Antibiotics and Tuberculosis Guide PDF

Antibacterials, Tuberculosis Dr. Kareem Mahmoud presented by Dr. Ayman Ahmed Reda  Learning outcomes Describe the bacterial cell structure. Explain the key terms concerning antibacterial drugs. Discuss the antibacterial drug targets. Describe the pathophysiology, risk...

Antibacterials, Tuberculosis Dr. Kareem Mahmoud presented by Dr. Ayman Ahmed Reda  Learning outcomes Describe the bacterial cell structure. Explain the key terms concerning antibacterial drugs. Discuss the antibacterial drug targets. Describe the pathophysiology, risk factors, signs and symptoms, and pharmacotherapy of tuberculosis.  Antibiotics Alexander Fleming in 1928 – Penicillinum, penicillin Selectively toxic Naturally produced by Bacteria and Fungi Ideally Not harmful to host Antibiotics: substances produced by some microorganisms or synthetic chemicals  Antibacterial terms Bacteriostatic: inhibits bacterial multiplication (e.g. tetracyclines, chloramphenicol, macrolides) Bactericidal: kills bacteria (e.g. penicillins, aminoglycosides) Minimum inhibitory concentration (MIC): minimum concentration of an antimicrobial capable of inhibiting the growth of an organism Minimum bactericidal concentration (MBC): lowest concentration that kills the pathogen Drug targets  Drug targets: Selective affecting bacterial Cell wall (peptidoglycan) Macromolecules cannot be taken up, must be synthesized Peptidoglycan – bacterial cell wall N-acetylglucosamine (NAG) and N-acetylmuramic acid (NAM) alternate Attached peptide side chains to NAM which are cross-linked with peptides polymeric lattice (By transpeptidase enzyme)  Cell wall synthesis inhibitors Drug targets: selective affecting bacterial macromolecules (peptidoglycan), Bactericidal mainly Cell wall synthesis inhibitors 1. β-lactam A. Penicillins B. Cephalosporins C. Monobactams and Carbapenems 2. Glycopeptides: Vancomycin, teicoplanin: binds to D-alanyl-D-alanine terminus of cell wall precursor units, inhibit cell wall synthesis, IV causes red man syndrome 3. Bacitracin cyclic peptide, topical for skin infections, inhibit cell wall synthesis  NOTE: β-lactam antibiotics: covalent binding with penicillin-binding proteins (transpeptidase)  no binding will occur between cross-linking peptides and tetrapeptide side-chain (attached to NAM) and therefore, cell wall synthesis will be inhibited.  β-lactam antibiotics Drug targets: selective affecting bacterial macromolecules (peptidoglycan), Bactericidal mainly  β-lactam class of antibiotics 1. Penicillins (example: Amoxicillin, Ampicillin, Penicillin G, Ticarcillin, Oxacillin) 2. Cephalosporins (example cephoperazone, ceftriaxone, cephalexin, cefixime, Cefaclor Cephalosporins) They are often grouped in terms of ‘generations’. The older ‘generation’ has primarily Gram-positive coverage (oral), while newer cephalosporins have a wide spectrum of activity (parentral), including Gram-negative and Gram-positive organisms. Mechanism: covalent binding with penicillin-binding proteins (Inhibit transpeptidase enzyme)cross-linking peptides will not bind to tetrapeptide side-chain. Penicillins also cause cell lysis by inhibiting the inactivation of autolytic enzymes (which break down the cell wall). Drugs of choice for URTI. Pregnancy category B  Drug targets: selective affecting bacterial macromolecules (peptidoglycan), Bactericidal mainly  β-lactam class of antibiotics They are Drugs of choice for URTI. Pregnancy category B Adverse effects: 1. GIT upset. 2. Some people are allergic to β-lactams and are prescribed alternatives (Macrolides). Contraindicated 1. They are contraindicated in Chronic kidney disease.  Inhibitors of proteins synthesis Drug targets: relatively selective affecting bacterial macromolecules (proteins) Tetracyclines – competes with tRNA for site A on ribosometRNA cannot reach site A Aminoglycosides – causes abnormal complementary base-pairing between tRNA and mRNAerroneous reading of mRNA Chloramphenicol – transpeptidation (transfer of peptide chain from tRNA on site P to tRNA at site A) inhibited Macrolides (Erythromycin, Azithromycin, Clarithromycin), fusidic acid – translocation (tRNA with growing peptide chain moving from site A to site P) inhibited  Drug targets:– protein synthesis (30S ribosomal subunits) Tetracyclines: inhibit protein synthesis through binding reversibly to the bacterial 30S ribosomal subunit and preventing the aminoacyl tRNA from binding to the A site of the ribosome. Examples (doxycycline- minocycline). They are bacteriostatic and used in UTI, RTI, and the intestinal infections and treatment of chlamydia, moderately severe acne and rosacea (tetracycline, oxytetracycline, doxycycline or minocycline). Doxycycline is also used as a prophylactic treatment for anthrax and malaria. Adverse effects: Phototoxicity and teratogenic where in pregnancy cause hepatotoxicity for mothers and fetal permanent teeth discoloration (yellow-brown in appearance) and impaired fetal long bones growth. Interactions: their absorption may be decreased by calcium containing drugs such as antacids Aminoglycosides: inhibit protein synthesis through action on 30s subunit and are useful primarily in infections caused by aerobic, Gram-negative bacteria, such as Pseudomonas, Acinetobacter, and Enterobacter. Adverse effects: inner ear toxicity causing sensorineural hearing loss and kidney damage (Acute kidney injury) with frequent use that could lead to chronic kidney disease.  Drug targets:– protein synthesis (50S ribosomal subunits) Chloramphenicol: Action: 50S ribosomal subunit Effective against Salmonella, aplastic anaemia Eye drops Fusidic acid  Action: 50S ribosomal subunit  Used for skin and soft tissue infections  Liver dysfunction  Creams and ointments Linezolid  Inhibits binding of 30S and 50S ribosomal subunits  Active against Gram-positive  Skin and soft tissue infections  Blood count should be monitored, optic neuropathy, MAO inhibitor  Drug targets:– protein synthesis (50S ribosomal subunits)  Lincosamides class of Antibiotics: Clindamycin - pregnancy category B Mechanism: Targeting 50S ribosomal subunits), stopping translocation, (tRNA with growing peptide chain moving from site A to site P), translation is terminated, protein synthesis hindered They are Good alternative for penicillin-allergic patients They are bacteriostatic, LRTI Adverse effects: Prolong QT interval, Inhibit CYP450  Inhibitors of nucleic acid synthesis Drug targets: relatively selective affecting bacterial macromolecules (nucleic acid) Inhibition of nucleotide synthesis (sulfonamides, trimethoprim) RNA polymerase inhibition (rifampicin: binds to bacterial RNA polymerase) DNA gyrase inhibition: Quinolones (ciprofloxacin, norfloxacin) Nitroimidazoles: metronidazole, Nitro group reduced by bacteria to produce nitroso free radical that disrupts DNA, metronidazole is active against anaerobic bacteria  Inhibitors of nucleic acid synthesis Drug targets: relatively selective affecting bacterial macromolecules (nucleic acid) Quinolone class of Antibiotics Example (Ciprofloxacin, Moxifloxacin, Norfloxacin, levofloxacin). Used for Gram-negative bacteria, in particular Haemophilus influenzae (not norfloxacin) and Pseudomonas aeruginosa. They are active against some Gram-positive bacteria, Legionella, some Mycobacteria, and Chlamydia trachomatis. Mechanism: They bind reversibly to DNA gyrase and topoisomerase IV thus stopping DNA transcription and replication. Adverse effects: Antibiotic-induced diarrhea (Clostridium difficile), skin sensitivity to UV, tendon and cartilage damage Ciprofloxacin Inhibit CYP1A2 (drug interactions)  (Sulfonamides) Drug targets: selective based on a metabolic process Folate synthesized in many bacteria species Humans cannot synthesize folate (diet) Sulfonamides: inhibits folate synthesis Trimethoprim: inhibits folate utilization Inhibits DNA synthesis Sulfonamide + trimethoprim = Septrin DS active against Pneumocystis jirovecii (Pneumocystis carinii) Respiratory tract infections, Urinary tract infections C.I: pregnancy, renal disease  Tuberculosis (TB) It is a type of bacterial infection caused by Mycobacterium tuberculosis, Mycobacterium avium and Mycobacterium bovis. These bacteria have a Cell wall that is waxy hydrophobic (mycolic acids). Transmission: Inhalation of small droplets from infected person who coughs or sneezes. Two million deaths every year  Types of TB Active TB Latent TB: 1- Pulmonary TB: -infected with TB without symptoms -more commonly occurring -bacteria present in the body, but immune -persistent productive cough, possibly with system able to prevent the infection breathlessness and haemoptysis spreading within the body 2- Extrapulmonary TB: -not infectious to other people -symptoms are specifically located to sites outside -active TB can occur, e.g. if immune of the lungs or tracheobronchial tree: lymph nodes system suppressed can be affected, bone or joint pain, abdominal pain, confusion and headache, skin lesions, or chest pain -is more common in children, people from countries with a high prevalence of TB and people with a weakened immune system  TB treatment (first-line drugs) 1- Ethambutol (active against mycobacteria, inhibits bacterial cell wall development, bacteriostatic, S.E: optic neuritis) 2- Pyrazinamide (active in acid conditions, especially in macrophages, interferes with mycolic acid production, S.E: hyperuricemia and arthralgia) 3- Rifampicin (inhibits RNA polymerase, Inducer of Cytochrome P450, S.E: GIT upset and discoloration of Urine) 4-Isoniazid (blocks synthesis of mycolic acids, bacteriostatic, S.E: Peripheral neuritis) TB treatment Pharmacotherapy, NICE NG33, September 2019 Active TB Latent TB 1-isoniazid + pyridoxine 1-isoniazid+ pyridoxine 2-rifampicin 2-rifampicin 3-pyrazinamide 4-ethambutol  Intensive phase: 2 months then  Continuation phase (Isoniazid and Rifampicin for further 6 months), longer in case of CNS TB.  In patients with: -central nervous system (CNS) TB: offer a course of corticosteroid when initiating anti-TB therapy -pericardial TB: offer a course of oral prednisolone when initiating anti-TB therapy  TB treatment (second-line drugs) If infection due to resistant bacteria or side-effects not tolerable from first-line drugs: aminosalicylic acid Multidrug-resistant TB (MDR-TB) and Extensively drug-resistant TB (XDR-TB)) amikacin MDR-TB resistant to capreomycin -isoniazid and rifampicin cycloserine azithromycin and clarithromycin XDR-TB resistant to moxifloxacin -isoniazid and rifampicin protionamide (not in UK market) -any fluoroquinolone bedaquiline -any of the three second-line injectables (amikacin, Delamanid capreomycin, and kanamycin) linezolid  Exam-style questions A. Cephalosporins B. Amoxicillin C. Ciprofloxacin D. Erythromycin E. Polymyxin B F. Rifampicin G.Sulphonamides Choose from A-F the most correct choice. Options maybe used once, twice or not at all. 1. They covalently bind to bacterial transpeptidase via their -lactam ring. This leads to impaired synthesis of the bacterial cell wall. A and B 2. They inhibit protein synthesis of bacterial cells by interacting with 50S ribosomal subunit. D 3. It inhibits bacterial DNA gyrase and thus interfere with nucleic acid synthesis c 4. Is a cationic peptide antibiotic that disrupts phospholipid integrity of bacterial cells E 5. It interferes with folate biosynthetic pathway in bacteria G 6. Is one of the first-line Anti-tuberculosis drugs. It inhibits Mycobacterium RNA polymerase F  Suggested reading Rang, H.P., Ritter, J.M., Flower, R.J. and Henderson, G. (2016) Rang and Dale's Pharmacology. 8th edn. China: Elsevier Churchill Livingstone. Pharmacology for Pharmacy and the health sciences: A patient-centred approach, Michael Boarder, second edition, Chapter 22: The treatment of infections. Study and revise the summary pages 606-610