Broad spectrum antibiotics - drdhriti


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A power point presentation on 'Broad Spectrum" antibiotics suitable for undergraduate MBBS level students.

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  • Fanconi syndrome (also known as Fanconi's syndrome) is a disease of the proximal renal tubulesof the kidney in which glucose, amino acids, uric acid, phosphate and bicarbonate are passed into the urine, instead of being reabsorbed. Fanconi syndrome affects the proximal tubule, which is the first part of the tubule to process fluid after it is filtered through the glomerulus. It may be inherited, or caused by drugs or heavy metals.
  • Broad spectrum antibiotics - drdhriti

    1. 1. Broad Spectrum Antibiotics –Tetracyclines and Chloramphenicol Department of Pharmacology NEIGRIHMS, Shillong
    2. 2. Tetracycline - History American Pharmaceutical Industry: In the 1940’s soil actinomycetes bacteria were systematicallyscreened for the elaboration of antimicrobial substances
    3. 3. 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)• Only Penicillin and Streptomycin available – – Orally effective with wider spectrum of activity – Hence : BROAD SPECTRUM – gm+ve, gm-ve, actinomycetes, rikettsiae and chlamydia
    4. 4. Streptomyces bacteria Stretpomyces aureofaciens 1948 CH3 CH3Chlortetracycline Cl OH CH3 N OH C NH OH OH O OH O O
    5. 5. Streptomyces bacteria Stretpomyces aureofaciens 1948 New Class of AntibioticChlortetracycline 4 ringed hydronaphthacene nucleus OH OH O OH O
    6. 6. CH3 CH3Cl OH CH3 N OH C NH OHOH O OH O O Chlortetracycline (1948)
    7. 7. CH3 CH3 OH CH3 N OH C NH OHOH O OH O O Tetracycline (1953)
    8. 8. Tetracyclines – common properties• Nucleus of 4 rings• Bitter solids and weakly water soluble – HCl salts are more soluble• Aqueous solutions are unstable• Same antimicrobial activity – only minor differences• Newer ones – high lipid solubility and greater potency
    9. 9. Tetracyclines - drugs• Naturally occuring: – Tetracycline, cholrtetracycline, oxytetracycline and demeclocycline• Semisynthetic occurring: – Doxycycline, minocycline, lymecycline, methacycline and rolitetracycline
    10. 10. Available drugs - characters• Tetracycline, oxytetracycline, demeclocycline – Orally given, short acting – Incompletely absorbed from stomach (60-80%) – Primarily excreted through the kidneys• Minocycline, doxycycline, tigecycline – Lipid soluble, parenteral possible, long acting – Completely absorbed from stomach (95-100%) – Excreted through liver
    11. 11. Tetracyclines – Antimicrobial spectrum• Bacteriostatic drugs: originally 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 s. aureus, pyrogens and enterococci• Bacilli (+ve): clostridia, listeria, anthracis etc, but not Mycobacteria• Gm-ve bacilli: Cholerae, Y. pestis, Helicobacter, Brucella etc. but H. Influanzae become insensitive• Enterobacteriocae: resistant and not effective - pseudomonas, klebsiella and salmonella• Enterococci: histolytica and plasmodia
    12. 12. Tetracyclines - Kinetics• Older ones less absorbed – 60-80% but doxy and mino – completely (food interferes)• Chelating property – milk, antacids and iron preparatons• Distribution: wide – Concentrated in liver, spleen and bone & teeth – minocycline in fats – Good CSF penetration• 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 occular preparations
    13. 13. Adverse Effects GI disturbances: Due to Irritation • Mild nausea and diarrhoea to severe, possibly life-threatening colitis and Oesophagitis 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 dangerousDifference of diarrhoea: Pus cell or RBCs (absent in irritationtype)(Doxycycline and Minocycline – less likely to cause diarrhoea)
    14. 14. Adverse Effects – contd. Liver damage: fatty infiltration – oxytetracycline safer; pregnancy – acute hepatic necrosis Kidney damage: accumulates except doxycycline – enhance existing kidney disease  FANCONY LIKE SYNDROME – outdated tetracycline (epitetracycline, anhydrotetracycline and anhydroepitetracycline) – glycosuria, proteinuria and aminoacidria etc. 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  Pregnancy and childhood - Temporary supression of one growth Antianabolic effect: reduction in Protein synthesis Diabetes Insipidus: antagonizes ADH and urine conc. property Vestibular toxicity: Minocycline (ataxia, vertigo, nystagmus)
    15. 15. Toxicity/Contraindications of Tetracyclines• Because drug is deposited in tooth dentine and enamel, brown bands form• Do not give to children or pregnant/nursing women(bone growth, deformities, stature)• Misc. side effects – Thrombophlebitis – Various WBC dystrophies – Increased intracranial pressure in neonates – Hypersensitivity reactions (superinfections)
    16. 16. Tetracyclines - uses1. Empirical therapy2. Rickettsial infections: Rocky Mountain Spotted Fever, All forms of typhus and Q fever (Coxiella burnetii)3. Venereal diseases: • Chlamydial urethritis/endocervicitis: Doxycycline • Lymphogranuloma venereum (Chlamydia trachomatis) • Granulloma inguinale (Klebsiella granulomatis)4. Atypical pneumonia: due to mycoplasma5. Cholera6. Plague7. Brucellocis: D 200+ R600/day X 6 weeks
    17. 17. Tetracyclines – other usesSecond choice drugs: To penicillins for tetanus,anthrax,actinomycosis and listerias To ceftriaxone/amoxy/azithro for gonorrhoea To penicillins for syphilis (allergic to pens) To pens for leptospirosis (doxy 100 mg BD 7 days) To azithromycin for chlamydia pneumonia To ceftriaxone and azithromycin for chancroid To streptomycin for tularemiaOther uses: UTI, Chloroquine Resistant falciparum adjuvant to quinine, Amoebiasis, Community aquired pneumonia, Acne vulgaris and COPD
    18. 18. Tetracyclines - Precautions• Pregnancy, lactation and children• Renal and hepatic insufficiency• Expiry Date• With diuretics• Intrathecal injection
    19. 19. Tetracyclines - MOAInhibition of Bacterial Protein Synthesis
    20. 20. Tetracycline Resistance Cross resistance* Not Minocycline Efflux pump 30S Ribosome Enzymatic Degradation Rare Plasmid encodes a genethat produces a membrane based protein that actively pumps out tetracyclines Ribosomal Mutation Protection Proteins (RPP’s) Proteins in the cytoplasm chemically degrade Tetracyclines
    21. 21. ChloramphenicolStreptomyces venezuelae
    22. 22. 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
    23. 23. 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
    24. 24. 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, entamoeba and plasmodia
    25. 25. 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
    26. 26. Pharmacokinetics• Given orally or parenterally• Wide distribution, including 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 250 mg – 500 mg (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
    27. 27. Adverse effects• Irritative effects – Nausea, vomiting, diarrhoea and pain in injection• Bone marrow depression: Notorious causes aplastic anaemia, agrannulocytosis, thrombocytopenia 1. Non dose related (idiosyncratic): genetic basis and unpredictable – long term leukaemias 2. Dose and duration related – predictable, reversible• 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
    28. 28. Chloramphenicol - Uses1. Enteric fever: Mainstay in the past (Resistance)2. Pyogenic meningitis as 2nd line to 3rd generation cefalosporins – child and allergics – Meningcoccal meningitis and H. influenzae3. Anaerobic infections – Bact. Fragilis4. Intraocular infections – Endophthalmitis5. Second choice: Brucellosis, UTI, rickettsial infections, conjunctivitis, external ear infections
    29. 29. Chloramphenicol - Precautions• Minor infections and undefined etiology• Infections treatable by other AMAs• Avoid repeated courses• Should not use more than 2-3 gms per day, use for less than 2 weeks and total dose should not exceed 28 gms.• Regular peripheral blood smear – reticulocyte count• No combination with other antimicrobials
    30. 30. Remember Adverse Effects and Indications! Thank you