Bacterial protein synthesis inhibitors

1. Bacterial protein synthesis inhibitors Haitham Mahmood Alwali Ph.D Pharmacology Al-Nahrain College of Medicine Haitham Alwali

2. The mechanisms of protein synthesis in microorganisms are not identical to those of mammalian cells. Bacteria have 70S ribosomes, whereas mammalian cells have 80S ribosomes. Differences exist in ribosomal subunits and in the chemical composition and functional specificities of component nucleic acids and proteins. Such differences form the basis for the selective toxicity of these drugs against microorganisms. Haitham Alwali

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4. Chloramphenicol, tetracyclines, and the aminoglycosides were the first inhibitors of bacterial protein synthesis to be discovered. and most of these drugs are now used for more selected targets. • Erythromycin, an older macrolide antibiotic, has a narrower spectrum of action but continues to be active against several important pathogens. • Newer inhibitors of microbial protein synthesis, which include streptogramins, linezolid, telithromycin, and tigecycline have activity against certain bacteria that have developed resistance to older antibiotics. Haitham Alwali

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6. MECHANISMS OF ACTION • Most of the antibiotics are bacteriostatic inhibitors of protein synthesis acting at the ribosomal level • With the exception of tetracyclines, the binding sites for these antibiotics are on the 50S ribosomal subunit. • Chloramphenicol inhibits transpeptidation (catalyzed by peptidyltransferase) by blocking the binding of the aminoacyl moiety of the charged transfer RNA (tRNA) molecule to the acceptor site on the ribosome-messenger (mRNA) complex. Haitham Alwali

7. Macrolides, telithromycin, and clindamycin, which share a common binding site on the 50S ribosome, also block transpeptidation. • Tetracyclinesbind to the 30S ribosomal subunit preventing binding of amino acid-charged tRNA to the acceptor site of the ribosome-mRNA complex. • Streptogramins are bactericidal acting by inhibiting tRNA synthetase activity, leading to a decrease in free tRNA within the cell. Haitham Alwali

8. Linezolidis mainly bacteriostatic. The drug binds to a unique site on the 50S ribosome, inhibiting initiation by blocking formation of the tRNA-ribosome-mRNA ternary complex. • Chloramphenicol does not bind to the 80S ribosomal RNA of mammalian cells, although it can inhibit the functions of mitochondrial ribosomes, which contain 70S ribosomal RNA. • Tetracyclines have little effect on mammalian protein synthesis because an active efflux mechanism prevents their intracellular accumulation. Haitham Alwali

9. CHLORAMPHENICOL A. Classification and Pharmacokinetics • Chloramphenicol has a simple and distinctive structure, and no other antimicrobials have been discovered in this chemical class. • It is effective orally as well as parenterally and is widely distributed, readily crossing the placental and blood-brain barriers. • Chloramphenicol undergoes enterohepatic cycling, and a small fraction of the dose is excreted in the urine unchanged. Most of the drug is inactivated by a hepatic glucuronosyltransferase. Haitham Alwali

10. B. Antimicrobial Activity • Chloramphenicol has a wide spectrum of antimicrobial activity and is usually bacteriostatic. Some strains of Haemophilusinfluenzae, Neisseria meningitidis, and Bacteroides are highly susceptible, and for these organisms chloramphenicol may be bactericidal. • It is not active against Chlamydia species. • Resistance to chloramphenicol, which is plasmid-mediated, occurs through the formation of acetyltransferases that inactivate the drug. Haitham Alwali

11. C. Clinical Uses Because of its toxicity, chloramphenicol has very few uses as a systemic drug. • It is a backup drug for severe infections caused by Salmonella species and for the treatment of pneumococcal andmeningococcal meningitis in beta-lactam-sensitive persons. • Chloramphenicol is sometimes used for rickettsial diseasesand for infections caused by anaerobes such as Bacteroidesfragilis. • The drug is commonly used as a topical antimicrobial agent Haitham Alwali

12. D. Toxicity 1. GIT disturbances—occur from direct irritation and from superinfections, especially candidiasis. 2. Bone marrow—Inhibition of red cell maturation. This action is dose-dependent and reversible. Aplastic anemia is a rare idiosyncratic reaction (approximately 1 case in 25,000–40,000 patients treated). It is usually irreversible and may be fatal. 3. Gray baby syndrome—occurs in infants and is characterized by decreased RBCs, cyanosis, and cardiovascular collapse. 4. Drug interactions—Chloramphenicol inhibits hepatic drug metabolizing enzymes Haitham Alwali

13. TETRACYCLINES A. Classification Drugs in this class are broad-spectrum bacteriostatic antibiotics with minor differences in their activities. B.Pharmacokinetics • Oral absorption is variable, and may be impaired by foods and multivalent cations (calcium, iron, aluminum). • Tetracyclines have a wide tissue distribution and cross the placental barrier. All the tetracyclinesundergo enterohepaticcycling. • The half-lives of doxycycline and minocycline are longer than those of other tetracyclines. • Tigecycline, formulated only for IV use, is eliminated in the bile and has a half-life of 30–36 h. Haitham Alwali

14. C. Antibacterial Activity Tetracyclines activity against species of Rickettsia, Chlamydia, Mycoplasma, and some protozoa. • Resistance mechanisms include the development of mechanisms (efflux pumps) for active extrusion of tetracyclines and the formation of ribosomal protection proteins that interfere with tetracycline binding. • These mechanisms do not confer resistance to tigecycline, with the exception of the multidrug efflux pumps of Proteus and Pseudomonas species. Haitham Alwali

15. D. Clinical Uses of Tetracyclines • Primary uses—are recommended in the treatment of infections caused by Mycoplasma pneumoniae (in adults), chlamydiae, rickettsiae, vibrios, and some spirochetes. • Secondary uses—Tetracyclines are alternative drugs in the treatment of syphilis. also used in the treatment of respiratory infections caused by susceptible organisms, for prophylaxis against infection in chronic bronchitis, and in the treatment of acne. Haitham Alwali

16. 3. Selective uses— • Specific tetracyclines are used in the treatment of gastrointestinal ulcers caused by Helicobacter pylori (tetracycline), • In Lyme disease (doxycycline), and in the meningococcal carrier state(minocycline). • Doxycyclineis also used for the prevention of malaria and in the treatment of amebiasis. • Demeclocycline inhibits the renal actions of antidiuretic hormone (ADH) and is used in the management of patients with ADH-secreting tumors. Haitham Alwali

17. 4. Tigecycline—derivative of minocycline include a broad spectrum of action that includes organisms resistant to standard tetracyclines. • The antimicrobial activity of tigecyclineincludes gram-positive cocci resistant to methicillin (MRSA strains) and vancomycin (VRE strains), beta-lactamase–producing gram-negative bacteria, anaerobes, chlamydiae, and mycobacteria. The drug is formulated only for intravenous use. Haitham Alwali

18. E. Toxicity • GIT disturbances mild nausea and diarrhea to severe, possibly life-threatening enterocolitis. Disturbances in the normal flora may lead to candidiasis (oral and vaginal) • Bony structures and teeth—Fetal exposure to tetracyclines may lead to tooth enamel dysplasia and irregularities in bone growth. Usually contraindicated in pregnancy. Treatment of younger children may cause enamel dysplasia and crown deformation. Haitham Alwali

19. 3. Hepatic toxicity—High doses of tetracyclines, especially in pregnant patients and those with preexisting hepatic disease, may impair liver function and lead to hepatic necrosis. 4. Renal toxicity—One form of renal tubular acidosis, Fanconi’s syndrome, has been attributed to the use of outdated tetracyclines. 5. Photosensitivity—Tetracyclines, especially demeclocycline, may cause enhanced skin sensitivity to ultraviolet light. 6. Vestibular toxicity—Dose-dependent reversible dizziness and vertigo have been reported with doxycycline and minocycline. Haitham Alwali

20. MACROLIDES A. Classification and Pharmacokinetics The macrolide antibiotics (erythromycin, azithromycin, and clarithromycin) • The drugs have good oral bioavailability, but azithromycinabsorption is impeded by food. • Erythromycin(via biliary excretion) t1/2 2hr and clarithromycin (via hepatic metabolism) t1/2 6hr • Azithromycin is eliminated slowly (half-life 2–4 d), mainly in the urine as unchanged drug. Haitham Alwali

21. B. Antibacterial Activity • Erythromycin has activity against many species of Campylobacter, Chlamydia, Mycoplasma, Legionella, gram-positive cocci. • Azithromycin is also effective in gonorrhea, as an alternative to ceftriaxone,and in syphilis, as an alternative to penicillin G. • Resistance to the macrolides in gram-positive organisms involves efflux pump mechanisms and the production of a methylase that adds a methyl group to the ribosomal binding site. Haitham Alwali

22. C. Clinical Uses Erythromycin is effective in the treatment of infections caused by M pneumoniae, Corynebacterium, Campylobacter jejuni, Chlamydia trachomatis, Chlamydophilapneumoniae, Legionella pneumophila, Ureaplasmaurealyticum, and Bordetella pertussis. The drug is also active against gram-positive cocci (but not penicillin-resistant Streptococcus pneumoniae [PRSP] strains) and beta-lactamase– producing staphylococci (but not methicillin-resistant S aureus [MRSA] strains). Haitham Alwali

23. Azithromycin has a similar spectrum of activity but is more active against H influenzae, Moraxella catarrhalis, and Neisseria. • Clarithromycin has almost the same spectrum of antimicrobial activity and clinical uses as erythromycin. The drug is also used for prophylaxis against and treatment of M avium complexand as a component of drug regimens for ulcers caused by H pylori. • Fidaxomicin has proved to be as effective as vancomycin for the treatment of C difficile colitis, possibly with lower relapse rate. Haitham Alwali

24. D. Toxicity • Adverse effects, especially with erythromycin, include gastrointestinal irritation (common) via stimulation of motolinreceptors, skin rashes, and eosinophilia. • A hypersensitivity-based acute cholestatic hepatitis may occur with erythromycin estolate. Hepatitis is rare in children, but there is an increased risk with erythromycin estolatein the pregnant patient. • Erythromycininhibits several forms of hepatic cytochrome P450 and can increase the plasma levels of many drugs, including anticoagulants, carbamazepine, cisapride, digoxin, and theophylline. Similar drug interactions have also occurred with clarithromycin, but not with azithromycin. Haitham Alwali

25. TELITHROMYCIN • Telithromycin is a ketolide structurally related to macrolides. • The drug can be used in community-acquired pneumonia including infections caused by multidrug-resistant organisms. • Telithromycinis given orally once daily and is eliminated in the bile and the urine. • The adverse effects of telithromycin include hepatic dysfunction and prolongation of the QTcinterval • The drug is an inhibitor of the CYP3A4 drug-metabolizing system. Haitham Alwali

26. CLINDAMYCIN A. Classification and Pharmacokinetics • Clindamycin inhibits bacterial protein synthesis via a mechanism similar to that of the macrolides. • Gram-negative aerobes are resistant because of poor penetration of clindamycin through the outer membrane. • Cross-resistance between clindamycin and macrolides is common. • Good tissue penetration occurs after oral absorption. Clindamycin undergoes hepatic metabolism, and both intact drug and metabolites are eliminated by biliary and renal excretion. Haitham Alwali

27. B. Clinical Use and Toxicity • The main use of clindamycin is in the treatment of severe infections caused by certain anaerobes such as Bacteroides. • Clindamycin is active against community-acquired strains of methicillin-resistant S aureus) and is recommended for prophylaxis of endocarditis in valvulardisease patients who are allergic to penicillin. • The drug is used in combination with pyrimethamine for AIDS-related toxoplasmosis. • The toxicity of clindamycin includes gastrointestinal irritation, skin rashes, neutropenia, hepatic dysfunction, and possible superinfections such as C difficile pseudomembranous colitis. Haitham Alwali

28. STREPTOGRAMINS • Quinupristin-dalfopristin, a combination of 2 streptogramins, is bactericidal and has a duration of antibacterial activity longer than the half-lives of the 2 compounds (postantibiotic effects). • Antibacterial activity includes penicillin-resistant pneumococci, methicillin-resistant (MRSA) and vancomycin-resistant staphylococci (VRSA. • Administered intravenously, the combination product may cause pain and an arthralgia-myalgia syndrome. • Streptogramins are potent inhibitors of CYP3A4 and increase plasma levels of many drugs Haitham Alwali

29. LINEZOLID The first of a novel class of antibiotics (oxazolidinones), • linezolid is active against drug-resistant gram-positive cocci, including strains resistant to penicillins (eg, MRSA, PRSP) and vancomycin (eg, VRE). The drug is also active against L monocytogenes and corynebacteria. • Linezolid is available in both oral and parenteral formulations • The drug is metabolized by the liver and has an elimination half-life of 4–6 h. • Thrombocytopenia and neutropenia occur, most commonly in immunosuppressed patients. Haitham Alwali

30. Aminoglycosides MODES OF ANTIBACTERIAL ACTION • Aminoglycosides effectiveness results from a concentration-dependent killing action. As the plasma level is increased above the MIC, aminoglycosides kill an increasing proportion of bacteria. • Many antibiotics, including penicillins and cephalosporins, cause time dependent killing of microorganisms. Haitham Alwali

31. Aminoglycosides are also capable of exerting a postantibiotic effect such that their killing action continues when their plasma levels have declined below measurable levels. • The toxicity of aminoglycosides depends both on a critical plasma concentration and on the time that such a level is exceeded. • These concepts form the basis for once-daily aminoglycoside dosing protocols, which can be more effective and less toxic than traditional dosing regimens. Haitham Alwali

32. PHARMACOKINETICS • Aminoglycosides are structurally related amino sugars attached by glycosidic linkages. • They are polar compounds, not absorbed after oral administration, and must be given intramuscularly or intravenously for systemic effect. • They have limited tissue penetration and do not readily cross the blood-brain barrier. Glomerular filtration is the major mode of excretion. • With normal renal function, the elimination half-life of aminoglycosides is 2–3 h. • Dosage adjustments must be made in renal insufficiency to prevent toxic accumulation. Haitham Alwali

33. MECHANISM OF ACTION • Aminoglycosides are bactericidal inhibitors of protein synthesis. Their penetration through the bacterial cell dependent on oxygen-dependent active transport( they have minimal activity against strict anaerobes). Aminoglycoside entry can be enhanced by cell wall synthesis inhibitors, which may be the basis of antimicrobial synergism. • Aminoglycosides bind to the 30S ribosomal subunit and interfere with protein synthesis in at least 3 ways: • they block formation of the initiation complex; • cause misreading of the code on the mRNA template; • they inhibit translocation (Figure 45–1). Haitham Alwali

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35. MECHANISMS OF RESISTANCE • Streptococcus pneumoniae, and enterococci are relatively resistant to aminoglycosides owing to failure of the drugs to penetrate into the cell. • Mechanism of resistance involves the plasmid mediated formation of inactivating enzymes. These enzymes are group transferases that catalyze the acetylation of amine functions on the aminoglycoside. • For example, transferases produced by enterococcican inactivate amikacin, gentamicin, and tobramycinbut not streptomycin. • Resistance to streptomycin, which is common, appears to be due to changes in the ribosomal binding site. Haitham Alwali

36. CLINICAL USES: • Gentamicin, tobramycin, and amikacinare important drugs for the treatment of serious infections caused by aerobic gram-negative bacteria, including Escherichia coli and Enterobacter, Klebsiella, Proteus, Providencia, Pseudomonas, and Serratia species. • Also for Haemophilusinfluenzae, Moraxella catarrhalis, and Shigella(not drugs of choice) • When used alone, aminoglycosides are not effective in the treatment of infections caused by gram-positive cocci ( used in combination with cell wall inhibitors ) Haitham Alwali

37. Streptomycin in combination with penicillinsis often more effective in enterococcalcarditisthan regimens that include other aminoglycosides. This combination is also used in the treatment of tuberculosis, plague, and tularemia. Other aminoglycosides are usually effective in these conditions. • Multidrug-resistant strains of Mycobacterium tuberculosis that are resistant to streptomycin may be susceptible to amikacin. Because of the risk of ototoxicity, streptomycin should not be used when other drugs will serve. Haitham Alwali

38. Owing to their toxic potential, neomycin and kanamycin are usually restricted to topical or oral use (eg, to eliminate bowel flora). • Netilmicin has been used for treatment of serious infections caused by organisms resistant to the other aminoglycosides. • Spectinomycin is an aminocyclitol related to the aminoglycosides. Its sole use is as a backup drug, administered IM as a single dose for the treatment of gonorrhea, most commonly in patients allergic to beta-lactams. Haitham Alwali

39. TOXICITY A. Ototoxicity • Auditory or vestibular damage (or both) may occur with any aminoglycoside and may be irreversible. Auditory impairment is more likely with amikacin and kanamycin; vestibular dysfunction is more likely with gentamicin and tobramycin. • Ototoxicity risk is proportional to the plasma levels. Ototoxicity may be increased by the use of loop diuretics. Because ototoxicity has been reported after fetal exposure, the aminoglycosides are contraindicated in pregnancy . Haitham Alwali

40. B. Nephrotoxicity Renal toxicity usually takes the form of acute tubular necrosis,which is often reversible, is more common in elderly patients. Gentamicin and tobramycin are the most nephrotoxic. C. Neuromuscular Blockade: A curare-like block may occur at high doses of aminoglycosides and may result in respiratory paralysis. D. Skin Reactions Allergic skin reactions may occur in patients, Neomycin is the agent most likely to cause this. Haitham Alwali