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ANTIBIOTICS Presented by Dr.Pavan kumar.G P.G.STUDENT CONTENTS TERMINOLOGY HISTORY OF ANTIBIOTICS RATIONALE OF DRUG USE PATTERNS OF MISUSE DRUG LEGISLATIONS CLASSIFICATION OF AMAS BACTERIAL GROWTH CURVE MODUS OPERANDI OF AMAS PRINCIPLES OF ANTIBIOTIC DOSING DRUG RESISTANCE SULFONAMIDES COTRIMOXAZOLE FLOUROQUINOLONES CEPHALOSPORINS CHLORAMPHENICOL AMINOGLYCOSIDES MACROLIDES MISCELLANEOUS ANTIBIOTICS ANTI FUNGALS &ANTI VIRAL DRUGS PENICILLINS TETRACYCLINES METRONIDAZOLE ANTIBIOTIC FAILURES NON-EFFECTIVE CONDITIONS IN DENTISTRY NEWER ANTI-MICROBIAL APPROACHES ANTIBIOMA BIBILOGRAPHY PHARMACOLOGY & THERAPEUTICS FOR DENTISTRY - Yagiela. Dowd. Neidle 5th edition ESSENTIALS OF MEDICAL PHARMACOLOGY - K.D.Tripathi 5th edition TEXTBOOK OF MICROBIOLOGY - R.Ananthanarayan & C.K.J.Paniker ORAL & MAXILLOFACIAL INFECTIONS - Topazian 4th edition MICROBIOLOGY AN INTRODUCTION - Tortora,Funke,Case 8th edition TERMINOLO GY ANTIBIOTICS-Substances produced by micro organisms which suppress the growth of or kill other micro organisms at very low concentrations. ANTI MICROBIAL AGENTS Substances produced synthetically as well As naturally obtained drugs that attenuate micro organisms. CHEMOTHERAPY Treatment of systemic infections with specific drugs that selectively suppress the infecting microorganisms without significantly affecting the host. DRUG Single active chemical entity present in medicine that is used for diagnosis,prevention,treatment/cure of a disease. HISTORY PERIOD OF EMPIRICAL USE Use of mouldy curd by chinese on boils Chaulmoogra oil by hindus in leprosy Chenopodium by aztecs for intestinal worms Mercury by paracelsus for syphilis Cinchona bark for fevers EHRLICHS PHASE OF DYES & ORGANOMETALLICS (1890-1935) If dyes could selectively stain microbes,they could be selectively toxic also. Atoxyl for sleeping sickness. Arsphenamine &norarsphenamine for syphilis EHRLICH also coined the term “Chemotherapy”. MODERN ERA It was in 1929 that ALEXANDER FLEMING by serendipity elaborated penicillin from the mould of P.notatum. DOMAGK in 1935 demonstrated the therapeutic effect of PRONTOSIL a sulfonamide dye. But it was from 1939-41when CHAIN & FLOREY carried on the studies of Fleming which culminated in the use of penicillins. In 1940s WAKSMAN & colleagues developed streptomycin from actinomycetes. THIS IS THE MOST DRUGGED GENERATION THE MYTH A PILL TO CURE EVERY ILL RATIONALE OF DRUG USE Need Aim Knowledge Route & dosage Alternatives Duration Observations Elimination Unwanted effects Precautions Contraindications Patients point if view Patient PATTERNS OF MISUSE They are used as “drugs of fear” to cover for potential errors of omission or commission & thereby prevent a claim of negligence. In many cases they are given to prevent infection & to ensure that was done to avoid later criticism. Inappropriate use of antibiotics in dentistry include *Antibiotic therapy initiated after surgery to prevent infection * Failure to use prophylactic antibiotics * As analgesics in endodontics *Overuse in situations in which pts are not at risk for metastatic infections. *Treatment of chronic adult periodontitis almost totally amenable to mechanical therapy. *Administration instead of mechanical therapy for periodontitis. * Long term administration in th management of periodontal disease. *Antibiotic therapy instead of incision & drainage. *Administrations to avoid claims of negligence. * Administrations in improper situations, dosage & duration of therapy. DRUG LEGISLATIONS Under the perview of CHEMICAL & PETROLEUM MINISTRY. But drug controller (Dept. of health & family welfare) possesses the power over the drug & the manufacturer. Various drug acts include Poisons act of 1919 Dangerous drugs act of 1930 Drug & magic remedies act of 1945 Drugs & cosmetics act of 1940 amended in 1955,60,62, 64,72 &1982. BACTERIAL GROWTH CURVE ANTIBIOTIC MECHANISM OF ACTION Inhibition of cell wall synthesis. Alteration of cell membrane integrity. Inhibition of ribosomal protein synthesis. Suppression of DNA synthesis. Inhibition of folic acid synthesis. PRINCIPLES OF ANTIBIOTIC DOSING M.I.C Conc. Dependent v/s time dependent antibiotics Post antibiotic effects (PAE) Microbial persistence & regrowth Dosing & resistance Antibiotic loading dose Duration & antibiotic dosing MICROBIAL DRUG RESISTANCE Enzymatic inactivation Modification/protection of target sites Altered cell membrane permeability Active drug efflux Failure to activate the drug Use of alternate growth requirements Over production of target sites q In addition drug resistance can also occur by MUTATION or GENE TRANSFER SULFONAMIDES First AMA effective against pyogenic infections. Sulfonamides still of clinical interest are Short acting (4-8hrs) sulfadiazine Intermediate acting (8-12hrs) sulfamethoxazole,etc Long acting (7days) sulfadoxine Special purposes sulfacetamide sod.,mafenide, silver sulfadiazine ANTI BACTERIAL SPECTRUM Primarily bacteriostatic agent against many gram+ve & gram_ve bacteria. Organisms still sensitive are St.pyogenes,H.influenzae,H.ducreyi,E.coli, V.cholera,Chalydiae,Actinomyces,Nocardia & Toxoplasma. PHARMACOKINETICS Rapidly & completely absorbed from GIT. PPB ranges from 10-95%. Crosses placenta freely. Primarily metabolised in liver by ACETYLATION. Excreted by kidney through glomerular filtration Good penetrability into brain & CSF. USES Suppressive therapy of chronic UTI. Streptococcal pharyngitis. Second drug of choice in LGV. In combination with Trimethoprim for many bacterial infections,p.carinii,etc. Sulfacetamide sol. (10-30%) for trachoma / inclusion conjunctivitis. Topical Silver sulfadiazine or Mafenide are used for preventing infections on burn surfaces. ADVERSE EFFECTS Nausea,vomitting & epigastric pain. Crystalluria is dose related. Hypersensitivity reactions in 2-5% pts.stevens-johnson syn & Exfoliative dermatitis are more common with long acting agents. Topical use is usually not recommended due to contact sensitization. COTRIMOXAZOLE Combination of TRIMETHOPRIM & SULFAMETHOAZOLE in the ratio of 1:20. Both are static but the combination is cidal in action. Combination is because of similar t1/2 of 10hrs. SPECTRUM: Active against S.typhi, Serratia, Klebsiella, Enterobacteria, P.carinii and many sulfonamide resistant strains. USES: UTI Specially valuable in chronic & recurrent cases & in prostitis. RTI like chronic bronchitis, facio maxillary infections & otitis media. Second DOC in typhoid. Bacterial diarrheas & dysentry. Chancroid (800mg+160mg BD/7 days) is one of the DOC. Granuloma inguinale alternative to doxycycline/ erythromycin. P.carinii prophylactic as well as therapeutic. ADVERSE EFFECTS: Rarely folate deficiency. Contraindicated in pregnancy as trimethoprim being an antifolate has teratogenic risk. Neonatal hemolysis & Methemoglobinemia can occur. Uremia in patients with renal diseases. Bone marrow hypoplasia in AIDS pt. For P.carinii infection. Cotrimoxazole + Diuretics cause higher incidence of Thrombocytopenia. FLOUROQUINOLONES FIRST GENERATION Cinoxacin Oxolinic acid Nalidixic acid SECOND GENERATION Lomefloxacin Ciprofloxcin Norfloxacin Ofloxacin Levofloxacin FLOUROQUINOLONES 3RD GENERATION Gatifloxacin Sparfloxacin Grepafloxacin Pazufloxacin 4th GENERATION Clinafloxacin Gemfloxacin Mofifloxacin Trovafloxacin CIPROFLOXACIN Inhibits the enzyme bacterial DNA gyrase which nicks double stranded DNA introduces _ve supercoils & then reseals the nicked ends. FQ action is similar to Topoisomerase IV . This damaged DNA is phagocytosed by exonucleases. SPECTRUM Most susceptible are aerobic, gram_ve bacilli especially Enterobacteriaceac, Neisseria, E.coli, S.typhi, K.pneumoniae, H.influenzae, H.ducreyi,V.cholera, Staph.aureus, P.aeruginosa, B.anthracis, M.tuberculosis, etc. Remarkable microbiological features of ciprofloxacin & other FQs include Rapidly bactericidal & highly potent. Relatively long PAE. Low freq. Of mutational resistance Protective streptococci & anaerobes are spared Active against B- lactams & aminoglycoside resistant bacteria Less active against acidic pH. PHARMACOKINETICS: Rapidly absorbed orally but food delays absorption. First pass metabolism occurs. High tissue penetrability. Excreted primarily in urine. INTERACTIONS: Plasma conc.of Theophylline, caffiene, & warfarin are increased by C.floxacin. NSAIDs may enhance CNS toxicity. Antacids, Sucralfate, & Fe salts if given concurrently reduce absorption. USES: UTIs Gonorrhoeas Chacroid 500mg/BD/3 days . Excellent alt. To Cotrimoxazole. . CONTD ADVERSE EFFECTS: GIT symptoms like Nausea, Vomitting, Bad taste. CNS dizziness, headache, anxiety, insomnia,impairment of concentration and dextereit. (CAUTION WHILE DRIVING). FIRST CHOICE DRUGS IN Typhoid Bone, soft tissue, gynecological & wound infections Diabetic foot In combination therapy for T.B CEPHALOSPORINS 1st generation Cefazolin Cephalexin Cefadroxil Cephradine Cephalothin* 2nd generation Cefuroxime Cefaclor Cefoxitin* 3rd generation Cefotaxime Cefoperaxone Ceftriaxone Ceftazidime Cefixime Cefdinir 4th generation Cefepime Cefpirome CEPHALOSPORINS 1st gen developed in 1960s have high activity against gram+ve bacteria. 2nd gen more active against gram_VE with some active against anaerobes. 3rd gen Introduced in 1980s, have highly augmented action against gram_ve enterobactericeac, B-lactamases, less active on gram+ve cocci. 4th gen developed in 1990s spectrum of action similar to 3rd gen. Highly effective in nosocomial pneumonia, febrile neutropenia, bacterimia, septicemia,etc. EVOLUTION OF CEPHALOSPORINS USES 1ST gen are used as alterntives to penicillin G. UTI & RTIs Penicillinase producing staphylococcal infections.Cephalothin is the DOC. May be combined with aminoglycosides in septicemias. 1st gen cephalosporins are used in surgical prophylaxis. Ceftazidime + Gentamicin for Pseudomonas meningitis. Ceftriaxone is the first DOC in gonorrhea caused by penicillinase producing m.o As alternative to FQs in typhoid, especially in children. 3rd gen cephalosporins are used in treatment of infections of neutropenic pts. ADVERSE EFECTS: Pain after i.m is very common. Hypersensitivity reactions similar to penicillins. Nephrotoxicity is highest with cephaloridine. A +ve coombs test occurs but hemolysis is rare. A disulfiram like reaction with alcohol has been reported with Cefoperaxone. CHLORAMPHENICOL Initially obtained from St.venezuelae in 1947. Has a nitrobenzene substitution. Inhibits bacterial protein synthesis by binding to 50s. SPECTRUM Primarily static but cidal at high conc. & against H.influenzae. A broad spectrum AMA. PHARMACOKINETICS Rapidly & completely absorbed orally. 50-60% PPB & t1/2 of 3-5 hrs. Crosses placenta & secreted in bile & milk. Undergoes glucoronic acid conjugation in liver & excreted in urine. INTERACTIONS Inhibits metabolism of Tolbutamide, Chlorpropamide, Warfarin, Phenytoin and Cyclophosphamide. Phenobarbitone, Phenytoin, Rifampin enhance the metabolism. USES Second choice drug in enteric fever. H.influenzae meningitis 50-75mg/kg/day/2weeks. Prefferred drug for intraocular infections like endopthalmitis. Topically effective in conjunctivitis, external ear infections. AS SECOND CHOICE DRUG TO TETRACYCLIN