AMA3 - Std Copy PDF - Antimicrobial Drugs

Name cell wall synthesis inhibitors Name 2 anti pseudomonal penicillin Name a narrow spectrum penicillin How can you prevent antibacterial resistance Name 2 betalactamase inhibitors....

Name cell wall synthesis inhibitors Name 2 anti pseudomonal penicillin Name a narrow spectrum penicillin How can you prevent antibacterial resistance Name 2 betalactamase inhibitors. Clinical importance. Name 2 cephalosporine. Spectrum of different generation cephalosporine 11/22/2024 Dr. Nazmun@AIMST 1 11/22/2024 2 Antimicrobial agents 3: Macrolides and Aminoglycosides Dr. Nazmun Nahar Alam  Specific Learning outcomes At the end of the lecture, students should be able to List the macrolide antibiotics and state their mechanism of action, therapeutic uses, and adverse effects. List the aminoglycoside antibiotics and state their mechanism of action, therapeutic uses, adverse effects and contraindications. Discuss the rationale and indications for AMA combinations. Discuss 'synergism and antagonism' of antimicrobial combinations with examples 11/22/2024 Dr. Nazmun@AIMST 4  Macrolides Macrolides Contain a macro cyclic lactone ring to which deoxy sugars are attached. Macrolides are: Erythromycin (Prototype), from natural source. Clarithromycin (Semi synthetic derivatives of erythromycin) Azithromycin (Semi synthetic derivatives of erythromycin) Clindamycin 11/22/2024 Dr. Nazmun@AIMST 5  Macrolides Characteristics: Broad spectrum of activity. Bacteriostatic drugs but at higher doses may act as bactericidal. Antibacterial spectrum is similar to that of penicillin G & bacteria resistant to penicillin may be sensitive. Preferred in patients allergic to Penicillins Effective against Gram+ve cocci (S. pyogenes, some S. pneumoniae & staphylococci), corynebacterium diphtheriae, Mycoplasma pneumoniae, chlamydiae, spirochaetes etc. 11/22/2024 Dr. Nazmun@AIMST 6  Macrolides Mechanism of action: Inhibit bacterial protein synthesis by acting on 50S ribosomes. Blocks translocation and prevent formation of initiation complexes. ADR: Remarkably well tolerated. GI upset, Superinfection. Erythromycin estolate is hepatotoxic, stearate is not hepatotoxic and is safer during pregnancy. Erythromycin & clarithromycin are enzyme inhibitors- interfere with metabolism of other drugs (warfarin etc.). 11/22/2024 Dr. Nazmun@AIMST 7  Macrolides ADME: oral & IV Erythromycin is acid sensitive & is administered as enteric-coated tablets or as esters (estolate or stearate). Crosses into placenta & prostate, secreted into bile & milk. The plasma half-life of erythromycin – 1.5 h, clarithromycin - 6h & azithromycin - 70 h. Azithromycin concentration in phagocytes (not in CSF) can reach 40 times higher than in the blood leading to enhanced intracellular killing of bacteria. 11/22/2024 Dr. Nazmun@AIMST 8  Macrolides - Uses As a penicillin substitute in patients allergic to penicillin or for treatment of infections with penicillin resistant organisms. Diphtheria, respiratory infections and infections in neonates. Lymphogranuloma venereum (LGV), Syphilis, Mycoplasma pneumoniae etc. To eliminate corynebacterium diphtheriae carrier state. Acne: Erythromycin is administered to inhibit lypolysis of sebum & inhibit the release of inflammatory fatty acids. Clarithromycin – For eradication of H. pylori in the treatment of peptic ulcer in combination with other drugs. Azithromycin – For outpatient therapy of community-acquired pneumonia, sexually transmitted diseases etc. 11/22/2024 Dr. Nazmun@AIMST 9  Erythromycin As penicillin substitute in patients allergic to penicillin or for treatment of infections with penicillin resistant organisms. Uses: Diphtheria, respiratory infections and infections in neonates. LGV, Syphilis, Campylobacter Jejuni, Mycoplasma pneumoniae, penicillin resistant organisms. to eliminate corynebacterium pneumoniae carrier state As a penicillin substitute in patients sensitive to penicillin. Acne: to inhibit lypolysis of sebum & inhibits the release of inflammatory fatty acids. 11/22/2024 Dr. Nazmun@AIMST 10  Clarithromycin Clarithromycin is slightly more effective than erythromycin, especially against intracellular organisms. Also effective against Mycoplasma pneumoniae, Haemophilus influenzae and H. pylori (causes relapse of peptic ulcer). Absorbed orally. Given twice a day as it is long acting. Less gastric irritation. Peptic ulcer - Used to prevent relapse of peptic ulcer by eradicating H. pylori. 11/22/2024 Dr. Nazmun@AIMST 11  Azithromycin: Compared to erythromycin - less active against gram +ve organisms, more active against H. influenzae & N. gonorrhoeae. Azithromycin’s unique PK include extensive tissue distribution (except CSF) and high drug concentrations within cells (including phagocytes), resulting in much greater concentrations of drugs in tissue or secretions. Given 1 h before meal or 2 h after meal. Absorbed well orally. Crosses into prostatic fluid, placenta & is secreted in bile. Long half life 70 h or 3 days, hence, given once a day (OD) & for 3 days- 5 days. No enzyme inhibition, hence, no related DI or ADR. Uses: For outpatient therapy of community-acquired pneumonia (CAP), pharyngitis, sexually transmitted diseases etc.. 11/22/2024 Dr. Nazmun@AIMST 12  Aminoglycosides Aminoglycosides are antibiotics containing amino sugars in glycosidic linkage. They are the main stay of treatment of aerobic gram-negative infections. Spectrum: Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Enterobacter Natural compounds Semi synthetic Streptomycin compounds Gentamicin Amikacin Tobramycin Netilmicin Kanamycin Neomycin 11/22/2024 Dr. Nazmun@AIMST 13  Aminoglycosides – Common features bactericidal – Inhibit bacterial protein synthesis. Narrow spectrum antibiotic- active against aerobic gram-negative bacteria. Not absorbed orally & not inactivated in GIT & produce local action on GIT. Administered parenterally for systemic action. E.g. TB Poor penetrability, do not cross BBB, low intracellular concentrations. ADR: Ototoxic, nephrotoxic, neuromuscular block, Narrow therapeutic index. Have post antibiotic effect. 11/22/2024 Dr. Nazmun@AIMST 14  Aminoglycosides - MOA Mechanism of action of aminoglycoside: Acts by binding with 30S subunit of ribosomes and "irreversibly" inhibits protein synthesis. By 1.Interfere the initiation complex of peptide chain formation. 2.Induces misreading of mRNA – leads to incorporation of incorrect amino acids. They are bactericidal against aerobic gram –ve organisms. Aminoglycoside is administered with a β-lactam, to provide synergy, to prevent resistance emergence & to expand the spectrum. E.g. streptococcal & enterococcal endocarditis 11/22/2024 Dr. Nazmun@AIMST 15  Aminoglycosides - Treatment regimen Half life of aminoglycosides – 2-3 h Required to be repeated every 8 h. Aminoglycosides exhibit concentration-dependent killing with a high PAE which is proportional to the peak serum concentration. Hence, once-daily dosing is adequate, with the advantages less toxic & feasible for outpatient therapy less expensive without need for repeated determinations of serum concentrations. The single high-dose, extended interval is generally preferred for aminoglycosides, with a few exceptions (during pregnancy, in neonates, etc.) 11/22/2024 Dr. Nazmun@AIMST 16  Aminoglycosides - ADME Only less than 1% of the drug is absorbed from GIT, hence, administered parenterally for systemic action. Aminoglycosides are no inactivated in the GIT, hence, can be given orally for local action in GIT. Tissue distribution is limited as also penetration into cells or CSF. Cross placenta and affect the fetus. Accumulate in the kidney & inner ear (ototoxic & nephrotoxic). Excreted by kidney in active form. 11/22/2024 Dr. Nazmun@AIMST 17  Aminoglycosides Streptomycin Uses: TB, Tularemia, Plague, Brucellosis, Bacterial endocarditis (with penicillin), Sexually transmitted diseases (Granuloma venereum etc.). Gentamicin Uses: Serious gram-ve infections, Serious infections of unknown etiology, UTI, Pneumonia, meningitis, For pseudomonas with penicillins or cephalosporins. Enterococcal endocarditis - synergistic with penicillins. 11/22/2024 Dr. Nazmun@AIMST 18  Aminoglycosides -Uses 1. In prophylaxis & treatment of gram-ve infections. 2. Streptomycin - to treat tuberculosis, plague, tularemia etc. 3. The cell wall damage caused by β- lactams increases the entry of the aminoglycoside into the organism & the combination is synergistic. Penicillin G & streptomycin are used in endocarditis caused by streptococcus viridans & enterococci (e.g. enterococcal endocarditis). 4. Gentamicin eye drops, ointment for conjunctivitis. 5. Neomycin is nephrotoxic & is used only for topical application. It is given orally for intestinal infections & hepatic encephalopathy. 11/22/2024 Dr. Nazmun@AIMST 19  Aminoglycosides Precautions / Contraindications: 11/22/2024 Dr. Nazmun@AIMST 20  Macrolides- Aminoglycosides- 11/22/2024 Dr. Nazmun@AIMST 21 Bacterial Protein Synthesis Inhibitors Drugs that binds 30S Drugs that binds 50s ribosomal subunits ribosomal subunits Tetracyclines Chloramphenicol Aminoglycosides Macrolides Clindamycin Linezolid 11/22/2024 Dr. Nazmun@AIMST 22 11/22/2024 Dr. Nazmun@AIMST 22  Reference Katzung, B.G., 2023.Basic and Clinical Pharmacology, 16th Edition. Lange Medical Books. Whalen, K., 2018. Lippincott® illustrated reviews: pharmacology. Wolters kluwer india Pvt Ltd. 11/22/2024 Dr. Nazmun@AIMST 23