1TETRACYCLINES AND CHLORAMPHENICOL Bacteriostatic NOT bactericidalTetracyclinesSumycin®Tetracyn®Panmycin® etcActisite® dental applications. *Bacterial active transport system which requires energyPGCMPorinsEnergy-dependentActive transport sysEntryI. Mechanism of antimicrobial activity:Tetracyclinecompetes with tRNA for the A site on 30s ribosomeII. Bacterial SusceptibilitiesMore active against Gram (+) than Gram (-) i.e.Haemophilus ducreyi, Brucella, Vibrio cholerae etc Effective agnst Anerobic/ facultative bactActinomyces, Rickettsia, Chamydia spp., spirochaetes and some protozoa (amoeba). Minocycline is also effective against N.meningitidis2III. Resistance to antimicrobial activity:Cross-resistance among Tetra depend on resistance mechanismsFluxEnzymeTetR protection proteinIV. Absorption, Distribution and ExcretionChlor < oxy/deme/tetra< doxy< mino (100%)Dairy productsaluminum hydroxide gels,calcium and magnesium salts iron preparationsIncomplete oral absorptions absorbed in empty stomach from stomach and upper small intestineImpairs absorptionChelateaccumulate in:dentine and enamel of unerupted teethreticuloendothelial cells of liver, spleen, bone marrow and boneready accessible to most tissuescross placental barrier and enter fetal circulation and amniotic fluidhigh concentration can appear in milksignificant concentrations found in CSF after I.V.doxycycline can be of value in treating patients with impaired renal functionprimary route of elimination is glomerular filtration except doxycycline (fecal)Therapeutic UseRickettsial infections (i.e. Rocky Mountain spotted fever, typhus, Q fever)Mycoplasma infectionsChlamydia infectionsTrachomaAnthraxBrucellosis (Tetra + rifampin/streptomycin)CholeraAcne (Tetra)DOXYCYCLINESide Effects:GI irritation lessen by concurrent food intake Photosensitivity (Sun burn) more particularly with demeclocycline and doxycyclineMinocycline can produce dose-related vestibular disturbances such as dizziness and nauseahepatic toxicity: Oxytetra and tetra (Pregnant woman more susceptible)renal toxicity: All but less with doxycycline3High doses of tetracycline can decrease protein synthesis in the host cells- an anti-anabolic effectdiscoloration of teeth in children; can effect the baby of pregnant patientsdrug interaction with penicillin's (do not use concurrently)Superinfection with yeast or resistant pathogenic bacteria may occur Summary•Doxycycline, most important member, broad spectrumSTDs, rickettsial infections, plague, brucellosis, RTI, Minocycline: Skin and soft tissue infections•Enter by porins/active transport sys in an energy-dependent Manner•Inhibit tRNA binding to A site•Bact develop resistance by generating ribsosomal protection protein, altering fluxes, enzyme inactivation•Inactivation by Chelating agents•GI irritation, Discoloration of teeth, photosensitivity, hepatic and renal toxicity Chloramphenicol (Chloromycetin) I. Mechanism:Chloramphenicolcan also block mitochondrial protein synthesisin mammalian cells, especially in erythropoetic cellsInhibits transferasesRapidly penetrates in bact cell (facilitative)II. Because of potential toxicity, only use in well defined and indicated conditions.III. Antibacterial activity•Broad; Gram (-) e.g., H. influenzae (bacteriocidal), N.meningitidis • anaerobic bacteria • Gram (+) cocci; clostridium •Gram(-) rods: E. coli, V. cholerae, Shingella, Chlamydia and Mycoplasma• not effective against pseudomonas, histolylica, Entamoeba4IV. Resistance:FluxAcetyl transferasesChloRibosomal mutationchloramphenicol succinate used for parenteral administrationV. Absorption, Distribution and Excretionparent drug readily absorbed in GI tractprodrug (chloramphenicol palmitate) hydrolyzed in duodenumreadily accessible to tissues and bodily fluidshigh concentration achieved in brainenters CSF at therapeutic concentrationsPresent in bile, milk, and placental fluidmetabolized in liver and inactive glucuronide metabolite excreted in urinecaution in treating patients with hepatic cirrhosisVI. Therapeutic use of Chloramphenicoli. Typhoid feverii. Bacterial Meningitisiii. Certain anaerobic infectionsiv. Riskettsial diseases, e.g., epidemic, murine, scrub and recrudescent typhus, Rocky Mountain spotted fever and Q feverv. Brucellosis (tetracycline-sensitive patients)(ONLY WHEN OTHER REGIME FAILS)VII. Untoward effectsHematological toxicity: most importantReduced generation of RBCAplastic anemiairreversible idiosynchratic reactionsHaematopoetic systemBone marrowMitoLeukemia5Neonatal toxicity: "gray baby syndrome"interferes with iron metabolismGlucuronyl transferase renal sec Chloramphenicol toxicityVIII. Drug InteractionsHepatic CYPsIncreased half life of: Warfarin, dicumarol, antiretroviral protease inhibitors etcChloramORConcurrent administration of phentobarbitalCYPsDecreasedhalf life of ChloramSummary•rarely used in US, Europe due to toxicity•Developing nations still use it: cheap and treat broad range of infections•Enters bact by facilitative transport•Inhibits transferases•Bact develops resistance by altering permeability of drug, ribosomal mutation, generation of acetyl transferases•Induces hematological toxicity, gray baby syndrome alternative names in many different countries:Alficetyn®Amphicol®Biomicin®Chloromycetin® (U.S., intravenous preparation) Chlorsig® (U.S., eye drops) Fenicol®Kemicetine® (UK, intravenous preparation) Laevomycetin®Phenicol®Nevimycin®Tifomycine® (France, oily chloramphenicol)
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