broad spectrum antibiotics - drdhriti
DESCRIPTION
A power point presentation on 'Broad Spectrum" antibiotics suitable for undergraduate MBBS level students.TRANSCRIPT
Broad Spectrum Antibiotics – Tetracyclines and Chloramphenicol
Department of Pharmacology NEIGRIHMS, Shillong
Tetracycline - History
American Pharmaceutical Industry: In the 1940’s soil actinomycetes bacteria were systematically
screened for the elaboration of antimicrobial substances
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
Streptomyces bacteria
Stretpomycesaureofaciens
Chlortetracycline
1948
C
O
NH
N
CH3CH3
OO OHOH
CH3OHCl
OH
OH
Streptomyces bacteria
Stretpomycesaureofaciens
Chlortetracycline
1948
New Class of Antibiotic
4 ringed hydronaphthacene nucleus
OO OHOHOH
C
O
NH
N
CH3CH3
OO OHOH
CH3OH
Chlortetracycline(1948)
Cl
OH
OH
C
O
NH
N
CH3CH3
OO OHOH
CH3OH
Tetracycline(1953)
OH
OH
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
Tetracyclines - drugs
• Naturally occuring:– Tetracycline, cholrtetracycline, oxytetracycline
and demeclocycline
• Semisynthetic occurring:– Doxycycline, minocycline, lymecycline,
methacycline and rolitetracycline
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
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
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
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 dangerous
Difference of diarrhoea: Pus cell or RBCs (absent in irritation type)(Doxycycline and Minocycline – less likely to cause diarrhoea)
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)
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)
Tetracyclines - uses
1. 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. Plague 7. Brucellocis: D 200+ R600/day X 6 weeks
Tetracyclines – other uses
Second 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 tularemia
Other uses: UTI, Chloroquine Resistant falciparum adjuvant to quinine, Amoebiasis, Community aquired pneumonia, Acne vulgaris and COPD
Tetracyclines - Precautions
• Pregnancy, lactation and children• Renal and hepatic insufficiency• Expiry Date• With diuretics
• Intrathecal injection
Tetracyclines - MOA
Inhibition of Bacterial Protein Synthesis
Tetracycline Resistance
Efflux pump 30S Ribosome Enzymatic Degradation
Proteins in the cytoplasmchemically degrade
Tetracyclines
RarePlasmid encodes a gene
that produces a membrane based protein thatactively pumps out
tetracyclines
RibosomalProtectionProteins(RPP’s)
Mutation
Cross resistance*Not Minocycline
Chloramphenicol
Streptomyces venezuelae
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
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
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
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
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
Adverse effects
• Irritative effects – Nausea, vomiting, diarrhoea and pain in injection• Bone marrow depression: Notorious causes aplastic anaemia,
agrannulocytosis, thrombocytopenia1. Non dose related (idiosyncratic): genetic basis and unpredictable – long term
leukaemias2. 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
Chloramphenicol - Uses
1. Enteric fever: Mainstay in the past (Resistance)2. Pyogenic meningitis as 2nd line to 3rd generation
cefalosporins – child and allergics– Meningcoccal meningitis and H. influenzae
3. Anaerobic infections – Bact. Fragilis4. Intraocular infections – Endophthalmitis5. Second choice: Brucellosis, UTI, rickettsial
infections, conjunctivitis, external ear infections
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
Remember Adverse Effects and Indications!
Thank you