Chemotherapy

At the end of this course, students should be able to: 1. describe host-drug-pathogen relationship in chemotherapy; 2. list the various ways of classification of antimicrobials based on type of organism against which primarily active, chemical structure, spectrum of activity; 3. define the common terminologies used in antimicrobial chemotherapy and enumerate the properties of an ideal antimicrobial agent; 4. describe the concept of combination therapy and identify the choices of antibacterial drugs used to treat common infections and enumerate the classes of antibacterial agents; 5. explain pharmacology of β-lactam antibiotics including their potential for cross- allergenicity, distribution characteristics, and contraindications of each group; 6. discuss the differences in spectrum of activity between the natural penicillins, the penicillinase-resistant penicillins, the aminopenicillins, the carboxypenicillins, the ureidopenicillins and the β-lactamase inhibitor combinations with attention to the specific drugs that have activity against Staph. aureus, Pseud. aeruginosa and Bact. fragilis; 7. list the differences in spectrum of activity between the four generations of cephalosporins, as well as the carbapenems and aztreonam, pharmacology of the cephalosporins, the 103 carbapenems and aztreonam, including risk of cross-reactivity between these classes and the penicillins; 8. explain the pharmacology of the various generations of quinolones, particularly those with activity against Staph. aureus, Strep. pneumonia, Pseud. aeruginosa, atypical bacteria and anaerobes; 9. describe pharmacology of aminoglycosides, with attention to drugs that display activity against Staph. aureus, Pseud. aeruginosa and tuberculosis; 10. enumerate factors that may alter pharmacokinetics of aminoglycosides and their dosage; 11. explain pharmacology of vancomycin and other drugs with activity against gram-positive aerobes; 12. describe pharmacology of tetracyclines and sulphonamides and the potential therapeutic advantages of the glycylcycline antibiotics and discuss pharmacology of clindamycin and metronidazole; 13. explain the necessity of dosage adjustment of antibacterial therapy in renal insufficiency and removal by haemodialysis; 14. describe the mechanisms by which bacteria develop resistance to the different classes of antibacterial agents; 15. enumerate treatment principles in tuberculosis, including major determinant outcome of treatment and ways to improve this; 16. explain the mechanisms of resistance in TB infection and reasons for resurgence and ways to stop epidemic; 17. describe the therapeutic indications of rifampicin and explain the pharmacology of antituberculosis drugs; 18. discuss pharmacology of drugs used in the treatment of leprosy; 19. enumerate distinctions between protozoal and helminth infections; 20. discuss the general approaches to anti-parasitic and anti-helminthic therapy; 21. list the drugs used in treatment of the specified parasitic and helminthic infections; 22. explain the pharmacology of the major drugs used in treatment of protozoal and helminth infections; and 23. list factors that lead to antimicrobial treatment failure.

Definition of common pharmacodynamics terminology used to describe the effects of antimicrobial therapy. Bacteriostatic. Bactericidal. Concentration-dependent and time- dependent bactericidal activity. Antimicrobials that display each of these properties. Combinations of antibiotics. Choice of antibacterial drugs in common infections. Penicillin, differences in chemical structure between the penicillins. Cephalosporins. Carbapenems and monobactams. General characteristics of β-lactam antibiotics including their mechanism of action. Elimination half-life, route of elimination and potential for cross-allergenicity. Differences in spectrum of activity between the natural penicillins. The penicillinase-resistant penicillins. The aminopenicillins. The carboxypenicillins. The ureidopenicillins and the β- lactamase inhibitor combinations with attention to the specific drugs that have activity against Staph. aureus, Pseud. aeruginosa and Bact. fragilis, distribution characteristics into the cerebrospinal fluid, urinary tract, lungs, skin/soft tissue and bone. Indications. Mechanism of action. Adverse effects and contraindications of each group. Mechanism by which bacteria develop resistance to penicillins. Cephalosporins, carbapenems and monobactams. Differences in spectrum of activity between the four generations of cephalosporins, as well as the carbapenems and aztreonam, indications, mechanism of action, adverse effects and contraindications, mechanism by which bacteria develop resistance, pharmacokinetics particularly those drugs that penetrate the CNS and those that require dosage adjustment, risk of cross-reactivity between these classes and the penicillins, major clinical uses of representative drugs within each generation of cephalosporin, carbapenems and aztreonam. 104 Quinolones. The various generations, spectrum of activity of the older and respiratory fluoroquinolones, particularly those with activity against Staph. aureus, Strep. Pneumonia, Pseud. aeruginosa, atypical bacteria and anaerobes, indications, mechanism of action, adverse effects, contraindications and major drug interactions, mechanism of resistance to the drugs. Major pharmacokinetic differences in terms of oral bioavailability, half-life, dosing interval, CSF penetration, route of excretion, necessity of dosage adjustment in renal insufficiency and removal by haemodialysis. Aminoglycosides. Spectrum of activity with attention to drugs that display activity against Staph. aureus, Pseud. aeruginosa and tuberculosis, indications, mechanism of action, adverse effects, contraindications and major drug interactions; mechanism of resistance to the drugs, major pharmacokinetic characteristics including understanding of patient characteristics that may alter the pharmacokinetic parameters of volume of distribution and clearance, as well as how these alterations may influence dosing. Vancomycin and other drugs with activity against Gram-positive aerobes. General spectrum of activity of vancomycin, quinupristin-dalfopristin, linezolid and daptomycin, indications, mechanism of action, adverse effects and contraindications, mechanism of resistance to the drugs, major pharmacokinetic characteristics including bioavailability, half-life, dosing interval, CSF penetration, route of excretion, necessity of dosage adjustment in renal insufficiency and removal by haemodialysis. Tetracyclines and sulphonamides. Spectrum of activity, indications, mechanism of action, adverse effects, contraindications and major drug interactions, mechanism of resistance to the drugs, major pharmacokinetic differences in terms of oral bioavailability, half-life, dosing interval, CSF penetration, route of excretion, necessity of dosage adjustment in end-organ dysfunction and removal by haemodialysis, potential therapeutic advantages of the glycylcycline antibiotics. Clindamycin and metronidazole. Spectrum of activity with emphasis on activity against anaerobes and Clostridium difficile, indications, mechanism of action, adverse effects, contraindications and major drug interactions, mechanism of resistance to the drugs, major pharmacokinetic differences in terms of oral bioavailability, half-life, dosing interval, CSF penetration, route of excretion, necessity of dosage adjustment in end-organ dysfunction and removal by haemodialysis. Antimycobacterial drugs. Indications, mechanism of action, adverse effects and contraindications of the first line antituberculosis drugs, treatment principles in treating M. tuberculosis infection, therapeutic indications of rifampicin, mechanisms of primary and secondary resistance in M. tuberculosis infection, reasons for resurgence of tuberculosis and ways to stop epidemic, major determinant outcome of treatment and ways to improve this basic pharmacology of drugs used in the treatment of leprosy (sulphones). Anti-parasitic drugs, distinction between protozoal and helminth infections, general approaches to therapy, general strategies and relevant drugs used to treat the following infections, malaria Amoebiasis, African Trypanosomiasis, American trypanosomiasis, Cryptosporidiosis and Toxoplasmosis. General strategies and relevant drugs used to treat major helminth infections. Principal indications, mechanism of action, adverse effects and contraindications of the major drugs used in treatment of protozoal and helminth infections. Malaria. Chloroquine, diamino pyrimidines, proguanil, primaquine, quinine and quinidine, artemisinins, antibiotics. Amoebiasis, metronidazole, emetine, dihydroemetine, iodoquinol, paromycin, amoebic liver abscess. Trypanosomiasis. Suramin, melarsoprol, melarsonyl, nifurtimox, benznidazole. Cryptosporidiosis, nitazoxanide. Toxoplasmosis, pyrimethamine, folinic acid, sulfadiazine, clindamycin. Schistosomiasis and paragonimiasis. Niridazole, antimony compounds, bithionol. Leishmaniasis, Sodium stibogluconate, pentamidine. Filariasis, diethylcarbamazine. Tapeworms, niclosamide. Roundworms, piperazine, thiabendazole, tetrachlorethylene, mebendazole. Antimycotic drugs Indications, mechanism of actions, adverse effects and contraindications of the most commonly used drugs; polyene antifungals (amphotericin B, nystatin), azole antifungals (imidazoles such as miconazole, clotrimazole and ketoconazole, triazoles such as fluconazole and itraconazole), echinocandins (caspofungin, micafungin and anidofungin) and others such as 5-flucytosine, griseofulvin and terbinafine. Antiviral Drugs. 105 Mechanism of action of major nucleoside and non-nucleoside analogues. Viruses targeted by the major nucleoside and non-nucleoside analogues and the relative benefits of each drug. Indications, mechanism of action and clinical efficacy of inhibitors of viral entry or dissemination. Mechanism of action leading to antiviral resistance. How drugs targeting different stages of viral infection can be synergistic when administered simultaneously. Nucleoside analogues (acyclovir, ganciclovir, idoxuridine, vidarabine, azidothymidine, dideoxy inosine, dideoxy cytosine). Non-nucleoside analogues (ribavirin, foscarnet), inhibitors of viral entry and dissemination (amantadine, neuraminidase inhibitors, pieconoril, interferons, passive antibody transfer). Antiretroviral drugs. How distinct antiretroviral drug classes target the different phases of HIV replication cycle, diagnostic criteria and therapeutic goals, indications, clinical uses, major adverse effects, contraindications and significant drug interactions for each class, utility and effectiveness of combination therapy, influence of presence of co-morbid conditions on antiviral regimen; nucleoside/nucleotide reverse transcriptase inhibitors, non-nucleotide reverse transcriptase inhibitors, protease inhibitors, viral integrase inhibitors, fusion inhibitors and chemokine receptor antagonists. Drugs used in treatment of malignant diseases. Major features of malignant disease. Review of cell kinetics, cell cycle specificity, cell cycle non- specificity. Cancer cell vs. bacterial infections. Importance of tumour cell heterogeneity and the development of resistance to chemotherapy as critical factors in determining treatment outcome. Process of antineoplastic drug development. Criteria for determining response to antineoplastic drugs. Importance of tumour staging in patient management. General principles of antineoplastic drug treatment. Rationale for administration of adjuvant chemotherapy. Concept of multiple drug-resistance, cumulative toxicity, schedule independent toxicity, concept of hormonally sensitive neoplasms and their treatments. Pharmacology of cytotoxic drugs. Characteristic indications, adverse effects, mechanism of resistance. Alkylating drugs (mechlorethamine, cyclophosphamide, chlorambucil, melphalan, busulfan). Antibiotics (Actinomycin D, Daunorubicin, Anthracycline mithramycin, Adriamycin), Antimetabolites (methotrexate, cytarabine, 5-flurouracil), Miscellaneous (procarbazine, nitroureas, hydroxyureas). Radioactive isotopes. Adrenal corticosteroids. Steroid hormones and antagonists. Drugs for immunotherapy.