Macrolides: A Detailed Overview of Class of Drugs PDF

SYEDA MEMOONA GILLANI Macrolides  The macrolides are a family of safe, bacteriostatic drugs that are generally used in the treatment of community acquired infections.  Erythromycin is the original agent and continues to be used in different ailments. Mechanism of Resistance  Resistance...

SYEDA MEMOONA GILLANI Macrolides  The macrolides are a family of safe, bacteriostatic drugs that are generally used in the treatment of community acquired infections.  Erythromycin is the original agent and continues to be used in different ailments. Mechanism of Resistance  Resistance has limited the use of this class of drugs recently.  Bacteria may be macrolide resistant due to a permeability barrier (enterobacteriaceae).  Active efflux pumps can expel the drug in Gram positive species.  A single step mutation in the 50 rRNA gene can confer high level macrolide resistance in some species.  Finally modification of the 50S rRNA subunit decreases binding of erythromycin. Indications for erythromycin  Bacterial infections of the lungs (chest or lower respiratory tract), eg bronchitis, bronchiectasis, pneumonia.  Whooping cough. Erythromycin may also be prescribed to prevent this infection in people who haven't been vaccinated against whooping cough and who are in close contact with someone who has it.  Bacterial infection of the nasal passages, sinuses or throat (upper respiratory tract infection), eg sinusitis, pharyngitis, laryngitis, tonsillitis.  Bacterial infection of the middle ear (otitis media) or outer ear canal (otitis externa).  Bacterial mouth infections, eg gum disease gingivitis.  Bacterial infection of the eyelids (blepharitis).  Bacterial infections of the skin or soft tissue, eg boils, abscesses, cellulitis, impetigo, erysipelas.  Bacterial infections of the stomach and intestines, eg Campylobacter enteritis.  Inflammation of the urethra due to bacterial infection (urethritis).  Inflammation of the prostate gland due to bacterial infection (prostatitis).  Chlamydia  Syphilis ,Diphtheria, Scarlet fever  Lyme disease  Acne  Usual Adult Dose of Erythromycin  Mild to moderate infection: 250 to 500 mg (base, estolate, stearate) or 400 to 800 mg (ethylsuccinate) orally every 6 hours. Severe infection: 1 to 4 g/day IV in divided doses every 6 hours or by continuous infusion.  Usual Pediatric Dose  Neonatal 50 mg/kg/day orally in divided doses every 6 hours for at least 2 weeks. Clarithromycin indication  Tonsillitis/Pharyngitis  Sinusitis  Bronchitis  Pneumonia  Mycoplasma Pneumonia  Skin and Structure Infection  Helicobacter pylori Infection  Mycobacterium avium-intracellulare - Prophylaxis  Mycobacterium avium-intracellulare - Treatment  Bacterial Endocarditis Prophylaxis  Legionella Pneumonia  Pertussis Prophylaxis  Pertussis Usual Adult Dose  Immediate-release: 500 mg orally every 12 hours for 14 days Extended-release: 1000 mg orally every 24 hours for 14 days  for Helicobacter pylori Infection  -In combination with omeprazole and amoxicillin: Clarithromycin 500 mg orally every 12 hours for 10 days  Usual Pediatric Dose  Immediate-release: 6 months or older: 7.5 mg/kg orally every 12 hours for 10 days Maximum dose: 500 mg/dose Azithromycin indications  Gonococcal Infection – Uncomplicated  Nongonococcal Urethritis  Chlamydia Infection  Cervicitis  Chancroid  Pelvic Inflammatory Disease  Chronic Obstructive Pulmonary Disease Acute  Bronchitis Usual Adult Dose  -Immediate-release: 500 mg orally as a single dose on day 1, followed by 250 mg orally once a day on days 2 to 5 -Extended-release: 2 g orally once as a single dose Parenteral: 500 mg IV once a day as a single dose for at least 2 days, followed by 500 mg (immediate-release formulation) orally to complete a 7- to 10-day course of therapy  Gonococcal urethritis and cervicitis: 2 g orally as a single dose Usual Pediatric Dose  6 months and older: Immediate-release: 10 mg/kg (maximum: 500 mg/dose) orally on day 1, followed by 5 mg/kg (250 mg/dose) orally once a day on days 2 to 5 16 years and older: Parenteral: 500 mg IV once a day as a single dose for at least 2 days, followed by 500 mg (immediate-release formulation) orally to complete a 7- to 10-day course of therapy Pharmacokinetics  Absorption incomplete but adequate from intestine  Inactivated by gastric HCL, hence given as : Enteric coated tablets or ester (stearate, ethyl succinate )  Food delays absorption  Not metabolized and actively secreted in bile ( major route of excretion )  Only 2-5 % is excreted in active form in urine  Widely distributed into most tissues, except the brain and CSF  Cross the placental barrier  Protein binding – 70- 80 % Pharmacokinetics  Acid stable  Food delays absorption but does’nt alter its extent  Metabolized by the liver to 14- hydroxy clarithro. ( active )  Widely distributed, except brain and CSF  Protein binding 40 – 70 %  Excreted in Urine – unchanged 20 – 40 %  Advantage over erythromycin  Lower frequency of GI intolerance  Less frequent dosing ( twice daily ) Azithromycin Pharmacokinetics  Rapidly absorbed from GIT  Food delays absorption  Widely distributed ( extensive tissue distribution ), except CSF  Protein binding 51%  Undergo some hepatic metabolism ( inactive )  Biliary route is the major route of elimination  Only 6% is excreted unchanged in the urine  Half- life approx. 3 days  Advantage over erythromycin & clarithromycin  Once daily dosing Adverse Effects  Erythromycin is significantly more likely to evoke gastrointestinal side effects, largely through stimulation of motility.  Co-administration with food may reduce GI upset.  High intravenous doses of erythromycin or clarithromycin have been associated with hearing loss and QT prolongation.  Allergic reactions, headache, taste disturbance, eosinophilia and hepatotoxicity are an infrequent occurrence with all the macrolides. Drug interactions  Erythromycin and clarithromycin are strong inhibitors of cytochrome P450 3A4 and may result in elevated concentrations of many drugs. Macrolides may be classified into 3 different groups in causing drug interactions.  The first group (e.g. troleandomycin, erythromycins) are those prone to forming nitrosoalkanes and the consequent formation of inactive cytochrome P450- metabolite complexes.  The second group (e.g. josamycin, flurithromycin, roxithromycin, clarithromycin, miocamycin and midecamycin) form complexes to a lesser extent and rarely produce drug interactions.  The last group (e.g. spiramycin, rokitamycin, dirithromycin and azithromycin) do not inactivate cytochrome P450 and are unable to modify the pharmacokinetics of other compounds.  It appears that 2 structural factors are important for a macrolide antibiotic to lead to the induction of cytochrome P450 and the formation in vivo or in vitro of an inhibitory cytochrome P450-iron- nitrosoalkane metabolite complex: ◦ the presence in the macrolide molecules of a non- hindered readily accessible N-dimethylamino group and ◦ the hydrophobic character of the drug.  Erythromycin with;  Clopidogrel: may reduce the metabolic activation of the prodrug clopidogrel and its antiplatelet effects.(inhibition of CYP450 3A4 enzymatic activity, which is responsible for the conversion of clopidogrel to its active metabolite.)  Coadministration leads to increase the plasma concentrations of digoxin. The proposed mechanism is inhibition of the P-glycoprotein-mediated intestinal efflux and/or renal tubular secretion of digoxin.  Coadministration increase the serum concentrations of theophylline, which may result in toxicity. The proposed mechanism is macrolide inhibition of CYP450 3A4, the isoenzyme partially responsible for the metabolic clearance of theophylline.  Coadministration significantly increase the plasma concentrations of ergot derivatives. The mechanism is macrolide inhibition of CYP450 3A4, the isoenzyme responsible for the metabolic clearance of ergotamine and related drugs.  Food may variably affect the bioavailability of different oral formulations and salt forms of erythromycin. The individual product package labeling should be consulted regarding the appropriate time of administration in relation to food ingestion. Grapefruit juice may increase the plasma concentrations of orally administered erythromycin. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruits. Clarithromycin;  Budesonide and clarithromycin; increase the absorption of budesonide into the blood stream. (swelling, weight gain, high blood pressure, high blood glucose, muscle weakness )  Ciprofloxacin together with clarithromycin can increase the risk of an irregular heart rhythm that may be serious and potentially life-threatening.  Clarithromycin may increase the blood levels of alprazolam. This can increase the risk and/or severity of side effects including excessive drowsiness, motor impairment, amnesia, anxiety, hallucinations, and breathing difficulties Azithromycin…..  Atorvastatin: possible increased risk of myopathy when azithromycin given with atorvastatin (serious condition called rhabdomyolysis that involves the breakdown of skeletal muscle tissue)  Coumarins, azithromycin possibly enhances anticoagulant effect of coumarins  Colchicine, azithromycin possibly increases risk of colchicine toxicity—suspend or reduce dose of colchicine (avoid concomitant use in hepatic or renal)  Antacid, absorption of azithromycin reduced by antacids.