonvulsants and barbiturates. May cause increase digoxin toxicity Contraindications: Pregnancy, renal or liver impairment or failure, children under 8 years of age |
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Chloramphenicol MOA
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Binds to the 50S ribosomal subunit A site (similar to macrolides and clindamycin), preventing the docking of aminoacyl tRNA.
Binds to mitochondrial ribosomes inhibing the activity of peptidyl transferase, causing side-effects |
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Clinical uses of Chloramphenico
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Broad-spectrum: Bacteriostatic: aerobic and anaerobic
gram-(+) and -(-) bacteria. Bactericidal for some gram-(-) bacteria, etc Rarely used: potential toxicity, bacterial resistance, availability of effective alternatives; may be considered e.g., typhus and Rocky Mountain spotted fever Alternative to a B-lactam antibiotic in patients showing a major hypersensitivity reaction to penicillin. Topical for eye infections-penetration of ocular tissues and aqueous humor |
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Name two classes of Folic Acid Metabolism Inhibitors
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Sulfonamides, Trimethoprim
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MOA and chemical structure of sulfonamides
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Sulfadiazine, Sulfamethoxazole, Sulfasalazine. The “Sulfa drugs” are structurally related
to para-aminobenzoic acid (PABA). Competitively inhibit folic acid production by suppressing the activity of dehydropteroate synthase Inhibition of tetrahydrofolate synthesis interrupts various metabolic reactions. |
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Antimicrobial activity and PK of sulfonamides
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Broad-spectrum, Bacteriostatic
Gram-(+) streptococci and pneumococci, Gram-(-) meningococci and gonococci, Gram-(-) bacilli (E. coli and shigellae) and more Active against chlamydia and some protozoa. Stimulate Rickettsiae. Largely replaced by less toxic, more effective agents. However, Trimethroprim/sulfamethoxazole combo has increased their use for the prophylaxis and treatment of specific microbial infections. Good oral absorption, extensive distribution (body and brain), inactivated by acetylation in the liver, eliminated by the kidneys, except sulfasalazine |
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Clinical uses and resistance to sulfonamides
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Enterocolitis: sulfasalazine
Burns: silver sulfadiazine Ocular infections Toxoplasmosis: sulfadiazine and pyrimethamine. Sulfamethoxazole can be formulated with phenazopyridine , an analgesic, to treat urinary distress in UTIs Overproduction of PABA (to compete with sulfonamides) Reduced affinity of dehydropteroate synthase for the sulfa drugs. Natural resistance if organisms import folic acid. |
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Adverse reactions and drug interactions with sulfonamides
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Crystalluria, Hematopoeitic toxicities, Photosensitivity, Skin
Rashes, Exfoliative dermatitis, GI distress Stevens-Johnson syndrome (skin and mucous membrane eruption), Kernicterus. Increase serum levels of oral anticoagulants sulfonylureas, and hydantoin anticonvulsants. Avoid use with methenamine (UTI) since it forms formaldehyde that condenses with sulfonamides |
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MOA of Trimethoprim / Sulfamethoxazole
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Trimethoprim is used in combination with sulfamethoxazole
because the two drugs markedly potentiate each other. Trimethoprim inhibits dihydrofolate reductase, while sulfamethoxazole inhibits dehydropteroate synthases, leading to an enhanced inhibition in THF synthesis. |
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Antimicrobial activity of Trimethoprim
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Broad spectrum, Synergism with a sulfonamide
(bactericidal), but bacteriostatic if used alone. Active against gram-(+), gram-(-), but not anaerobes. Also active to chlamydia. Prevent recurrent UTI urinary track infections, treat upper respiratory infections, bronchitis. Mutations of dihydrofolate reductase.Natural resistance if organism imports folic acid. Metabolic bypass |
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Clinical uses of Trimethoprim
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Good oral absorption.
Extensive distribution, including the brain. Inactivated by oxidation and conjugation. Excreted mostly by the kidney, some in feces. Prevent recurrent UTI urinary track infections, treat upper respiratory infections, bronchitis. Mutations of dihydrofolate reductase. Natural resistance if organism imports folic acid, Metabolic bypass |
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DNA Replication and Transcription Inhibitors: Fluoroquinolones. Name some
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Fluoride derivatives of nalidixic acid. Large number, including
Ciprofloxacin LevofloxaciN All have fluorinated R6 (-F) |
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MOA of fluoroquinolones
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Block bacterial DNA synthesis (transcription & replication) by inhibiting α-subunit of DNA gyrase (topoisomerase II) and topoisomerase IV (separating DNA strands). The two strands of double-helical DNA must be separated to permit DNA duplication or transcription
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Antimicrobial activity of fluoroquinolones
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BROAD-SPECTRUM. BACTERICIDAL
EFFECTIVE AGAINST GRAM-(+) AND (-), LIMITED ACTIVITY AGAINST ANAEROBES ONLY CIPROFLOXACIN AND LEVOFLUOXACIN ARE ACTIVE AGAINST PSEUDOMONA AEUROGINOSA. Also effective against CHLAMYDIAE MYCOPLASMA |
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Clinical uses and resistance of fluoroquinolones
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Genital (acute and chronic UTIs; Gonorrhea), GI, bone,
joint and complicated skin infections. Conjunctivitis: ciprofloxacin ophthalmic solution Anthrax: ciprofloxacin is FDA approved to treat and protect people who have been exposed to anthrax spores Different fluoroquinolones show specific pharmacological profile (antibacterial effects) Mutation at quinolone binding site. Reduced access-reduced porin number. Drug efflux |
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DNA Replication and Transcription Inhibitors: Fluoroquinolones. Name some
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Fluoride derivatives of nalidixic acid. Large number, including
Ciprofloxacin LevofloxaciN All have fluorinated R6 (-F) |
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MOA of fluoroquinolones
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Block bacterial DNA synthesis (transcription & replication) by inhibiting α-subunit of DNA gyrase (topoisomerase II) and topoisomerase IV (separating DNA strands). The two strands of double-helical DNA must be separated to permit DNA duplication or transcription
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Antimicrobial activity of fluoroquinolones
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BROAD-SPECTRUM. BACTERICIDAL
EFFECTIVE AGAINST GRAM-(+) AND (-), LIMITED ACTIVITY AGAINST ANAEROBES ONLY CIPROFLOXACIN AND LEVOFLUOXACIN ARE ACTIVE AGAINST PSEUDOMONA AEUROGINOSA. Also effective against CHLAMYDIAE MYCOPLASMA |
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Clinical uses and resistance of fluoroquinolones
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Genital (acute and chronic UTIs; Gonorrhea), GI, bone,
joint and complicated skin infections. Conjunctivitis: ciprofloxacin ophthalmic solution Anthrax: ciprofloxacin is FDA approved to treat and protect people who have been exposed to anthrax spores Different fluoroquinolones show specific pharmacological profile (antibacterial effects) Mutation at quinolone binding site. Reduced access-reduced porin number. Drug efflux |
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Adverse reactions of fluoroquinolones
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Generally well tolerated. May cause GI distress, headache,
dizziness, insomnia, skin rush; damage growing cartilage. They are not usually suggested for children younger than 18-yr-old (cartilage damage) & contraindicated during pregnancy or patients allergic to other quinolones. and cause arthralgia |
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PK and drug interacations with fluoroquinolones
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Generally good oral absorption and extensive body
distribution (except the brain), but enoxacin penetrates into the CNS. Mostly partially metabolized and eliminated via the kidneys (some exceptions). Cause cardiac arrhythmias when used with some anti- arrhythmic agents. Generally, there is an increased chance of seizures when used with NSAIDS. Decreased absorption with sucralfate, cations, antacids, dairy and citric acid |
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Name UTI bacteriostatics and other antibiotics
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1. Nitrofurantoin
Acute (and chronic) urinary tract infection 2. Methenamine UTIs prophylaxis but not as a primary agent for treatment 3. Metronidazole: vaginitis and other bacterial infections 4. Mupirocin: Used topically for staphylococci-caused impetigo. May cause local itching, rash contact dermatitis…….. 5. Polymyxins: Because of toxicity use restricted to topical therapy of resistant gram-negative infections |
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MOA of Nitrofuranton
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Mechanism of Action and Antimicrobial Activity
Bacteria reduce Nitrofurantoin more easily than mammalian cells and reduced drug products damage bacterial DNA Bacteriostatic, active against E.coli and enterococci, but not proteus, Pseudomonas and Enterobacters. |
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Nitrofuranton pharm phacts
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Clinical Uses: primarily to treat UTIs, also prophylaxis for recurrent UTIs.
Pharmacokinetics: good oral absorption; partially eliminated by the kidneys. Adverse Reactions: GI distress, anorexia, hemolytic anemia, neuropathies, renal failure. Resistance: Inability to reduce the drug nitrogen in the presence of oxygen. Susceptible bacteria rarely become resistant. |
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MOA and clinical use of Methenamine
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Mechanism of Action and Antimicrobial Activity
Antiseptic converted to formaldehyde in water and low urinary pH; nearly all bacteria are sensitive. Clinical Uses: prophylactic treatment for recurrent UTI, formulated with mandelate or hippurate to increase effectiveness. |
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Methenamine pharm phun phacts
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Pharmacokinetics
Good oral absorption, concentrated in acidic compartments (e.g., in the urinary tract, bladder, and gastric juices). Adverse Reactions: GI distress; frequency of micturition, albuminuria, hematuria and rashes Drug Interactions: Form insoluble compound with sulfa drugs Resistance: Proteus that raise pH in urine are resistant Contraindications: Hepatic disease since ammonia is produced |
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Flagyl MOA and clinical uses
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MA and Antimicrobial Activity:
Anti-protozoal drug, with potent activity against anaerobes (e.g., trichomonas). Inhibits DNA synthesis Clinical Uses: vaginitis (trichomonas and bacterial vaginosis), amebiasis (intestinal, amebic dysentery; hepatic, abscesses), & giardiasis (giardia, diarrhea). |