Tetracycline and Chloramphenicol

Pharmacology of tetracycline and chloramphenicol

1. Tetracycline and Chloramphenicol - Broad Spectrum Antibiotics

2. Tetracycline - History American Pharmaceutical Industry: In the 1940’s soil actinomycetes were systematically screened for the elaboration of antimicrobial substances

3. Broad spectrum – Why ?? Name given as they contrasted to the existing Antibiotics - Only Penicillin and Streptomycin (1944) available Orally effective Wider spectrum of activity – gm+ve cocci gm+ve bacilli including anerobes (Clostridia) gm- ve bacilli including anerobes ( Vibrio cholerae , H. pylori, Brucella etc.) Spirochaetes (T. paalidum ) Rickettsiae and chlamidiae Entamoeba Histiolytica and Plasmodia

4. Tetracyclines A class of antibiotics named for their nucleus of four (“tetra-”) hydrocarbon rings All are obtained from soil actinomycetes 1948 first one – chlortetracycline (aureomycin) – S. aureofaciens (Yellow coloured colony) Oxytetracycline from S. rimosus (1950) Tetracycline (1953)

5. Tetracyclines - drugs Naturally occuring: Tetracycline, cholrtetracycline, oxytetracycline and demeclocycline Semisynthetic occurring: Doxycycline, minocycline , tigecycline , lymecycline, methacycline and rolitetracycline

6. Available drugs - characters Tetracycline, oxytetracycline, demeclocycline Lower potency (250-500 mg tid ) Orally given, short acting (t 1/2 – 6-8 Hrs) Incompletely absorbed from stomach (60-80%) Primarily excreted through the kidneys Minocycline , doxycycline, tigecycline Higher potency (100 - 200 mg) Lipid soluble, long acting (t 1/2 – 18-24 Hrs) Completely absorbed from stomach (95-100%) Excreted through liver

7. Tetracyclines - MOA Inhibition of Bacterial Protein Synthesis by binding to 30S ribosomes – aminoacyl -t-RNA to mRNA-ribosome complex – interfered Why do not affect host cells ? – transport and sensitivity

8. Tetracyclines - MOA Inhibition of Bacterial Protein Synthesis

9. Resistance Develops slowly in graded manner Tetracycline concentrating mechanism lessens Efflux pump Plasmid mediated synthesis of “protection protein” Tetracycline inactivating enzyme Cross resistance

10. Tetracyclines – Antimicrobial spectrum Bacteriostatic drugs: o riginally all types of organisms except viruses and fungi – Both, gm+ve and gm-ve bacteria, Rickettsiae, Chlamydia, Mycoplasma, actinomycetes and some protozo Cocci: All +ve and –ve cocci S. pneumoniae, gonococi, meningitidis are sensitive. Resistance developed to Staph aureus , pyrogens and enterococci Bacilli (+ve): clostridia, listeria, anthracis etc, but not Mycobacteria Enterobacteriocae : resistant and not effective - pseudomonas, klebsiella and salmonella

11. Tetracyclines - Kinetics Older ones less absorbed – 60-80% (food interferes) but doxy and mino – completely Chelating property – milk, antacids and iron preparations Distribution: wide and variable protein binding (different members) Concentrated in liver, spleen and bone & teeth – minocycline in fats Good CSF penetration 1/4 th of plasma) – no relation with inflammation Excretion: Primarily in urine (dose adjustment in renal failure) Doxycycline is exception (bile) Preparations: Oral capsules, ½ to 2 Hrs pre and post food No IM: painful (oxy and tetra available) Also cream, ointment and ocular etc. preparations – high risk of sensitization

12. Adverse Effects GI disturbances: Due to Irritation Mild nausea and diarrhoea to severe, possibly life-threatening colitis and Oesophageal ulcer etc. Superinfection: Disturbances in the normal flora (Diabetics) Candidiasis (oral and vaginal ) – soreness and redness of mouth black hairy tounge and inflammatory lesions in vulva, vagina etc. Staphylococcal enteritis (S. aureus) – hospitalized patients – loss of appetite, abdominal discomfort and watery diarrhoea, Pseudomembranous colitis - C . difficile (profuse diarrhoea and fever) – Rare but dangerous Difference of diarrhoea: Pus cell or RBCs (absent in irritation type) ( Doxycycline and Minocycline – less likely to cause diarrhoea)

13. Toxicity – contd. Liver damage: fatty infiltration Kidney damage: accumulates except doxycycline Phototoxicity : Sunburn like - Skin rashes, mainly after topical application Erythema, brown black discolouration of nails and loosening etc. Doxycycline and demeclycline - more Teeth and Bones: Brown discolouration - Calcium tetracycline chelate (orthophosphate) Deciduous teeth – ill formed and prone to carries teeth Affect the crown of permanent anterior dentition Pregnancy and childhood - Temporary supression of Bone growth Antianabolic effect: reduction in Protein synthesis Diabetes Insipidus: antagonizes ADH and urine conc

14. Tetracyclines - uses Empirical therapy: Mixed Infections Rickettsial infections: Rocky Mountain Spotted Fever, All forms of typhus and Q fever ( Coxiella burnetii ) Atypical pneumonia: due to mycoplasma. Brucellosis : D 200+ R600/day X 6 weeks Plague : Bubonic and Pneumonic plague

15. Tetracyclines – other uses Other uses: UTI , Chloroquine Resistant falciparum adjuvant to quinine , Amoebiasis, Community aquired pneumonia, Acne vulgaris and COPD

16. Chloramphenicol Streptomyces venezuelae

17. Chloramphenicol ( streptomyces venezuelae ) A natural product (contains a nitrobenzene moiety) Now all are synthetic products Yellowish white crystalline solid Stable aqueous solution Nitrobenzene – antibacterial activity

18. Chloramphenicol - MOA Binds to 50S ribosomal subunit Prevents peptide bonds from forming and blocking proteins synthesis Bacteriostatic - Effective against a wide variety of organisms Mainly like tetracycline - +ve, -ve, Rikettsiae and mycoplasma Generally used as drug of last resort for life-threatening infections

19. Chloramphenicol – Differences with Tetracycline Highly effective against S. typhi (RESISTANT NOW) More effective against H. influenzae, B. pertissis, N. menigitidis Less active against gm+ve cocci and spirochaetes Not effective against – chlamydia, entmoeba and plasmodia

20. Resistance - chloramphenicol High incidence of Resistance due to indiscriminate use in the past – developing countries Resistant strains of S. typhi developed due to transfer of R plasmid. R Plasmid mediated-formation of acetyl- transferases that inactivate the drug Acetyl – chloramphenicol does not bind to ribosomes Other mechnisms – decreased permeability (passive and facilitated diffusion) Lowered affinity of ribosomes to chloramphenicol

21. Pharmacokinetics Given orally or parenterally Wide distribution – serous cavities and CSF Present in bile, milk, and placental fluid Conjugated in liver (glucoronic acid) Cirrhotics & neonates have low conjugating ability Little is excreted unchanged in urine T1/2 = 3-5 hrs Available as capsules 250mg – 500mg (maximum dose 28 gm in a course of less than 2 weeks) Also as inj. 0.25, 0.5 and 1 g per vial Eye drops 0.4% and ear drops

22. Adverse effects Irritative effects – Nausea, vomiting, diarrhoea and pain in injection Bone marrow depression: Notorious causes aplastic anaemia, agrannulocytosis, thrombocytopenia Hypersensitive effects – Rashes, fever, glossitis and angioedema Gray Baby Syndrome: (2-9 days after dose of 100mg/kg) Within 24 hours, baby starts to vomit, stops eating, rapid and irregular respiration, abdominal distension, periods of cyanosis, and pooping loose green stool Baby then turns ashen gray and becomes flaccid and hypothermic Also can occur in adults who are cirrhotics Death in 40% of cases (CVS collapse) Due to Inability to metabolised & excrete chloramphenicol

23. Chloramphenicol - Uses Enteric fever: Mainstay in the past meningitis as 2 nd line to 3 rd generation cefalosporins – child and allergics Meningcoccal meningitis and H. influenzae Anaerobic infections – Bact. Fragilis Intraocular infections – endophthalmitis Second choice : brucellosis , UTI, rickettsial infections, conjunctivitis , external ear infections

24. Remember Adverse effects and Resistance! - Preserve Thank you