New Mansoura University Pharmacology III-Lecture (4) PDF

New Mansoura University Faculty of Pharmacy Pharm D Program __________________________________________________________ _________________ pharmacology-iii & Biostatistics Protein Synthesis Inhibitors 2...

New Mansoura University Faculty of Pharmacy Pharm D Program __________________________________________________________ _________________ pharmacology-iii & Biostatistics Protein Synthesis Inhibitors 2 Lecture(3)  Macrolides and Ketolides The macrolides are a group of antibiotics with a macrocyclic lactone structure to which one or more deoxy sugars are attached. Erythromycin was the first of these drugs to have clinical application, both as a drug of first choice and as an alternative to penicillin in individuals with an allergy to β-lactam antibiotics. Clarithromycin and azithromycin have some features in common with, and others that improve upon, erythromycin. Te l i t h r o m y c i n , a s e m i s y n t h e t i c d e r i v a t i v e o f erythromycin, is a “ketolide” antimicrobial agent.  Macrolides and Ketolides v Mechanism of action The macrolides and ketolides bind irreversibly to a site on the 50S subunit of the bacterial ribosome, thus inhibiting 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.  Macrolides and Ketolides v Antibacterial spectrum 1. Erythromycin This drug is effective against many of the same organisms as penicillin G; therefore, it may be considered as an alternative in patients with penicillin allergy. 2. Clarithromycin Clarithromycin has activity similar to erythromycin, but it is also effective against Haemophilus influenzae and has greater activity against intracellular pathogens such as Chlamydia, Legionella, Moraxella, Ureaplasma species, and Helicobacter pylori.  Macrolides and Ketolides v Antibacterial spectrum 3. Azithromycin Although less active than erythromycin against streptococci and staphylococci, azithromycin is far more active against respiratory pathogens such as H. influenzae and Moraxella catarrhalis. Extensive use of azithromycin has resulted in growing Streptococcus pneumoniae resistance. 4. Telithromycin Telithromycin has an antimicrobial spectrum similar to that of azithromycin. Moreover, the structural modification within ketolides neutralizes the most common resistance mechanisms that render macrolides ineffective. Macrolides and Ketolides  Macrolides and Ketolides v Resistance Resistance to macrolides is associated with: 1) the inability of the organism to take up the antibiotic, 2) the presence of efflux pumps, 3) a decreased affinity of the 50S ribosomal subunit for the antibiotic in gram-positive organisms, and 4) the presence of erythromycin esterases in gram-negative organisms such as the Enterobacteriaceae. Erythromycin has limited clinical use due to increasing resistance. Both clarithromycin and azithromycin share some cross-resistance with erythromycin. Telithromycin may be effective against macrolide-resistant organisms.  Macrolides and Ketolides v Pharmacokinetics 1. Absorption The erythromycin base is destroyed by gastric acid; thus, either enteric-coated tablets or esterified forms of the antibiotic are administered and all have adequate oral absorption. Clarithromycin, azithromycin, and telithromycin are stable in stomach acid and are readily absorbed. Food interferes with the absorption of erythromycin and azithromycin but can increase that of clarithromycin. Telithromycin is administered orally without regard to meals. Erythromycin and azithromycin are available in IV formulations.  Macrolides and Ketolides v Pharmacokinetics 2. Distribution Erythromycin distributes well to all body fluids except the CSF. It is one of the few antibiotics that diffuse 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, and serum concentrations are low. It has the largest volume of distribution of the four drugs.  Macrolides and Ketolides v Pharmacokinetics 3. Elimination Erythromycin, azithromycin and telithromycin undergo hepatic metabolism. They are also excreted in the bile. Partial reabsorption occurs through the enterohepatic circulation. In contrast, clarithromycin is hepatically metabolized, and the active drug and its metabolites are mainly excreted in the urine. The dosage of this drug should be adjusted in patients with renal impairment. They inhibit the oxidation of a number of drugs through their interaction with the cytochrome P450 system. Interference with the metabolism of drugs such as theophylline, statins, and numerous antiepileptics has been reported for clarithromycin.  Macrolides and Ketolides v Adverse effects 1. Gastric distress and motility Gastrointestinal upset is the most common adverse effect of the macrolides and may lead to poor patient compliance (especially with erythromycin). The other macrolides seem to be better tolerated. Higher doses of erythromycin lead to smooth muscle contractions that result in the movement of gastric contents to the duodenum, an adverse effect sometimes employed for the treatment of gastroparesis or postoperative ileus. 2. Cholestatic jaundice This adverse effect occurs most commonly with the estolate form of erythromycin; however, it has been reported with other formulations and other agents in this class.  Macrolides and Ketolides v Adverse effects 3. Ototoxicity Transient deafness has been associated with erythromycin, especially at high dosages. Azithromycin has also been associated with irreversible hearing loss. 4. QTc prolongation 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.  Macrolides and Ketolides v 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. v Drug Interactions Erythromycin, telithromycin, and clarithromycin inhibit the hepatic metabolism of a number of drugs, which can lead to toxic accumulation of these compounds. An interaction with digoxin may occur. One theory to explain this interaction is that the antibiotic eliminates a species of intestinal flora that ordinarily inactivates digoxin, leading to greater reabsorption of digoxin from the enterohepatic circulation.  Fidaxomicin Fidaxomicin is a macrocyclic antibiotic with a structure similar to the macrolides; however, it has a unique mechanism of action. Fidaxomicin acts on the sigma subunit of RNA polymerase, thereby disrupting bacterial transcription, terminating protein synthesis and resulting in cell death in susceptible organisms. Fidaxomicin has a very narrow spectrum of activity limited to gram-positive aerobes and anaerobes. While it possesses activity against staphylococci and enterococci, it is used primarily for its bactericidal activity against Clostridium difficile. Because of the unique target site, cross-resistance with other antibiotic classes has not been documented.  Fidaxomicin Following oral administration, fidaxomicin has minimal systemic absorption and primarily remains within the gastrointestinal tract. This is ideal for the treatment of C. difficile infection, which occurs in the gut The most common adverse effects include nausea, vomiting, and abdominal pain. Anemia and neutropenia have been observed infrequently. Hypersensitivity reactions including angioedema, dyspnea, and pruritus have occurred. Fidaxomicin should be used with caution in patients with a macrolide allergy, as they may be at increased risk for hypersensitivity.  Chloramphenicol The use of chloramphenicol, a broad-spectrum antibiotic, is restricted to life-threatening infections for which no alternatives exist. v Mechanism of action Chloramphenicol binds reversibly to the bacterial 50S ribosomal subunit and inhibits protein synthesis at the peptidyl transferase reaction. Because of some similarity of mammalian mitochondrial ribosomes to those of bacteria, protein and ATP synthesis in t h e s e o rga n e l l e s m ay b e i n h i b i te d a t h i g h c i rc u l a t i n g chloramphenicol concentrations, producing bone marrow toxicity.  Chloramphenicol v Antibacterial spectrum Chloramphenicol is active against many types of microorganisms including chlamydiae, rickettsiae, spirochetes, and anaerobes. The drug is primarily bacteriostatic, but it may exert bactericidal activity depending on the dose and organism. v Resistance Resistance is conferred by the presence of enzymes that inactivate chloramphenicol. Other mechanisms include decreased ability to penetrate the organism and ribosomal binding site alterations.  Chloramphenicol v Pharmacokinetics Chloramphenicol is administered intravenously and is widely distributed throughout the body. It reaches therapeutic concentrations in the CSF. Chloramphenicol primarily undergoes hepatic metabolism to an inactive glucuronide, which is secreted by the renal tubule and eliminated in the urine. Dose reductions are necessary in patients with hepatic and/or renal dysfunction. Chloramphenicol is also secreted into breast milk and should be avoided in breastfeeding mothers.  Chloramphenicol v Adverse effects 1. Anemias Patients may experience dose-related anemia, hemolytic anemia (observed in patients with glucose-6-phosphate dehydrogenase deficiency), and aplastic anemia. Aplastic anemia is independent of dose and may occur after therapy has ceased.  Chloramphenicol v Adverse effects 2. Gray baby syndrome Neonates have a low capacity to glucuronidate the antibiotic, and they have underdeveloped renal function, which decreases their ability to excrete the drug. This leads to drug accumulation to concentrations that interfere with the function of mitochondrial ribosomes, causing poor feeding, depressed breathing, cardiovascular collapse, cyanosis (hence the term “gray baby”), and death. Adults who have received very high doses of chloramphenicol may also exhibit this toxicity. v Drug interactions Chloramphenicol inhibits some of the hepatic mixed-function oxidases, preventing the metabolism of drugs such as warfarin and phenytoin, which may potentiate their effects.  Clindamycin Clindamycin (lincosamides) has a mechanism of action that is similar to that of the macrolides. Clindamycin is used primarily in the treatment of infections caused by gram-positive organisms, including MRSA and streptococcus, and anaerobic bacteria. Resistance mechanisms are the same as those for erythromycin, and cross-resistance has been described. C. difficile is resistant to clindamycin, and the utility of clindamycin for gram-negative anaerobes (for example, Bacteroides sp.) is decreasing due to increasing resistance.  Clindamycin Clindamycin is available in both IV and oral formulations, but use of oral clindamycin is limited by gastrointestinal intolerance. It distributes well into all body fluids but exhibits poor entry into the CSF. Clindamycin undergoes extensive oxidative metabolism to active and inactive products and is excreted into bile and urine. Accumulation has been reported in patients with either severe renal impairment or hepatic failure. Low urinary excretion of active drug limits its clinical utility for urinary tract infections. In addition to skin rash, the most common adverse effect is diarrhea, which may represent a serious pseudomembranous colitis caused by overgrowth of C. difficile.  Quinupristin/Dalfopristin Quinupristin/dalfopristin is a mixture of two streptogramins in a ratio of 30 to 70, respectively. Due to significant adverse effects, this combination drug is normally reserved for the treatment of severe infections caused by vancomycin-resistant Enterococcus faecium (VRE) in the absence of other therapeutic options. v Mechanism of action Each component of this combination drug binds to a separate site on the 50S bacterial ribosome. They prevent the elongation of peptide chains. Thus, they synergistically interrupt protein synthesis. The combination drug has bactericidal activity against most susceptible organisms and has a long PAE.  Quinupristin/Dalfopristin v Resistance Enzymatic processes commonly account for resistance to these agents. In some cases, the enzymatic modification can change the action from bactericidal to bacteriostatic. An active efflux pump can also decrease levels of the antibiotics in bacteria. v Pharmacokinetics Quinupristin/dalfopristin is available intravenously. It does not achieve therapeutic concentrations in CSF. Both compounds undergo hepatic metabolism, with excretion mainly in the feces.  Quinupristin/Dalfopristin v Adverse effects Venous irritation commonly occurs when quinupristin/dalfopristin is administered through a peripheral rather than a central line. Hyperbilirubinemia occurs in about 25% of patients, resulting from a competition with the antibiotic for excretion. Arthralgia and myalgia have been reported when higher doses are administered. Quinupristin/dalfopristin inhibits the cytochrome P450 CYP3A4 isoenzyme, and concomitant administration with drugs that are metabolized by this pathway may lead to toxicities.  Oxazolidinones Linezolid and tedizolid are synthetic oxazolidinones developed to combat gram- positive organisms, including resistant isolates such as MRSA, VRE, and penicillin- resistant streptococci. v Mechanism of action Linezolid and tedizolid bind to the bacterial 23S ribosomal RNA of the 50S subunit, thereby inhibiting the formation of the 70S initiation complex and translation of bacterial proteins. Like other agents that interfere with bacterial protein synthesis, linezolid and tedizolid are bacteriostatic; however, linezolid has bactericidal activity against streptococci. Because they are bacteriostatic, the oxazolidinones are not recommended as first-line treatment for MRSA bacteremia. Linezolid is an alternative to daptomycin for infections caused by VRE. Oxazolidinones  Oxazolidinones v Resistance Resistance primarily occurs via reduced binding at the target site. Reduced susceptibility and resistance have been reported in S. aureus and Enterococcus sp. v Pharmacokinetics Linezolid and tedizolid are well absorbed after oral administration. IV formulations are also available. These drugs distribute widely throughout the body. Although the metabolic pathway of linezolid has not been fully determined, it is known that it is metabolized via oxidation to two inactive metabolites. The drug is excreted both by renal and nonrenal routes. Tedizolid is metabolized by sulfation, and the majority of elimination occurs via the liver, and drug is mainly excreted in the feces. No dose adjustments are required for either agent for renal or hepatic dysfunction.  Oxazolidinones v Adverse effects The most common adverse effects are gastrointestinal upset, nausea, diarrhea, headache, and rash. Thrombocytopenia has been reported, usually in patients taking the drug for longer than 10 days. Irreversible peripheral neuropathies and optic neuritis causing blindness have been associated with greater than 28 days of use, limiting utility for extended-duration treatments. Linezolid and tedizolid possess nonselective monoamine oxidase inhibitory activity and may lead to serotonin syndrome if given concomitantly with large quantities of tyramine- containing foods, selective serotonin reuptake inhibitors, or monoamine oxidase inhibitors. The condition is reversible when the drug is discontinued. Q1: The mechanism of action of macrolides involves: a) Inhibition of DNA gyrase b) Binding to the 50S ribosomal subunit c) Inhibition of cell wall synthesis d) Disruption of the cell membrane Q2: Which of the following macrolides is most associated with causing gastrointestinal motility issues? a) Erythromycin b) Clarithromycin c) Azithromycin d) Telithromycin Q3: Telithromycin is classified as a: a) Macrolide b) Ketolide c) Lincosamide d) Oxazolidinone Q4: Which macrolide has the highest tissue concentration, particularly in macrophages and fibroblasts? a) Erythromycin b) Clarithromycin c) Azithromycin d) Telithromycin Q5: Fidaxomicin is primarily used to treat: a) MRSA infections b) Clostridioides difficile infections c) Pseudomonas infections d) Legionella infections Q6: Which of the following drugs is associated with Gray baby syndrome? a) Erythromycin b) Fidaxomicin c) Chloramphenicol d) Azithromycin Q7: The most serious adverse effect of clindamycin is: a) Nephrotoxicity b) Pseudomembranous colitis c) Hepatotoxicity d) Ototoxicity Q8: Quinupristin/dalfopristin is primarily used for infections caused by: a) MRSA b) VRE c) Pseudomonas aeruginosa d) Clostridioides difficile Q9: A major adverse effect of prolonged linezolid use is: a) Nephrotoxicity b) Thrombocytopenia and optic neuritis c) Hepatotoxicity d) Pulmonary fibrosis Q10: Which of the following drugs should be avoided in breastfeeding mothers? a) Clarithromycin b) Linezolid c) Chloramphenicol d) Azithromycin thank you