Introduction to Chemotherapeutic Agents

Introduction to Chemotherapeutic Agents Antimicrobial Agents • Substances that kill bacteria without harming the host. • History: – Arsenic: 1800s for syphilis. – Sulfonamides: 1935. – Penicillin( Antibiotics): 1940. – Antimicrobials have revolutionized the treatment of bacterial infections as well as enhanced the advancement of medical and surgical treatment. – Patient’s natural resistance plays a major role. 2 Importance of Antimicrobials • Helped control, treat, eradicate, and prevent many serious and very common diseases( syphilis, gonorrhea, TB). Military importance • Enhanced the outcomes of many aggressive or new surgical and instrumental procedures(heart surgery, laparoscopy). • Penicillin discovery was listed as the most important drug discovery in the 20th century. 3 Definitions • Chemotherapeutic agent: – Any chemical compound that selectively acts on microbes or cancer cells. • Antimicrobial Agent: – An agent( natural, semisynthetic, or synthetic) that selectively kills or slows down the growth of microbes in vitro and in in vivo when used in low concentration. • Antibacterial Agent: – An agent that kills or slows down the growth of bacteria. • Antibiotic Agent: – A natural substance produced by a micro-organism to kill another microbe. 5 Definitions • Disinfectants: – Agents that kill bacteria on the surface of objects like surgical instruments or floors: • Chemical: e.g. phenol which is too toxic for skin surfaces • Physical: ionizing radiation or high heat( sterilization and pasteurization) • Antiseptics: – Agents used topically to affect bacteria on the surface of the skin, or mouth cavity. e.g. iodine or 70% alcohol 6 Classifications of Antibacterial Agents • Antibacterials can be classified according to: • Chemical Structures : – Beta lactams, Aminoglycosides, Sulphonamides, Quinolones. Etc.... • Mechanism of Action • Type of Action: – Bacteriostatic – Bactericidial . • Spectrum of Activity: – Antistaph, Anti TB, Anti Richetsia • Width of the Spectrum: – Broad or Narrow 7 Narrow Spectrum vs Broad Spectrum • Relates to the number of microbes that are susceptible to the action of the drug i.e. Narrow (limited number) or Broad (wide) – Penicillin G is a narrow spectrum drug because it is only effective against gram-positive microbes – Tetracyclines are broad spectrum drugs effective against gram-positive and gram-negative microbes. Superinfection – Wide spectrum antimicrobial, does not mean superiority. – Wide spectrum drugs might cause • Note: Never confuse these terms with potency levels of the drugs or efficacy (i.e. Narrow are weak, and Broad are strong). 8 Narrow Spectrum vs Broad Spectrum Narrow Spectrum vs Broad Spectrum • Broad spectrum antibiotics are used when the infectious agent is unknown. • Narrow spectrum antibiotics are prescribed when the micro-organisms have been identified from tissue samples. 10 Mechanisms of Action • Inhibition of Cell Wall Synthesis • Disruption of Cell Membrane • Inhibition of Protein Synthesis • Interference with Metabolic Processes 11 Main Targets of Antimicrobials Summary of Common Antimicrobials Beta-lactams (penicillins, cephalosporins) Broad-spectrum antibiotics. Flucloxacillin and co-amoxicillin are effective against some penicillin-resistant organisms. Aminoglycosides (streptomycin, gentamicin, tobramycin) Effective against gram negative bacteria e.g. Pseudomonas. Reserved for serious infections e.g. septicaemia, meningitis, hospital-acquired pneumonia. Glycopeptides (vancomycin, teicoplanin) Effective against Staphylococci resistant to other drugs, including many strains of MRSA. Tetracyclines (doxycycline, minocycline) Broad-spectrum antibiotics 14 Summary of Common Antimicrobials Macrolides (erythromycin) Broad-spectrum antibiotics, prescribed if patient is allergic to penicillins. Metronidazole Prescribed for surgical prophylaxis, bacterial vaginosis, pressure sores, leg ulcers. Quinolones (ciprofloxacin) Effective against gram negative bacteria, gonorrhoea, gastro-intestinal infections. Antitubercular drugs (rifampicin, isoniazid, rifabutin, streptomycin) Reserved for treatment/ containment of tuberculosis(TB). sulphonamides (cotrimoxazole, trimethoprin) Co-trimoxazole is reserved for serious infections associated with HIV/AIDS. Trimethoprin is prescribed for urinary tract infections. 15 Inhibition of Cell Wall Synthesis • Most bacteria possess a relatively rigid cell wall to protect from osmotic changes. – When bacteria divide, a new cell wall is synthesized. – Interruption of this synthesis, leads to new microbes which are susceptible(vulnarable) to external osmotic influences, causing cell rupture and death. • Examples: Penicillins, cephalosporins, vancomycin and bacitracin 16 Disruption of the Microbial Cell Membrane • This mechanism involves effects on cell membrane mechanisms of transportation leading to increased permeability of membranes, and consequently, external influences will have greater effect leading to death of the bacteria. • Examples: Polymyxin, Colistin Note: These agents are more toxic systemically than agents that inhibit cell wall synthesis. 17 Inhibition of Protein Synthesis • Proteins are vital for growth and repair. • These drugs act either at: – Site of protein synthesis (Ribosomes) – Within the nucleus by inhibiting synthesis of nucleic acids • DNA replication / RNA synthesis = TRANSCRIPTION • Examples: Tetracyclines, aminoglycosides and macrolides (erythromycin) • Drugs in this group exploit structural differences between microbial and human cells – This effect inhibits growth, but does not lead to death. – High dose can lead to toxicity. 18 Interference with Metabolic Processes • Agents working through this mechanism are structurally similar to Para-aminobenzoic acid (PABA) which is a precursor of folic acid, which is necessary for nucleic acid and protein synthesis and consequently, bacterial growth. – Drugs in this group exploit microbial dependence on synthesizing their own folic acid, whilst humans get it from diet. • Examples: Sulphonamides, Trimethoprim 19 Uses of Antimicrobials • Treatment of bacterial infections in accordance with culture and sensitivity testing or knowledge of prevalent organisms. • Promoting growth of animal herds. • Prophylaxis: – surgery e.g. gastro-intestinal surgery, joint replacement. – meningitis contacts – surgical/ dental procedures in patients with artificial heart valves or heart valve lesions. 20 How Antibiotics Promote Animal Growth • Stimulation of intestinal synthesis of vitamins by bacteria. • Reduction in total numbers of bacteria in the intestinal tract with a lowering of competition between microorganisms and host animals for nutrients. • Inhibition of harmful bacteria which may be mildly pathogenic or toxin-producing. Antimicrobial Resistance • Primary Resistance: • Acquired Resistance: – By mutation (about 1 in 10 million )or by sharing the resistance genes of resistant organisms. • Clinical Resistance: – Failure of an antimicrobial to eradicate infection, despite the apparent ability of the agent to kill the microbe ' in vitro. – May be due to impaired host immunity, inadequate drug delivery, and foreign material in the site of a wound. 22 Methods of Resistance • Diminished transport into the bacterium: – The bacterium loses the porin that normally transports the antibiotic into the cell. – The bacterium has a pump that pumps out the drug. • Altered binding site: – The PBP can still carry out its function, but the drug can no longer bind to it. • Enzymes that break down the antibiotic: – Best examples are beta lactamases. – There are many other enzymes that break down aminoglycosides, chloramphenicol, and so on. • Multiple drug resistance involving all these mechanisms 23 Antimicrobial Misuse • Taking antimicrobials when they are not needed: – For undiagnosed fever – For viral infections • Taking antimicrobials incorrectly: – Stopping treatment when symptoms disappear - not finishing the whole dose of the prescription to save for future use. – Sharing or using someone else’s medicine. – Using a lower dose • Antimicrobial misuse is the main cause for antimicrobial resistance. Choosing an Antibacterial – The infecting organism. – The correct antibacterial. – Site of infection. – Route of administration. – Drug history of the patient. – Complicating factors such as pregnancy. – Cost. 27