Protein Synthesis Inhibitors (Macrolides + Ketolides) PDF

Pharmacology 3 Protein synthesis inhibitors Part 1: Macrolides + Ketolides Dr. Lina Tamimi Introduction MOA inhibit bacterial protein synthesis by: binding to and interfering with ribosomes. Most are few are bactericidal against bacteriostatic certain organisms...

Pharmacology 3 Protein synthesis inhibitors Part 1: Macrolides + Ketolides Dr. Lina Tamimi Introduction MOA inhibit bacterial protein synthesis by: binding to and interfering with ribosomes. Most are few are bactericidal against bacteriostatic certain organisms Tetracycline and macrolide resistance is common. All may be administered orally, Except for: tigecycline and the streptogramins Macrolides The macrolides are a group of closely related compounds characterized by : macrocyclic lactone ring attached to deoxy sugars. Macrolides are bacteriostatic drugs not appropriate for infections in which bactericidal activity is usually required (meningitis, endocarditis, etc.)  Macrolides are the most used antibiotics in the outpatient setting because ??? Broad spectrum generally and coverage of respiratory pathogens. But….. increasing resistance to these agents (especially in Streptococcus pneumoniae). To combat this resistance, the ketolide derivatives (including telithromycin) have been introduced with better coverage of resistant S.pneumoniae  Macrolides & Ketolides 1- Erythromycin: oral, parenteral, topical  was the first of these drugs to find clinical application  drug of first choice and as an alternative to penicillin in individuals with an allergy to β-lactam antibiotics. 2-Telithromycin: oral  a semisynthetic derivative of erythromycin  The first “ketolide” antimicrobial agent. 3- Azithromycin: oral, parenteral  is derived from erythromycin by addition of a methylated nitrogen into the lactone ring.  Its spectrum of activity, mechanism of action, and clinical uses are similar to those of clarithromycin.  4- Clarithromycin: oral, parenteral  methylated form of Erythromycin but with improved features  Some common features with Azithromycin Spectrum:  Ketolides and macrolides have similar antimicrobial coverage.  Ketolides are active against many macrolide-resistant gram-positive strains.  MOA bind irreversibly to a site on the 50S subunit of the bacterial ribosome translocation steps of protein synthesis. They may also interfere with other steps, such as transpeptidation. Generally considered to be bacteriostatic they may be bactericidal at higher doses. Their binding site is either identical to or in close proximity to that for clindamycin and chloramphenicol. Blocking peptide bond formation  Antibacterial spectrum 1. Erythromycin: is effective against many of the same organisms as penicillin G (Figure 39.10) it may be used in patients with penicillin allergy. The least spectrum than Azithromycin, clarithromycin, and telithromycin 2. Clarithromycin: has activity similar to erythromycin but it is also effective against H. influenzae. Its activity against intracellular pathogens is higher than that of erythromycin. 3. Telithromycin: antimicrobial spectrum similar to that of azithromycin. It neutralizes the most common resistance mechanisms 11  4. Azithromycin: less active against strep. and staph. than Erythromycin active against respiratory infections due to H. influenzae and Moraxella catarrhalis. Extensive use of azithromycin has resulted in growing St. pneumoniae resistance. preferred therapy for urethritis caused by Ch. trachomatis. Myco. avium is preferentially treated with clarithromycin or azithromycin. Against: Atypicals other gram-positive Haemophilus influenzae organisms: Staphylococcus Moraxella catarrhalis aureus (except for Helicobacter pylori methicillin-resistant S. Mycobacterium avium aureus) Therapeutic applications of macrolides Copyright © 2015 Wolters Kluwer All Rights Reserved  Resistance Resistance to macrolides is associated with: (mechanisms): 1) the inability of the organism to take up the antibiotic 2) the presence of efflux pumps 3) decreased affinity of the 50S ribosomal subunit for the antibiotic, resulting from the methylation (methylase-mediated) of an adenine in the 23S bacterial ribosomal RNA in g+ve organisms 4) the presence of plasmid associated erythromycin esterases in g-ve organisms such as Enterobacteriaceae. 14  Resistance to erythromycin has been increasing, thereby limiting its clinical use (particularly for S. pneumoniae). Cross-Resistance clarithromycin and azithromycin with erythromycin But……. telithromycin may be effective against macrolide resistant organisms.  Administration Erythromycin:  erythromycin base is destroyed by gastric acid:  enteric-coated tablets or esterified forms of the antibiotic are administered.  Similar to azithromycin …….. available in IV formulations Pharmacokinetics: 1- Absorption:  All are adequately absorbed upon oral administration (Figure 39.11).  All (except Erythromycin) are stable in stomach acid  Food interferes with the absorption of azithromycin  Food increase the absorption of clarithromycin 2. Distribution: Erythromycin: distributes well to all body fluids except the CSF. It is one of the few antibiotics that diffuses into prostatic fluid and it also accumulates in macrophages.  All four drugs concentrate in the liver.  Clarithromycin, azithromycin, and telithromycin are widely distributed in the tissues. Azithromycin:  concentrates in neutrophils, macrophages, and fibroblasts  serum levels are low.  It has the longest half-life and the largest volume of distribution of the four drugs 17 3. Elimination: Erythromycin and Telithromycin  extensively metabolized hepatically.  They inhibit the oxidation of a number of drugs through their interaction with the cytochrome P450 system. Clarithromycin: Interfere with the metabolism of drugs, such as: theophylline statins numerous antiepileptics 4. Excretion: Erythromycin and azithromycin  are primarily concentrated and excreted in the bile as active drugs  Partial reabsorption occurs through the enterohepatic circulation. Clarithromycin  clarithromycin and its metabolites are eliminated by the kidney as well as the liver.  The dosage of this drug should be adjusted in patients with renal impairment. Adverse effects 1. Gastric distress and motility 2. Cholestatic jaundice particularly erythromycin estolate 3. Ototoxicity 19 Contraindications Patients with hepatic dysfunction should be treated cautiously with: erythromycin, telithromycin, or azithromycin, because these drugs accumulate in the liver. Severe hepatotoxicity with telithromycin has limited its use, given the availability of alternative therapies. macrolides and ketolides may prolong the QTc interval and should be used with caution in those patients with proarrhythmic conditions or concomitant use of proarrhythmic agents. Drug interactions: 1- Erythromycin, telithromycin, and clarithromycin: inhibit the hepatic metabolism of a number of drugs, which can lead to toxic accumulation of these compounds (Figure 39.14). Azithromycin ????? 2- An interaction with digoxin may occur. In this case, the antibiotic eliminates a species of intestinal flora that ordinarily inactivates digoxin, thus leading to greater reabsorption of the drug from the enterohepatic circulation. Pharmacokinetics of selected macrolides Copyright © 2015 Wolters Kluwer All Rights Reserved Macrolides interactions Copyright © 2015 Wolters Kluwer All Rights Reserved  Erythromycin Indications: is a drug of choice in: -corynebacterial infections diphtheria -corynebacterial sepsis -Erythrasma (affects the skin) in folds caused by corynebacterium  Azithromycin Compared with clarithromycin, azithromycin is typically given for a shorter period because ????? 1- long intracellular half-life (40 to 68 hours) 2- slow release from tissue sites. So!!!! for many infections, a once-daily 5-day regimen is as effective as 10-day courses of the other macrolides.  Community-acquired pneumonia can be treated with azithromycin given as : 500-mg loading dose followed by :250-mg single daily dose for the next 4 days. The 2 g extended-release oral suspension of azithromycin: long half-life given as a single dose as it has an even shorter regimen should be taken :one hour before or two hours after food Because it has a 15-member (not 14-member) lactone ring: azithromycin does not inactivate cytochrome P450 enzymes therefore, is free of the drug interactions that occur with erythromycin and clarithromycin. Against: The 1 g packet was designed for single-dose extended-release oral suspension of azithromycin treatment of: non-gonococcal urethritis Chlamydia trachomatis cervicitis. It is mixed in 2 ounces of water immediately before ingesting. Clarithromycin Clarithromycin immediate-release tablets can be taken with or without food clarithromycin extended-release tablets should be administered with food.  Fidaxomicin  a macrocyclic antibiotic with a structure similar to the macrolides; however, it has a unique mechanism of action. MOA  acts on the sigma subunit of RNA polymerase, thereby disrupting bacterial transcription, terminating protein synthesis, and resulting in cell death in susceptible organisms. Against:  very narrow spectrum ----- g+ve aerobes and anaerobes.  staphylococci and enterococci  primarily for its bactericidal activity against Clostridium difficile.  No cross-resistance ????? Due to the unique target site.  Following oral administration, fidaxomicin has minimal systemic absorption and primarily remains within the GIT.  low rate of adverse effects  This is ideal for the treatment of C. difficile infection which occurs in the gut. Side effects : 1. Nausea 2. Vomiting 3. abdominal pain 4. Hypersensitivity reactions including: angioedema, dyspnea, and pruritus  Fidaxomicin should be used with caution in patients with a macrolide allergy as they may be at increased risk for hypersensitivity. Anemia and neutropenia have been observed infrequently.  Clinical indications Against: 1. Azithromycin is preferred over clarithromycin in : outpatients with community-acquired pneumonia who have comorbidities, such as COPD 2. Clarithromycin and azithromycin are the primary agents used to treat: Mycobacterium avium complex infections 3. Upper and lower respiratory tract infections caused by: chlamydia, Atypical mycobacterial infections 4. Traveler’s diarrhea (azithromycin). 5. Clarithromycin is a key component in the treatment of H. pylori–induced GI ulcer disease in combination with other drugs and acid-suppressive agents.  Ketolides: Telithromycin Fatal hepatotoxicity potentially fatal exacerbations of myasthenia gravis visual disturbances. Against: Its FDA-approved indication in mild to moderate community-acquired pneumonia. It is administered as a once-daily dose of 800 mg, which results in peak serum concentrations of approximately 2 mcg/mL. Side effects : It is a reversible inhibitor of the CYP3A4 enzyme system may slightly prolong the QT interval.  CLINDAMYCIN STREPTOGRAMINS CHLORAMPHENICOL OXAZOLIDINONES: 1. Linezolid. Refer to table 2. Tedizolid of summary PLEUROMUTILINS: 1. Lefamulin