Broad Spectrum Antibiotics

1. BROAD SPECTRUM ANTIBIOTICS TETRACYCLINE & CHLORAMPHENICOL DR. MOHAMMED ABDUL RAOF PHARMACOLOGY(D.C.M.S).

2. STRUCTURE OF TETRACYCLINE STRUCTURE OF TETRACYCLINE TETRACYCLINES have a ring structure: F OUR-CYCLIC-ANTHRACYCLIN Different substitution on ring structure affecting their pharmacokinetics

3. TETRACYCLINE It is a BROAD-SPECTRUM ANTIBIOTIC. O btained from soil actinomycetes. Slightly bitter & weakly water soluble . Discovered by- DR.YELLAPRAGADA SUBBA RAO. TETRACYCLINES have a ring structure: FOUR-CYCLIC-ANTHRACYCLIN Different substitution on ring structure affecting their pharmacokinetics. Consumption of out-dated Tetracycline – Fanconi’s syndrome.

4. CLASSIFICATION OF TETRACYCLINE: GROUP 1: Shorter Acting (t1/2 =6-10 hours) TETRACYCLINE, CHLORTETRACYCLINE OXYTETRACYCLINE GROUP 2: Intermediate Acting(t1/2=12-13 hours) DEMECLOCYCLINE METHACYCLINE GROUP 3: Long Acting(t1/2=18-20 hours) DOXYCYCLINE MINOCYCLINE

5. P harmacodynamics : Tetracycline's are bacteriostatic. The carrier involved in the active transport of tetracycline's are absent in the mammalian 60S/40S cellular ribosomal units, hence they cannot damage host but selectively toxic to the microorganisms only. In Gram positive bacteria's – tetracycline's enter the cytoplasm by an energy-dependent active transport system, once inside the bacterial cell, tetracycline's inhibit the bacterial protein synthesis by binding to their 30S ribosomal subunit and blocking the attachment of t-RNA & m-RNA resulting in the peptide chain growth failure. In Gram negative bacteria's - tetracycline's enter the outer membrane by passive diffusion through their pore channels.

6. The tetracycline's (T) bind to the 30S subunit and prevent binding of the incoming charged tRNA unit. Step 1 in protein synthesis.

7. Pharmacokinetics: Tetracycline's are absorbed from GIT with variable bioavailability Tetracycline's are widely distributed except C.S.F. cross placental barrier excreted in the milk. Tetracycline's are readily deposited in teeth, bones and tumours. Dairy products, antacids & iron preparation's impair tetracycline's absorption either by chelation/altering the gastric PH except doxycycline and minocycline. Tetracycline induces the action of Phenytoin, Warfarin & C hlorpropamide Metabolized in the liver, concentrated in bile and excreted in urine. In renal impairment needs dose adjustment for long acting tetracycline's except Doxycycline .

8. Anti Microbial spectrum : HIGHLY ACTIVE Rickettsia, Chlamydia Psittaci, Chlamydia Trachomatis , Chlamydia Pneumoniae. HIGHLY EFFICACIOUS Spirochete's like - Borrelia burgdorferi, Borrelia recurrentis. HIGHLY SENSITIVE Atypical pathogen like -Mycoplasma pneumoniae, -Ureaplasma urealyticum. Gram -negative bacilli like – Vibrio Cholerae,Brucella abortus Helicobacter pylori, Yersinia pestis Actinomyces israeli,Francisella tularensis .

9. RESISTANCE : Four mechanisms by which an organism develops resistance to tetracycline's- Decreased cell permeability of the drug. Increased drug efflux from bacteria by energy-dependant process. Initiation of ribosomal protection which results in decreased affinity for the drug by ribosomes binding sites. Enzymatic inactivation of the drug. Almost all gram-positive and gram-negative cocci and gram negative bacilli have become resistant. Some gram positive bacilli are inhibited without clinical benefit.

10. CONTRA INDICATIONS : Renal impairment Hepatic insufficiency Pregnancy Lactation in Children’s less than 10years of age . Intraathecial injections should be avoided. 12/14/2012 10

11. CLINICAL USES & DOSES: TREATMENT DISEASE CONTROL USES/DOSES FIRST CHOICE Rocky mountain fever, Typhus fever, Relapsing fever, Psittacosis, Lyme disease, Atypical pneumonia. Group1 : 250mg QID oral/iv Group 2:300mg BID ora l Group 3:100mg BID oral/iv EFFECTIVE Brucellosis,H.Pylori, Tularaemia,Plague, Bacteraemia,Acne v, Abscesses,Trachoma,Non specific urethritis / cervicitis,Chronic Amoebiasis,Resistant malaria. Tetracycline in combination with Streptomycin/ Bactrim DS/Amoxicillin. ERADICATION OF CARRIER STATE Meningococcal, swimming pool granuloma, Anthrax. Minocycline 100mg BID oral for 5days

12. Precautions During pregnancy and lactation Avoided in patients on diuretics Renal/hepatic insufficiency Avoid preparation beyond expiry date Do not mix injectable TC with penicillin-inactivation occurs. Do not inject tetracycline's Intra- thecally . 12/14/2012 12

13. ADVERSE EFFECTS : ROUTE OF ADMINISTRATION ADVERSE EFFECTS ORAL ADMINISTRATION Nausea, Vomiting, Epigastric burning, diarrhoea, Stomatitis, Chronic fungal Esophagitis, Inhibit intestinal flora . I.V. ADMINISTRATION Thrombophlebitis. I.M. ADMINISTRATION Painful local irritation OINTMENTS Painful local irritation & sensitization. CHRONIC ADMINISTRATION Super infections , Stomatitis, Chronic fungal esophagitis, temporary suppression of bone growth, Staining of teeth, Headache, Pseudotumour cerebri,Vestibular toxicity, Anti-anabolic effects , Minocycline photosensitivity, Hepatotoxicity in pregnancy, Cumulative renal toxicity in impaired renal functions,Demeclocycline induced nephrogenic diabetes insipidus.

14. CHLORAMPHENICOL It is a NATURALLY OCCURING BROAD-SPECTRUM ANTIBIOTIC largely bacteriostatic isolated from STREPTOMYCES VENEZUELAE. It is yellowish white crystalline light-sensitive & intense bitter in taste. CHLOROMYECTIN posses a NITRO GROUP AS NITROBENZENE MOIETY which is responsible for its anti-bacterial property. Chloramphenicol is active against a wide range of Gram-negative organisms, Gram positive organisms and serious anaerobic infection. Chloramphenicol is used topically for treating conjunctivitis and external ear infections. Chloramphenicol was earlier drug of choice for typhoid fever.

15. P harmacodynamics : Chloramphenicol is bacteriostatic in low doses and bactericidal in high doses . MOA : inhibits bacterial protein synthesis by binding to the 50S ribosomal subunit. In Gram positive bacteria-enter the cytoplasm by an energy-dependent active transport system, tetracycline's inhibit the bacterial protein synthesis by binding to 50S ribosomal subunit and blocking the attachment of t-RNA & m-RNA resulting in the peptide chain growth failure. In Gram negative bacteria’s-enter the outer membrane by passive diffusion through pores.

16. Chloramphenicol (C) and macrolides (M) bind to the 50S ribosomal subunit and block transpeptidation Step 2 in the bacterial protein synthesis .

17. Pharmacokinetics : Chloramphenicol on oral administration rapidly and completely absorbed from GIT. Chloramphenicol widely distributed throughout the body tissues and fluids including C.S.F . Crosses placental barriers & also present in breast milk. Metabolized in the liver by Glucuronyl conjugation, concentrated in bile or excreted in urine. Plasma half-life is 3-5 hours. Paracetamol increases the bioavailability. Chloramphenicol is a potent enzyme inhibitor, inhibits the metabolism of morphine, w arfarin,..

18. Anti Microbial spectrum : HIGHLY ACTIVE Salmonella typhi, Haemophilus influenza, Neisseria meningitides, Streptococcus pneumonia, Penicillin-resistant Bacteroides fragilis. SENSITIVE Spirochetes', Rickettsia, Mycoplasma, Klebsiella, Chlamydia.

19. RESISTANCE : Three mechanisms by which a bacteria develops resistance to C hloramphenicol- Decreased cell permeability of the drug. Initiation of ribosomal protection which results in decreased affinity for the drug by ribosomes binding sites. Production of R-plasmid as well as chromosomal mediated chloramphenicol acetyltransferase that metabolizes chloramphenicol to an inactive form. CONTRA INDICATIONS : Renal impairment, Hepatic insufficiency, Pregnancy, N eonates, blood forming diseases.

20. ADVERSE EFFECTS : Chloramphenicol induces bone marrow depression and aplasia, use is no longer . SEVERE / FATAL Idiosyncratic Aplastic anaemia –It is unrelated to the dose has a genetic cause. Gray baby syndrome –neonates cannot conjugate chloramphenicol, slow GFR can lead to fatal neonatal toxicity. Super-infection. REVERSIBLE Dose related bone marrow depression when daily doses exceeds 3-4gram/day for more than 1-2weeks.Recovery after 3-6weeks of Discontinuation of treatment. IRRITABLE EFFECTS Nausea, Vomiting, Diarrhoea, Pain on injection.

21. As an clinician our advice to the patients:

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