Aminoglycosides, Fluoroquinolones, Sulfonamides and Metronidazole Flashcards
Aminoglycosides
Streptomycin, Gentamicin (Garamycin), Kanamycin (Katrex), Tobramycin (Nebcin), Amikacin (Amikin), Neomycin
Aminoglycosides Spectrum of Action
Active against aerobic Gram- and some Gram+ bacteria
Aminoglycosides Mechanism of Action
Bactericidal (unique) but concentration-dependent, Bind to 16S rRNA of 30S subunit of ribosome to interfere with protein synthesis, Also cause misreading of mRNA (at low dose) producing abnormal proteins
Aminoglycosides Resistance
Plasmid-encoded production of transferase enzymes that induced metabolism of drug to inactive products (Enzymes - Acetyltransferases, Phosphotransferases and Adenyltransferases), Impaired entry of drug into cells by alteration of porins or other proteins needed for drug entry, Decrease binding of drug to 30S ribosome
Aminoglycoside + Penicillin
Enterococcal endocarditis
Aminoglycoside
Neutropenic fever (Pseudomonas) following chemotherapy, Medical emergency, Third choice adjuncts
Aminoglycoside + Beta lactam
Klebsiella, Staph. A, Pseudomonas, Meningitis due to Pseudomonas, Also for UTI
Neosporin (Neomycin, Polymyxin B, Bacitracin combination)
Topical skin infections, Sterilize bowel before bowel surgery
Paromomycin (Humatin)
Ameobiasis, Cestodiasis (Tapeworm infection) and Intestinal amebiasis, Hepatic coma, Leishmaniasis
Streptomycin
Bubonic plague, Tularemia, TB
Garamycin
Gram- rods, E.Coli, Pseudomonas, Salmonella, Shigella
Aminoglycosides Pharmacokinetics
Weak bases so may interact chemically with penicillins and cephalosporins if mixed in high concentration in parenteral administration (Chemical interaction), Administered IV as poor absorption from GI, Enters perilymph of inner ear (Toxic) also concentrate in renal cortex - Can be topically absorbed from burns and wounds when used in antibacterials
Aminoglycosides Adverse Effects
Renal damage, Eight nerve toxicity (Damage to vestibular or Cochlear sensitive hair cells) - Accumulate in endolymph and periplymph to damage hair cells - Can occur with fetal exposure in pregnancy; High conc. = Nondepolarizing neuromuscular blockade leading to respiratory paralysis (Compete with Ca++ at presynaptic sites resulting in release of Ach, fail of postsynaptic end plate to depolarize and muscle paralysis)
Fluoroquinolones
Ciprofloxacin (Cipro), Ofloxacin (Floxin), Levofloxacin (Levaquin), Sparfloxacin (Zagam)
Spectrum of Action
Active against aerobic Gram- bacteria, Some active VS Gram+ organisms; Levofloxacin and Sparfloxacin w/ good activity VS Gram+, Useful for URI by common pathogens like H.influenzae, M.cararrhails and Newer agents (Levofloxacin, Gatifloxacin, Trovofloxacin) active VS pneumonia (not Ciprofloxacin, Ofloxacin, Norfloxacin), Prophylaxis and treatment of neutropenic infections, Bone, joint and soft tissue infections, Ciprofloxacin was choice for post-exposure prophylaxis of inhalation anthrax terror attack (2001)
Fluoroquinolone Dental Use
Quinolone Antibiotics - Ciprofloxacin (500mg, BID for 10d) used to treat refractory periodontal infections that contain Actinobacillus actinomycetemcomitans and other Gram-, facultative anaerobic rods; Ciprofloxacin used for orodental infection caused by Pseudomonas, Used for infections caused by susceptible organisms
Fluoroquinolones Mechanism of Action
Bactericidal, Inactivate DNA Gyrase (Topoisomerase II, Gram-) and Topoisomerase IV (Gram+) and promote DNA strand breaks
Fluoroquinolones Resistance
Mutations in DNA gyrase or influx/efflux mechanism
Fluoroquinolone Pharmacokinetics
Well absorbed from GI tract, Chelate metal ions (Which reduce absorption), Well distributed - Except CNS (Ofloxacin and Cipro exceptions when meninges inflame), Eliminated by metabolism and urinary and fecal excretion
Fluoroquinolone Adverse Effects
N,V, abdominal pain, superinfection; Black box warning - Permanent cartilage damage and arthropathy - tendon pain, rupture, tendonitis, Black box warning - myasthenia gravis, Black box warning - neurotoxicity (Peripheral or central neuropathy), dizziness, headache, peripheral neuropathy, restlessness, confusion; Contraindicated in children and pregnancy, Photosensitivity rxn and rashes, Anaphylactic reactions or shock; Have negative effects on fracture repair in animal models (Chondrotoxicity in cartilage of diff animal species), High doses of Quinolones found to cause matrix degeneration and erosion of articular cartilage in juvenile animals (Chondrocytes involved in fracture healing process, Adverse effect on chondrocyte function manifests as decreased mechanical properties of fracture callus
Ciprofloxacin Drug Interations
Inhibits CYP1A2 - Increase Theophylline has a low TI and Increase clozapine - an toxic atypical antipsychotic w/low TI (80%); Inhibit CYP3A4 (Increase Midazolam, Increase Carbamazepine)
Fluoroquinolones Withdrawn
Temafloxacin (Immune hemolytic anemia), Trovafloxacin (Hepatotoxicity), Grepafloxacin (Cardiotoxicity), Cinafloxacin (Phototoxicity)
Sulfonamides and Trimethoprim
Trimethoprim combined with Sulfamethoxazole - Co-trimoxazole TMP-SMX (Bactrin, Septra),
Sulfisoxazole (Gantrisin) and Sulfamethoxazole (Bactrim)-UTI (Alternate agents for bacillus dysentery)
Mefanide (Sulfamylon);
Pyrimethamine + Sulfadiazine - Treat Toxoplasmosis
Sulfacetamide - Ophthalmic
Mafenide and Silver Sulfadiazine - Prevent bacterial colonization of burns
Sulfonamides and Trimethoprim Spectrum of Action
Active against Gram+ and Gram- bacteria some chlamydiae (Ex. Trachoma, Actinomycetes and Pneumocystis), Co-trimoxazole useful for Pneumocystis carinii infections in AIDS patients
Sulfonamides and Trimethoprim Mechanism of Action
Sulfonamides are competitive inhibitors of synthesis of folic acid from p-aminobenzoic acid (PABA), Folic acid synthesis does not occur in humans (Used from diet), Trimethoprim inhibits dihydrofolate reductase in bacteria but not man
DHFR Inhibitors and Sulfonamides
Sulfonamide decreases intracellular conc. of dihydrofolate and increases effectiveness of DHFR inhibitor (Trimethoprim) which outcompetes dihydrofolate for binding to enzyme
Sulfonamides and Trimethoprim Resistance
Common, Combination of TMP-SMX reduces incidence of resistance, Increased synthesis of PABA, Decrease uptake, Increased efflux, Mutation in PABA binding site on dihydropteroate synthase resulting in reduced affinity of enzyme for sulfonamides, Altered dihydrofolate reductase (Trimethoprim)
Sulfonamides and Trimethoprim Pharmacokinetics
Usually administered orally although sulfadiazine is available for parenteral injection, Well absorbed from GI tract except succinylsulfathiazole which is hydrolyzed in bowel to active non-absorbed drug, Well distributed including CSF - Trimethoprim achieves high conc. in prostate, Metabolized mainly by acetylation of p-amino group to inactive toxic N-hydroxy metabolites, Excreted primarily in urine by GF, Rate of excretion varies - Some cases (Sulfamethoxazole) the acetylated metabolite is less soluble in urine than parent drug - Renal damage due to crystalluria (Rare if adequate urine flow), Take with full glass of water to prevent precipitation in kidney
Sulfonamides and Trimethoprim Adverse Effects
Acute hemolytic anemia, primarily in individuals w/G6PD-deficient erythrocytes, Allergic rxns, Skin rashes, Serum sickness; Kernicterus in infants (Displace bilirubin), Rare bone marrow depression, Photosensitivity rxn; Sulfanilamide causes metabolic acidosis by inhibiting carbonic anhydrase (Actetazolamide and other carbonic anhydrase diuretics), Hypoglycemia (sulfonylurea anti diabetics), Goiter in rats (Thiouracil group of antithyroid drugs)
Metronidazole Spectrum of Action
Flagyl Protozoal infections (Amoeba and Giardia - Kills gut bacteria needed for digestion), Anaerobic Gram- (Bacteroides) - C. diff associated diarrhea and colitis, H.pylori infections; Highly effective VS Gram- anaerobic pathogens responsible for acute orofacial infections and chronic periodontitis (ANUG), Combine with beta-lactams for serious infections, Kills spirochetes
Metronidazole Mechanism of Action
Concentration dependent killer, Diffuses into cells and nitro group reduced to metabolites that damage DNA, proteins and membranes, leading to cell death;
Metronidazole Selectivity of Action
Fermentation enzymes of anaerobic organisms and mechanisms of Metronidazole activation - PFOR-Dependent activation and Nitroreductase-Dependent activation: Selectivity of action due to fact anaerobes have enzyme pyruvate ferredoxin oxidoreductase (PFOR) that converts pyruvate to acetyl coA and in process generates reduced ferredoxin, reduced ferredoxin then transfers electrons to Metronidazole which is reduced and therefore active
Anaerobes express nitroreductases that selectively reduce metronidazole, while generating NADP+
Metronidazole Pharmacokinetics
IV and PO reaches all tissue and body fluid - CSF penetration good, even enters abscess
Metronidazole Adverse Effects
Pregnancy C, Safe after 14wks gestation, Rare seizures, Other CNS toxicity, Headache, Neuropathy, Metallic taste, Disulfiram like effect, Pancreatitis
Metronidazole Uses In Dentistry
Highly effective VS Gram- anaerobic pathogens responsible for acute orofacial infections and chronic periodontitis, Used in combination w/beta-lactams for refractory/rapidly progressing periodontitis and serious orofacial infections, Drug of choice for treatment of initial bout of mild or moderate C.difficile associated pseudomembranous colitis
Metronidazole Drug Interactions
Disulfiram effect (Inhibit acetaldehyde dehydrogenase leading to build up of acetaldehyde and symptoms of "hangover" like vomit and nausea with alcohol) - Accumulate alcohol metabolite of metronidazole in patients with renal dysfunction contribute to nephrotoxicity Metronidazole inhibit excretion of lithium which leads to lithium toxicity and renal damage; Mechanism with Warfarin - Increases effect of warfarin by inhibiting CYP2C9, Exists as mix of 2 stereoisomers S(-) and R(+) with S(-) racemate being more potent - Inhibits ring oxidation of only S(-) isomer, Inhibition of warfarin metabolism results in clinically significant drug interaction and increased effectiveness of warfarin, Check INR if antibiotics taken within 2-3days
Metronidazole Prescription
Treat C.diff - 500mg, q8h for 14days, repeat once more if persists
Treat anaerobic infection - 250mg, q6h for 5days with water
