chemotherapy lecture notes.1.ppt
- 1. CHEMOTHERAPY BY OBAKIRO SAMUEL BAKER (BSC & MSC) sobakiro@gmail.com DCM 2.2 / DNS2.1 March 2013
- 2. Outline • Introduction/ history of chemotherapy • Basic terminologies • General classification of chemotherapeutic agents • Antiseptics and disinfectants • Assignments
- 3. History of chemotherapy Chemotherapy refers to the use of Chemicals (drugs) to treat cancer and microbial infections. Before the discovery of antimicrobial agents, large number of people always died from common illnesses. Now many illnesses are easily treated with antimicrobials. However, many antimicrobial drugs are becoming less useful due to dev’t of resistance.
- 4. History cont’d • Ancient Egyptians, the Chinese, and Indians of central America all used molds to treat infected wounds. However, they did not understand the connection of the antibacterial properties of mold and the treatment of diseases • ?? S. American Indians Chewed bark of cinchona tree ----> malarial fever(Plasmodium spp.); • Wore sandals furry with mould -----> foot infections • ~ 1630 Europeans used Quinine (bark of cinchona) -----> malaria (Plasmodium spp.)
- 5. History cont’d • Louis Pasteur Identified bacteria as causative agent of disease towards the end of the 19th century • Robert Koch (Germ theory) proposed that since the germs are the ones that cause diseases, then we need to find out how to stop them. • In 1877 Pasteur discovered that Soil bacteria injected into animals made Anthrax harmless. • In 1888 de Freudenreich Isolated product from bacteria with antibacterial properties but were toxic and unstable. • 1910 Paul Ehrlich observed that certain dyes stain bacterial cells and not animal cells. He suggested that these could be used to harm bacterial cells but not human cells. Thru Systematic search, he discovered a chemical that could be used to cure syphilis. • 1928 –Alexander Fleming discovered penicillin, produced by Penicillium
- 6. History cont’d • 1935 G. Domagk discovered protocol ( sulphonamide) with a broad range of antimicrobial activities. • 1939 Rene Dubos Isolated gramicidin and tyrocidin from Bacillus brevis; Active against gram positive bacteria • 1942 The manufacturing process for Penicillin G Procaine was invented by Howard Florey and Ernst Chain .Penicillin could now be sold as a drug. • Fleming, Florey, and Chain shared the 1945 Nobel Prize for medicine for their work on penicillin. • In 1943, American microbiologist Selman Waksman made the drug streptomycin from soil bacteria, the first of a new class of drugs called aminoglycosides. Streptomycin could treat diseases like tuberculosis, however, the side effects were often too severe. • By 1945 Pharmacologists had 5488 derivatives of sulfanilamide (sulfonamides). • Since 1950, new classes of antimicrobial agents have been discovered
- 8. Check point All medicines are drugs NO All drugs are medicines Which one is true??
- 9. Basic terminologies • Chemotherapy- refers to the use of Chemicals (drugs) to treat cancer and microbial infections. • Chemotherapeutic agent/ drug – refers to any chemical used in the treatment, relief and prophylaxis of a disease. • Prophylaxis- refers to the use of a drug to prevent the potential for infection of a person at risk. • Microbial infection – any disease or disorder caused by a microorganism. Eg bacterial infection, viral, fungal, protozoal infections etc • Antimicrobial agent- any chemical substance that can kill or inhibit growth of micro- organism regardless of its origin. • Antibiotic - any chemical substance produced by natural metabolic processes of some microorganisms that can kill or inhibit the growth of other microorganisms. • Natural drugs- these are chemical substances from biological origin that are used to treat infections in their unchanged form. Eg natural penicillins
- 10. Terminologies continued • Semisynthetic drugs- chemical substances from biological origin that are used to treat infections when modified in the lab after being isolated from their natural sources • Synthetic drugs - chemical substances that are used to treat infections when completely manufactured from the lab. • Spectrum – refers to the range of microorganisms a given drug can effectively kill or control. a broad spectrum antibiotic is the one which is effective against a wide variety of microbial types e.g both gram positive and gram negative bacteria while a narrow spectrum antibiotic is effective against a limited array of microbial types e.g gram positive bacteria only or gram negative bacteria only. • Bactericidal drug – a drug that kills the bacterium • Bacteriostatic drug – a drug that inhibits the growth of the bacterium • Drug Resistance – the decrease in the effectiveness of a drug in treatment of a given infection as a result of the causative microorganism developing mechanisms that shield it from the toxic effects of the drug. • Therapeutic index – the ratio of the lethal dose to the effective dose of a drug. It is ameasure of the relative toxicity of the drug. • Selectivity - - ability of a drug to kill harmful microbes without destroying host cells
- 11. GENERAL CLASSIFICATION OF CHEMOTHERAPEUTIC AGENTS 1. Antibacterial drugs 2. Antituberculous & Antileprotic drugs 3. Antiprotozoal drugs 4. Antifungal drugs 5. Antiviral drugs 6. Antihelmenthic drugs 7. Anticancer /antineoplastic/Cytotoxic drugs
- 14. Do we have any ideal drug??
- 15. Antiseptics and disinfectants An antiseptic is a chemical substance that is capable of destroying or preventing microorganisms on open surfaces of living tissues (animate) thus limiting or preventing their harmful effects of infection. Examples of antiseptics include; iodine, ethanol, chlorhexidine. A disinfectant is a chemical substance that is capable killing and removing microorganisms, including potentially pathogenic ones from the surfaces of inanimate objects. It does not only bring about killing of microorganisms, but also reducing them to a level acceptable for a defined purpose, for example, a level which is neither harmful to health nor to the quality of perishable goods. Examples of disinfectant include; formaldehyde, chlorine, hypochlorite etc
- 16. Ideal properties of an antiseptic and a disinfectant • Should have a broad spectrum activity killing a wide range of microorganisms. • Should be selectively toxic to the microorganism but non toxic to the human cells( large selectivity index) • Should be highly stable under different physical conditions like PH, temperature other chemicals. • Should be toxic to the microorganisms capable of killing even resistant strains( low lethal dose) • Sldnt induce allergic reactions to the human tissues • Should be Cheap to buy, available and easy to use. • Should not cause irritations to the human eye and skin • Should be non-corrosive to the skin for convenient usage. • Should act rapidly bringing its lethal action on all forms of micro-organisms in a short period of time. • Does not lead to development of antimicrobial resistant forms. • Remain active for a long period of time so as to kill microorganisms
- 17. Check points All antiseptics are disinfectants!!!!!!! NO All disinfectants are antiseptics!!!!!!!!!! Which one is correct?
- 18. Assignment • Instructions: -to be handed in the next lecture - should not exceed 2 pages Questions : a)Describe the detailed structure of a bacterium cell. b) Distinguish between Gram positive and gram negative bacteria and give examples of each. c) Outline the different chemical classes of antibacterial compounds giving two common examples of each used in your local setting.
- 19. ANTIBACTERIAL AGENTS OUTLINE Review of the bacterial structure and classification Review of the various bacteria and their infections Classification of antibacterial agents Discussion of each class (sub classes / examples, mechanism of action, resistance, side effections indications & contraindications)
- 20. Review- bacterial structure Is an example of Prokaryotic cells (lack a true nucleus ). The DNA (genetic material) is dispersed within the cytoplasm (due to the absence of a nuclear membrane) The DNA is one long chromosome that is highly folded (nucleoid). No membrane bound organelles. Has a cell surface membrane that encloses cytoplasm that contains enzymes, ribosome, food granules and in same species additional circular pieces of genetic material(plasmids). All posses mesosome Parasitic forms lack chlorophyll Externally, the cell membrane is enclosed by a cell wall made up of peptidoglycan Some have flagella for locomotion Others have a slimy layer (capsule)
- 21. Structure cont’d
- 22. Gram positive and gram negative bacteria • Both gram-positive and gram-negative bacteria have a cell wall made up of peptidoglycan and a phospholipid bilayer with membrane-spanning proteins. • However, gram-negative bacteria have a unique outer membrane, a thinner layer of peptidoglycan, and a periplasmic space between the cell wall and the membrane. • In the outer membrane, gram-negative bacteria have lipopolysaccharides (LPS), porin channels, and murein lipoprotein all which are absent in gram-positive bacteria. • LPS, blocks antibiotics, dyes, and detergents protecting the sensitive inner membrane and cell wall. • Thus gram-negative cells are more difficult to destroy eg they are resistant to lysozyme and penicillin attack.
- 23. Check point Put + for gram positive and – for gram negative on the following bacteria: S. aureus E. coli Neisseria Spirochetes pseudomonas Enterococcus MRSA V. Cholera S. typhi
- 24. Common gram positive & negative bacteria Actinomyces (+) Bacillus ( +) Clostridium ( +) Enterococcus ( +) Mycobacterium ( +) Staphylococcus ( +) Streptococcus ( +) Streptomyces (+) Spirochete (-) Chlamydia ( -) Enterobacter ( -) Escherichia ( -) Helicobacter ( -) Klebsiella (gram -) Neisseria (gram -) Proteus (gram -) Pseudomonas (gram -) Salmonella ( -) Vibrio (-)
- 25. Classification of anti bacterial agents a) basing on the mechanism of action;
- 28. b) Basing on the chemical nature Class Mechanism of action Examples β-lactams Inhibit bacteria cell wall synthesis Penicillins, cephalosporins, bacitracin, monobactams Quinolones Inhibit bacterial nucleic acid synthesis Nalidixicacid, ciprofloxacin Aminoglycosides Inhibit protein synthesis gentamicin, tobramycin, amikacin, netilmicin, kanamycin, streptomycin, and neomycin sulfonamides Inhibit metabolic pathway ( folate metabolism) trimethoprim and sulfamethoxazole Heterocyclic compounds containing nitrogen Disruption of cell membrane function Polymyxins Tetracyclines Inhibit protein synthesis by binding to Chlortetracycline Oxytetracycline
- 29. Cell wall synthesis inhibitors 1. B- lactams These prevent the synthesis of bacterial cell wall (peptidoglycan layer) by interfearing with the cross linkages of the peptides to the carbohydrate molecules. This results into weakened cell walls and eventually the bacterium lyses and hence bactericidal. Thus , effective only on growing bacteria. The functional unit is the B- lactam ring that binds to the enzyme that cross links the NAM subunits. This prevents the growth of the bacteria. Examples include: penicillins, cephalosporins, monobactams, vancomycin, carbapenems, bacitracin
- 30. Mechanism cont’d The weakness in the cell wall causes the cell to burst and hence die
- 31. Resistance to B- lactams • The bacteria that are resistant secrete an enzyme B-lactamase that hydrolyses the B- lactam ring
- 32. Penicillins • The most widely effective and least toxic drugs known. • But increased resistance has limited their use. • Members of this family differ from one another in the R substituent attached to the 6-aminopenicillanic acid residue. • The nature of this side chain affects the antimicrobial spectrum, stability to stomach acid, cross-hypersensitivity, and susceptibility to bacterial degradative enzymes (β- lactamases).
- 33. Classification of penicillins a) Basing on source 1. natural penicillins eg penicillin G and penicillin v 2. Semi- synthetic penicillins eg methicillin, oxacillin, cloxacillin,ampicillin, amoxicillin etc 3. synthetic penicillin b) Basing on spectrum 1. narrow spectrum peinicllins eg pen G & pen V 2.Effective against gram + bacteria and some few non secreting B- lactamases (penicillinases)
- 34. 2. Antistaphylococcal Penicillins (eg, Nafcillin, methicillin, oxacillin) These penicillins are resistant to staphylococcal -lactamases. They are active against staphylococci and streptococci but not against enterococci, anaerobic bacteria, and gram-negative cocci and rods. 3. Extended-Spectrum Penicillins (Ampicillin,amoxicillin, amoxiclav and the Antipseudomonal Penicillins) These drugs are effective against both gram positive and gram-negative organisms. Like penicillin, however, they are relatively susceptible to hydrolysis by B -lactamases.
- 35. Mechanism of action • The penicillins interfere with the last step of bacterial cell wall synthesis(transpeptidation or cross-linkage), resulting in exposure of the osmotically less stable membrane. • Cell lysis can then occur, either through osmotic pressure or through the activation of autolysins. • Penicillins target various proteins on the bacterial cell membrane especially the penicillin-binding proteins (PBPs) are bacterial enzymes that catalyse the crosslinking of the peptides so as to form the peptidoglycan layer.
- 36. Resistance to penicillins 1. Inactivation of antibiotic by B–lactamase (most common mechanism) 2. Modification of target PBPs thru mutations eg MRSA which has altered PBP with reduced affinity 3. Impaired penetration of drug to target PBP eg gram negative bacteria due to the impermeable outer layer and in gram positive absence of porins. 4. Efflux pumps which continously pump out the antibiotic .
- 37. Pk of penicillins • Can be orally or parentally administered • Varied absorption after oral administartion eg Pen G poorly absorbed while pen V well absorbed. Absorption depends on the nature of the R- group. • Absorption interfeared by food . To be taken 2hrs before or after meal • Protein binding varies from drug to drug but insignificant. Well distributed. • Doesnot readiy cross the BBB but when the meninges are greatyly inflammed it crosses • Mainly excreted by the kidney but also thru bile and breast milk • Have ahigh therapeutic index and hence safe
- 38. Indications (clinical uses) • Pneumonia • Meningitis • UTI • Typhoid Side effects Hypersensitvity like skin rash (cross reactive & cross sensitive) Hepatitis Cuases seizures in patients with impaired renal function
- 39. Penicillins and aminoglycosides (synergism) • Because penicillins alter the permeability of bacterial cells, these drugs can facilitate the entry of other antibiotics (such as aminoglycosides) that might not ordinarily gain access to intracellular target sites. • This can result in enhanced antimicrobial activity and hence synergism.
- 40. Group work 1.By visiting the training hospital or otherwise, outline the different penicillins that are in clinical practices and their indications. why are they falling out of favors? 2. classify the different cephalosporins in clinical practice basing on their generation. N.B Groups to present in the next lecture theirs findings.
- 41. Cephalosporins • Resemble penicllins in their mode of action • Differ in the ring attached to the b-lactam ring Classification: Classified into generations basing on spectrum of activity 1. First-generation cephalosporins (cefadroxil, cefazolin, cephalexin, cephalothin, cephapirin, and cephradin) • very active against gram-positive cocci, such as pneumococci, st reptococci, and staphylococci. • Not active against MRSA, E coli, K pneumoniae, P. aerugi nosa, proteus, enterobacter, Serratia marcescens, citro bacter, and acinetobacter. N.B Cefazolin is the only first-generation parenteral cephalosporin still in general use
- 42. SECOND-GENERATION CEPHALOSPORINS Examples include cefaclor,cefamandole, cefonicid, cefuroxime, cefprozil, loracarbef, and ceforanide and the structurally related cephamycins cefoxitin, cefmetazole, and cefotetan, which have activity against anaerobes. This is a heterogeneous group of drugs with marked individual differences in activity, pharmacokinetics, and toxicity. In general, they are active against organisms inhibited by first-generation drugs, but in addition they have extended gram-negative coverage. Cefamandole, cefuroxime, cefonicid, ceforanide, and cefaclor are active against H influenzae but not against serratia or B fragilis. As with first-generation agents, none is active against enterococci or P. aeruginosa
- 43. THIRD-GENERATION CEPHALOSPORINS • cefoperazone, cefotaxime, ceftazidime, ceftizoxime, ceftriaxon e, cefixime, cefpodoxime proxetil, cefdinir, cefditoren pivoxil, c eftibuten, and moxalactam. • have expanded gram-negative coverage. • some are able to cross the blood-brain barrier. • active against citrobacter, S marcescens, and providencia • Also effective against b-lactamase-producing strains of haemop hilus and neisseria. • Ceftazidime and cefoperazone are the only two drugs with usef ul activity against P aeruginosa. • Not reliably active against enterobacter species, Serratia, provid encia, and citrobacter.
- 44. FOURTH-GENERATION CEPHALOSPORINS • Cefepime is an example of a so-called fourth-generation cep halosporin. • It is more resistant to hydrolysis by chromosomal B -lactamas es (eg, those produced by enterobacter). • It has good activity against P aeruginosa, Enterobacteriaceae, S aureus, and S pneumoniae, MRSA, haemophilus and neisser ia. • Useful in treatment of enterobacter infections • It penetrates well into cerebrospinal fluid.
- 45. GENERAL PK • May be given orally or parentally but mostly parentall y due to poor absorption • Variable absorption after oral admin • Well distributed to various body fluids • Metabolism not significant • Excreted thru glomerular filtration and bile • Dose adjustement basing on PK and age Indications (clinical use) • UTIs • Systemic infections
- 46. Adverse effects • Allergy • Nephrotoxicity • Severe pain • Thrombophlebitis (inflammation of the veins) contraindications Alcoholics Renal dysfunction Allergic patients
- 47. Other cell wall synthesis inhibitors • Vancomycin: hinders peptidoglycan elongation by Interfere with particular bridges that link NAM subunits in many Gram-positives. • Cycloserine: inhibits the formation of the basic pep tidoglycan subunits. causes serious CNS effects • Bacitracin Blocks transportation of NAG and NAM subunits from cytoplasm to the growing peptidoglycan. Highly nephrotoxic and given only topically • Isoniazid and ethambutol Disrupt mycolic acid formation in mycobacterium
- 48. • Monobactams are drugs with a monocyclic b-l actam ring. • They are relatively resistant to b-lactamases a nd active against gram-negative rods (includin g pseudomonas and serratia). • They have no activity against gram-positive ba cteria or anaerobes. • Aztreonam is the only monobactam available i n the USA
- 49. BETA-LACTAMASE INHIBITORS (CLAVULANIC ACID, SULBACTAM,& TAZOBACTAM) • resemble b -lactam molecules but have very weak antibacter ial action. • potent inhibitors of many but not all bacterial b -lactamases a nd can protect hydrolyzable penicillins from inactivation by th ese enzymes. • most active against A –lactamases bacteria, staphylococci, H i nfluenzae, N gonorrhoeae, salmonella, shigella, E coli, and K p neumoniae. • Not active against enterobacter, citrobacter, serratia, and pseu domonas. • Can be combined with penicillins like amoxiclav
- 50. Carbapenems • Carbapenems are structurally related to b-lactam antibiotics .Ertapenem, im ipenem, and meropenem are licensed for use in the USA. • Imipenem has a wide spectrum with good activity against many gram-negat ive rods, including P aeruginosa, gram-positive organisms, and anaerobes. • It is resistant to most b-lactamases but not metallo- -lactamases. Enterococc us faecium, MRSA,Clostridium difficile. • Imipenem is inactivated by dehydropeptidases in renal tubules, resulting in l ow urinary concentrations. Consequently, it is administered together with a n inhibitor of renal dehydropeptidase, cilastatin. • Meropenem is similar to imipenem but has slightly greater activity against g ram-negative aerobes and slightly less activity against gram-positives. • It is not significantly degraded by renal dehydropeptidase and does not requ ire an inhibitor. • N.B Common side effects are nausea, vomiting, diarrhea, skin rashes, a nd reactions at the infusion sites.
- 51. Summary of cell wall synthesis inhibitors
- 52. PROTEIN SYTHESIS INHIBITORS The process of protein synthesis is as below Bacterial ribosome has 2 parts: – 30S binds to mRNA to translate mRNA into amino acids, which form proteins – 50S required for peptide elongation 3 phases from mRNA to protein – Initiation – Elongation – Termination
- 53. MECHANISM OF ACTION • Bind irreversibly to ribosome • mRNA cannot bind to Ribosome (30S) to form amino acid chains (polypeptide) or elongate the chains to form proteins (50S) • Absence of these functional proteins Disrupts ma ny essential bacterial functions leading to cell de ath. • Examples: Aminoglycosides, Macrolides/Ketolid es, Tetracyclines, Lincomycins, Chloramphenicol, Oxazolidinones
- 54. MOA cont’d
- 57. Group assignment For each of the classes of protein synthesis inhibitors , discuss with examples the mechanism of actions, mechanism of resistance, general P.K citing exceptions, side effects, indications and contraindications. Each group should organize a 5 min presentation which will be scored out of 10 in the next lecture.
- 58. AMINOGLYCOSIDES • Structurally consist of hexose sugar units ( stre ptidine or streptamine) linked to amino acids by glycosidic bonds • They are water-soluble, stable in solution, and more active at alkaline than at acid pH. • Poorly absorbed after oral adininistration • Active mainly on gram negative bacteria • Examples streptomycin, neomycin, kanamycin , amikacin, gentamicin, tobramycin, sisomicin , netilmicin,
- 59. MOA • Bind irreversibly on the 30s ribosomal sub unit and prevent initiation of translation or cause misreading of the MRNA . This results into abs ence of functional bacterial proteins and henc e cell death. • Entry of these drugs is energy depedent and t hus requires oxygen
- 60. MOR 1) production of a transferase enzyme that inactivates the aminoglycoside by adenylylation, acetylation, or phosphorylation. (2) There is impaired entry of aminoglycoside into the cell. Due to mutation or deletion of a porin (proteins) involved in transport and maintenance of the electrochemical gradient (3) Alteration in the binding site on the ribosome due to mutation. 4) Natural resistance by anaerobes
- 61. General pk • Mainly administered parentally ( IM and IV) • Poorly absorbed after oral administration • Not Well distributed due to the polar nature • Do not penetrate the BBB • Metabolism not significant • Excreted by the kidney • Have a narrow therapeutic index and thus require TDM • Given single dose daily (originally three times a day ) • Dosage adjustments must be made to avoid accumulation of drug and toxicity in patients with renal insufficiency N.B. Aminoglycoside toxicity is both time- and concentration- dependent.
- 62. Adverse effects • Ototoxicity • Nephrotoxicity Indications Gram negative infections UTIs TB – streptomycin Severe sepsis, meningitis, infected burns and wounds and pneumonia- Gentamicin N.B. usually given with cell wall synthesis inhibitors
- 63. contraindications • Neonates • Renal insufficiency • Pregnant and lactating mothers
- 64. Tetracyclines Dicovered in the 1950’s but encountered great resistance Classified basing on source and duration of action
- 65. MOA • Bind reversibly on the 30s ribosomal sub unit and prevent initiation of translation or cause misreading of the MRNA . This results into abs ence of functional bacterial proteins and thus i nhibit bacterial growth hence bacteriostatic. • N.B. entry is by passive diffusion and also by e nergy dependent pumps
- 66. MOR (1) Impaired influx or increased efflux by an activ e transport protein pump; (2) Ribosome protection due to production of proteins that interfere with tetracycline binding to the ribosome; (3) Enzymatic inactivation. N.B.Tet(AE) efflux pump-expressing gram- negative species are resistant to the older tetracyclines, doxycycline, and minocycline. They are susceptible, however, to tigecycline, which is not a substrate of these pumps.
- 67. General pk • Can be administered orally and parentally • Variable absorption after oral admin • Absorption reduced by food • Distributed widely to tissues and body fluids • Metabolism not significant • Excreted mainly in urine and bile except doxycyclin e which excreted in feaces. N.B. Classified as short-acting (6–8 hrs), intermediate-acting (12 hrs) long-acting (16–18 hrs). Tigecycline( glycylcycline) has a half-life of 36 hrs.
- 68. Indications • STDs • UTIs • Chlamydia • Trachoma • Mycoplasma infections • Cholera • Pneumonia • brucellosis
- 69. Adverse effects hypersensitivity,Renal toxicity, local tissue toxicity, photosensitization, GI distress, discolors teeth, inhibits bone growth in children, potentially teratogencic, hepatotoxicity, vestibular toxicity Contraindication Pregnant and lactating mothers Neonates
- 71. Chloramphenicol • Potent broad-spectrum drug with unique nitrobenzene structure • Blocks peptide bond formation and protein synthesis • Only made synthetically today • Very toxic, restricted uses, can cause irreversible damage to bone marrow • Broad-spectrum(Typhoid fever, brain abscesses, rickettsial, and chlamydial infections)
- 72. MOA • binds reversibly to the 50S subunit of the bact erial ribosome and inhibits the peptidyl transf erase step of protein synthesis hence preventi ng elongation of the growing polypeptide. • Chloramphenicol is a bacteriostatic broad-spe ctrum antibiotic that is active against both aer obic and anaerobic gram-positive and gram-ne gative organisms.
- 73. General pk • well absorbed after oral administration • Chloramphenicol succinate used for parenteral administration is highly watersoluble • distributed into total body water • excellent penetration into CSF, ocular and joint fluids • rapidly excreted in urine, 10% as chloramphenicol; 90% as glucuronide conjugate • systemic dosage need not be altered in renal insufficiency but mu st be reduced markedly in hepatic failure • Newborns less than a week old and premature infants also clear Chloramphenicol less well, dosage should be reduced at 25 mg/kg/d
- 74. Indications 1.Typhoid fever but replaced by fluorinated quinolones. 2.Bacterial meningitis (H.influenza) + penicillin. 3.Topically in eye infections e.g conjunctivitis. 4.Anerobic infections e.g anerobic brain abscess. • Generally used as drug of last resort for life-t hreatening infections
- 75. Adverse effects of chloramphenicol: 1.GIT upset & super infection. 2.Bone marrow depression (dose independent or idiosyncrasy)- Rare but lethal side effect is aplastic anemia 3.Gray baby syndrome in neonates. 4.Optic neuritis. 5.Inhibition of hepatic microsomal enzymes that metabolize several drugs hence undesirable drug- drug interaction.
- 76. Macrolides • Naturally occurring compounds that are end p roducts of secondary metabolism. • Mostly extracted from plants, marine organis ms, ormicroorganisms • prototype drug is Erythromycin. • Other examples include Azithromycin, Clarithromycin,Josamycin,Midecamycin, Roxithromycin, Spiramycin. • Ketolides: Telithromycin
- 77. MOA • Bind reversibly to 50s unit of the ribosome blocking t ranslocation of peptides from A-site to P-site of ribos ome thus preventing elongation of the growing amin oacid chain. RESISTANCE: • reduced permeability of the cell membrane or active efflux • Production of esterases that hydrolyze macrolides • modification of the ribosomal binding site by chromo somal mutation
- 78. Erythromycin: • prototype • distributed into total body water • poor CSF penetration • food interferes with absorption • serum half life is app. 1.5 h normally and 5 hours in patients w ith anuria • not removed by dialysis • metabolized in the liver • traverses the placenta and reaches the fetus N.B. Erythromycin is destroyed by stomach acid and must be administered with enteric coating.Stearates and esters are fairly acid-resistant and somewhat better absorbed. erythromycin estolate is the best-absorbed oral preparation.
- 79. INDICATIONS Erythromycin is a drug of choice in Corynebacterial infections (diphtheria, coryne bacterial sepsis, erythrasma); Respiratory, neonatal, ocular, or genital chlam ydial infections; Community-acquired pneumonia. N.B its spectrum of activity includes pneumococcus, mycoplasma, and legionella.
- 80. Adverse Effects: - GIT dysfunction, - intrahepatic cholestatic jaundice N.B. Erythromycin metabolites can inhibit cytochrome p450 enzymes and thus increase the serum concentrations of theophylline, oral anticoagulants, cyclosporine and methylprednisolone;
- 82. PK • excellent absorption • low concentration in CSF • well bone penetration • excreted mainly via the liver, bile and urine • half life is 2.5 hours normally and 6 hours in patients with anuria • more toxic than erythromycin
- 83. Indications • Clindamycin is more clinically used than Lincomyc in in : - prophylaxis of endocarditis in patients with valvular heart disease - dental procedures - most important indication is the treatment of severe anaerobic infection caused by bacteroides and other anaerobes that often participate in mixed infections - + aminoglycoside or cephalosporin used to treat penetrating wounds of the abdomen and the gut
- 84. Adverse effects • Diarrhea, nausea, skin rashes, impaired liver f unction and neutropenia;
- 85. DNA SYNTHESIS INHIBITORS These are active against a variety of gram-positive and gram-n egative bacteria. They block bacterial DNA synthesis by inhibiting bacterial topo isomerase II (DNA gyrase) and topoisomerase IV. Inhibition of DNA gyrase prevents the relaxation of positively s upercoiled DNA that is required for normal transcription . Inhibition of topoisomerase IV interferes with separation of re plicated chromosomal DNA into the respective daughter cells during cell division. bactericidal classes : quinolones and fluoroquinolones. Examples include: nalidixic acid, ciprofloxacin, norfloxacin, g atifloxacin, levofloxacin, moxifloxacin, gemifloxacin
- 86. May be classified into generations 1.First generation: nalidixic acid 2.Second generation : ciprofloxacin 3.Third generation : levifloxacin 4.Fourth generation : moxifloxacin
- 87. Mechanism of resistance • Mutations in the bacterial chromosomal genes encoding DNA gyrase or topoisomerase IV • Active transport of the drug out of the bacter ia . N.B . Cross resistance occurs between members
- 88. pk • Well absorbed after oral admin • Oral absorption impaired by divalent cations i ncluding those in anti-acids • Distributed widely in body fluids • Elimination is by the kidney • Half lives varies ; forexample 3 hrs- norfloxacin and ciprofloxacin 10 hrs. – pefloxacin > 10 hrs. – sparfloxacin Long half life : Levofloxacin, moxifloxacin, sparfloxacin, trovafloxacin
- 89. Indications • UTIs • Typhoid • Bone, Joint, and Soft Tissue Infections. • Respiratory tract infections esp those caused by pseudomonas and entrobacter (cipro) • Gastrointestinal and Abdominal Infections • Sexually Transmitted Diseases. • Prostatiti • chlamydial urethritis • cervicitis • prophylaxis and treatment of anthrax • prophylaxis of infection in neutropenic patients
- 90. Adverse effects • GIT disturbances (N/V/D) • Skin rash (Steven Johnson syndrome) • CNS side effects like headache and dizziness • Photosensitivity Adverse effects & contraindications of Fluoroquinolones: • Nephrotoxicity. • Arthropathy in children less than 18 years. • Inhibit liver microsomal enzymes → dangerous drug interactiona as ↑ lev el of theophylline & warfarin. • Others – insomnia, abn liver function test • Trovafloxacin – associated rarely with acute hepatitis and hepatic failure • Tendinitis – may rupture • N.B. The following drugs were removed from the mrket because of their t oxicity: temafloxacin (immune hemolytic anemia), trovafloxacin (hepatotoxicity), grepafloxacin (cardiotoxicity), and clinafloxacin (phototoxicity).
- 91. DRUG INTERACTION: • Theophylline – increase metabolism of theoph ylline – elevated concentration -seizures CONTRAINDICATIONS: • Quinolones are contraindicated in pregnancy, Nursing mothers & patients less than 18 years (children) as it may lead to arthropathy.
- 93. Anti metabolites : Sulphonamides and trimethoprim Sulfonamides : • 1st antibiotic to be used in humans (1932) • Contain sulphur and are mainly synthetic • Bacteriostatic, interfere with folic acid pathwa y • Examples : sulfadiazine,sulfadoxine, sulfaceta mide,sulfasalazine and sulfamethoxazole.
- 94. Classification • Classified basing on duration if action into ; 1.Short acting (6-9hrs) e.g Sulfacytine , Sulfisoxazole , Sulfamethizole 2. Medium acting (10-12hrs) e.g Sulfadiazine, Sulfamethoxazole, Sulfapyridine 3. Long Acting (greater 24hrs) e.g Sulfadoxine
- 95. Mechanism of action: Inhibits growth by reversibly blocking folic acid sy nthesis Sulfonamides are structural analogues of PABA ( a precursor metabolite in the folic acid pathway) thus they competitively inhibit dihydropteroate s ynthase (the first enzyme in the folate pathway) l eading to inhibition of folic acid synthesis consequently inhibition of DNA & RNA synthesis N.B. human cells utilize already formed folic acid COZ do not make folic acid and are not affected
- 96. Trimethoprim and Pyrimethamine Trimethoprim selectively inhibits bacterial dihydrofolic acid re ductase, which converts dihydrofolic acid to tetrahydrofolic aci d, a step leading to the synthesis of purines and ultimately to DNA. Trimethoprim is about 50,000 times less efficient in inhibition of mammalian dihydrofolic acid reductase. Pyrimethamine selectively inhibits dihydrofolic acid reductase of protozoa compared with that of mammalian cells. Trimethoprim or pyrimethamine is used in combination with a sulfonamide to block sequential steps in folate synthesis, resul ting in marked enhancement (synergism) of the activity of bot h drugs. N.B. The combination often is bactericidal, compared with the bacteriostatic activity of a sulfonamide alone.
- 97. Mechanism cont’d
- 98. Mechanism of resistance Occurs as a result of mutations that: 1. Cause overproduction of PABA 2. Cause production of a folic acid synthesizing enzyme that has a low affinity for Sulfonamides 3. Cause a loss of permeability to the sulfonamides
- 99. General pk - 3 major groups: 1. Oral, absorbable 2. Oral, non-absorbable 3. Topical 4. Intravenous Preparation: Absorbed from stomach and small intestine - distributed widely to tissues and body fluids (CSF), placenta and fetus - protein binding 20% to over 90% - therapeutic concentration – 40-100 ug/ml of blood - peak blood levels – 2h to 6 h after oral ingestion - metabolism: glucoronidation or acetylation in liver - eliminated in urine-mainly by glomerular filtration
- 100. Oral, Non-absorbable Agents e.g Sulfasalazine • More effective than soluble sulfonamides or other a ntimicrobials taken orally in inflammatory bowel dise ase, ulcerative colitis, enteritis, other inflammatory b owel disease • Split by intestinal microflora to yield: Sulfapyridine – absorbed and may lead to toxic symptoms N.B. If more than 4 g of sulfasalazine is taken per day esp. in persons who are slow acetylators 5- aminosalicylate (5-ASA) – released in colon in high concentrations & is responsible for anti- inflammatory effect
- 101. Indications / clinical uses 1. Urinary tract infection Sulfisoxazole – 1 gm 4x daily} combined with PHENAZOPYRIDINE Sulfamethoxazole – 1 g 2-3 x daily } (U.T. anesthetic) 2. Respiratory infections 3. Sinusitis, bronchitis, pneumonia 4. Dysentery 6. Acute Toxoplasmosis – Sulfadiazine + Pyrimethamine – Synergistic – Dosage – Sulfadiazine – 1 g 4x daily – Sulfadiazine + pyrimethamine – 75 mg loading dose ffd by 25 mg OD – Folinic Acid – administered to minimize bone marrow suppression 7. Eye infection (topical sulfacetamide). 8. Burns (topical silver sulfadiazine). 9. Ulcerative colitis (sulfasalazine). 10. Malaria - sulfadoxine + pyrimethamine (fansidar) – 2nd line agent in treatment for malaria
- 102. Adverse effects of sulfonamides 1. Hypersensitivity reactions. – Cross allergy with the ffg. Carbonic anhydrase inhibitors, thiazides, furosemide, bumetanide, furosemide, diazoxide, sulfonylureas, hypoglycemics 2. Urinary tract disturbances: Sulfas may ppt. in urine at neutral or acid pH -Crystalluria: Crystalluria & nephrotoxicity due to insoluble metabolite precipitation and can be avoided by ↑ fluid intake & alkalinization of urine pH-Crystalluria – treated with sod. Bicarbonate to alkalinize urine and fluids to maintain adequate hydration.
- 103. Adverse effects cont’d 3. Hemopoietic disturbances as granulocytopenia ,thrombocytopenia and hemolytic anemia in patients with G6PD deficiency - increased risk of kernicterus in newborns when sulfonamides are taken near the end of pregnancy. sulfonamides displaces bilirubin from plasma protein → cross BBB in premature infants→CNS depression. 5. Drug interaction as it ↑ plasma level of oral hypoglycemic & anticoagulants due to plasma protein displacement. 6. Most common adverse effects: Fever, skin rashes, exfoliative dermatitis, nausea, vomiting, urticaria, photosensitivity 7. Hematuria 8. Stevens-Johnson Syndrome – uncommon but serious and potentially fatal type of skin & mucous membrane eruptions 9. Stomatitis
- 104. Trimethoprim-Sulfamethoxazole (Co-Trimoxazole) Combination of sulfamethoxazole (400mg)+ tr imethoprim(80mg). Synergistically active antimicrobial agent whic h blocks two sequential steps in the folate pat hway in bacteria preventing formation of nucl eotides: Sulfamethoxazole – competitively in corporation of PABA into folic acid and Trimet hoprim inhibits dihydrofolate reductase preve nting the reduction of dihydrofolate to tetrahy drofolate
- 105. Advantages of the combination: 1. Synergestic combination (increases spectrum). 2. More potent. 3. Less and delayed bacterial resistance. 4. Bactericidal & wider spectrum including proteus, salmonella, shigella, Hemophilus influenza & gonococci. 5. Exhibits selective toxicity for bacteria which must synthesize their own folic acid. • Trimethoprim is more potent, more lipid soluble and has a greater volume of distribution than sulfa drugs • Penetrates CSF well • 65-70% of each drug is protein bound • Eliminated in the urine within 24 h – reduce dose by half if cre atinine clearance is 15-30 ml/min
- 106. Therapeutic uses 1.Urinary tract infections,gonococcal urethritis and prostatitis. 2.Salmonella & shigella infections. 3.Respiratory tract infections due to H. influenza & pneumococci. 4. Typhoid fever Adverse effects • Dermatological effects, GI effects (glossitis, NVD) CNS disturbances (headache, depression, hallucinations) Hematologic reactions( aplastic, hemolytic and macr ocytic anemia, coagulation disorders)Vasculitis, Rena l impairment or damage.
- 107. Disrupters of Cell Membranes Interference with cell membrane integrity – Few damage cell membrane e.g Polymixn B – Binds membrane of Gram – cells and alters permeability Leading to leakage of cellular contents and and hence cell death. N.B. Also bind eukaryotic cells but to lesser extent – Limits use to topical application
- 108. Polymyxins (A, B, C, D, and E) • Obtained from soil bacterium Bacillus polymyxa • Usually applied topically, often with bacitracin, to treat skin infections caused by Pseudomonas • Internally, can cause numbness in the extremities, serious kidney damage, and respiratory arrest Polymyxin B • Group of basic peptides active against Gram (-), bactericidal • Treatment of serious enteric infections(Pathogenic E. coli, Shigella, • Enterobacter, Klebsiella and Pseudomonas , not Proteus) • Poor tissue distribution • Attach to and disrupt bacterial cell membrane, bind and inactivate endotoxin
- 109. Daptomycin – Approval by FDA September 2003 for treatment of complicated skin and soft tissue infections – Mechanism of action: disruption of plasma membrane function. – Bacteriocidal against multidrug-resistant, gram- positive bacteria, Methicillin-resistant Staphylococcus aureus, Vancomycin-resistant enterococci, Glycopeptide-intermediate and - resistant S. aureus, Penicillin-resistant Streptococcus pneumoniae - Fast bacteriocidal action - Concentration-dependent killing - Post antibiotic effect - Once daily dosing & Excreted mainly by kidneys
- 110. URINARY ANTISEPTICS Urinary antiseptics (uroseptics) are agents that exert antibacterial activity in the urine but have little or no systemic antibacterial effect. Examples Nitrofurantoin, Fosfomycin Nitroxoline UTIs can be divided into two; 1. Lower tract infections • bladder (cystitis) • urethra (urethritis)) 2. Upper tract infections • ureters and kidneys (pyelonephritis)
- 111. Complicated UTI with factors that predispose to ascending bacterial infection. Uncomplicated UTI without abnormality or impairment of urine flow.
- 112. Antibiotic management of Uncomplicated UTIs LOWER TRACT First-line therapy •Sulphamethoxasole/ Trimetoprim • Fluoroquinolones • Urinary antiseptics Second-line therapy • Penicillins • Cephalosporins • Fluoroquinolones UPPER TRACT • Penicillins • Cephalosporins • Carbapenems • Fluoroquinolones (II-IV generations) • Aminoglycosides N.B. Urinary antiseptics used only in the treatment of lower urinary tract infections
- 113. Nitrofurantoin Antibacterial Spectrum • High antibacterial activity E.coli, Staphylococcus, saprophyticus • Low antibacterial activity S. aureus,Streptococcus spp, Klebsiella . MOA: inhibits bacterial DNA synthesisS S.E: Alergical reactions: rash, urticaria. • Pulmonitis and pulmonary fibrosis • Haemolysis and haemolytic anaemia in patients with G-6-PD deficiency. • Colours urine a dark orange-brown. • • Antagonism with quinolones.
- 114. ANTIMYCOBACTERIAL AGENTS • Tuberculosis (TB) is a chronic infectious disease killing about 2 million peopl e globally and about 27000 people in Uganda every year (WHO, 2011). • The situation is escalated by co-infection with HIV among TB patients with 5 0 % of the HIV patients having TB (Copp, 2003). • TB is caused by Mycobacterium tuberculosis which is a slowly growing and h ealing bacillus. It mainly affects the respiratory system (pulmonary / infectio us TB) but also affects other organs (non-infectious TB). • The bacteria possess a unique cell wall made up of mycolic acid and arabino galactan responsible for many of the medically challenging physiological cha racteristics of tuberculosis, including resistance to antibiotics and host defe nse mechanisms (Copp, 2003). • It is transmitted from person to person via cough droplets from people wit h the active respiratory disease (WHO, 2011). • Management of TB has become a serious problem due to development of multidrug Resistant TB and extensively drug Resistant TB (Pauli et al., 2005).
- 115. TREATMENT OF TB TREATMENT CONCERNS • Anti-tuberculous drugs • DOT (Directly observed therapy) • Multi-drug resistant tuberculosis • Combination therapy • Long duration of treatment FIRST LINE ANTI-TB: Isoniazid,Rifampicin,Pyrazinamide, Ethambutol. SECOND-LINE DRUGS: Streptomycin,Capreomycin, Clarithromycin,Ciprofloxacin and cycloserine.
- 116. TREATMENT OF TB Currently susceptible TB is treated with multiple drugs to a void drug resistance and to increase therapeutic outcome i n two phases for six months. An intensive phase during which four drugs are given for t wo months (rifampicin, isoniazid, pyrazinamide, and etham butol or streptomycin) FIRST LINE THERAPY. The continuation phase involves giving two drugs for four months (isoniazid and rifampicin). This long period of treatment reduces compliance and adh erence to treatment (Camacho-corona et al., 2008). This has promoted the development of multi drug resistant TB which is expensive to treat (Pauli et al., 2005) and exten sively drug resistant TB which is virtually untreatable.
- 117. MDR TB is a form of TB which is resistant to two of the first line anti TB drugs rifampicin and isoniazid. XDR TB is a form of TB resistant to all the first line drugs which are safe, two of the injectable second line drugs and atleast one fluoroquinolone MDR-TB is an increasing global problem, with most cases arising from a mixture of physician error and patient non-compliance during treatment of susceptible TB TB Prevention • Role of immunization -BCG (bacillus Calmette Guerin) • Improved social conditions- housing /nutrition • Case detection & treatment • Contact tracing • Evidence of infection / disease • Treatment of infected / diseased contacts
- 118. RIFAMPICIN
Editor's Notes
- #49: D