Introduction to Chemotherapy Pt1 Nov 2024 Notes PDF

Introduction to Chemotherapy Part One Lixin Liu Dept. of Anatomy, Physiology and Pharmacology Email: [email protected] Phone: 306-966-6300 CPPS 304.3, November 28, 2024 1...

Introduction to Chemotherapy Part One Lixin Liu Dept. of Anatomy, Physiology and Pharmacology Email: [email protected] Phone: 306-966-6300 CPPS 304.3, November 28, 2024 1 Objectives Describe how selective toxicity is achieved with given drugs Describe the mechanisms of action of given drugs Describe the harms associated with given drugs, including mechanisms of resistance 2 Overview Chemotherapy is the use of (chemicals) drugs to eradicate pathogenic organisms or neoplastic cells in the treatment of infectious diseases or cancer. Chemotherapy is based on the principle of selective toxicity, i.e., a chemotherapeutic drug inhibits a vital function of invading organisms or neoplastic cells that differs qualitatively or quantitatively from the functions of host cells. 3 The chemotherapeutic drugs includes: Antimicrobial drugs Antimicrobacterial agents Antifugal agents Antiviral agents Antiparasitic drugs Antineoplastic and immunopharmacology drugs 4 The History: The earliest use of antibiotics was probably the treatment of skin infections with moldy bean curd by ancient Chinese, Egyptians, and other cultures. The modern antibiotics can be traced to the work of Louis Pasteur and his pupil, Paul Vuillemin, who observed the antagonism of one bacterium against another (antibiosis) and predicted that substances derived from microbes would someday be used to treat infectious diseases. Several decades later, Alexander Fleming observed that the growth of his staphylococcal cultures was inhibited by a Penicillium contaminant. Fleming postulated that the fungus produced a substance (penicillin) which inhibited the growth of staphylococci. His observations eventually led to the isolation and use of penicillin for treating bacterial infections. The discovery of penicillin stimulated the discovery and development of many other antibiotics and revolutionized the treatment of infectious diseases. 5 Synthetic drugs have also provided major advances in the treatment of infectious diseases and cancer. During the Renaissance, Paracelsus used mercury compounds for the treatment of syphilis. In the late 19th and early 20th centuries, Paul Ehrlich pioneered the search for selectively toxic compounds and discovered arsphenamine (Salvarsan), an arsenical compound for the treatment of syphilis. Ehrlich, who became known as the father of chemotherapy, also studied bacterial stains as potential antimicrobial agents. He reasoned that a stain’s selective affinity for bacteria could be coupled with an inhibitory action to halt microbial metabolism and destroy invading organisms. This concept led to the discovery of sulfonamides that were originally derived from a bacterial stain called Prontosil. The sulfonamides were the first effective drugs for the treatment of systemic bacterial infections, and their development accelerated the search for other antimicrobial agents. 6 Part One: Antimicrobial Drugs Antimicrobial drugs Antimicrobacterial agents Antifugal agents Antiviral agents Antiparasitic drugs Antineoplastic and immunopharmacology drugs 7 8 Classification of Antimicrobial Drugs: based on their site and mechanism of action and are subclassified on the basis of their chemical structure cell wall synthesis inhibitors protein synthesis inhibitors metabolic and nucleic acid inhibitors cell membrane inhibitors 9 Sites of action of antimicrobial drugs. Antimicrobial drugs include cell wall synthesis inhibitors, protein synthesis inhibitors, metabolic and nucleic acid inhibitors (e.g., inhibitors of folate synthesis, of DNA gyrase, and of RNA polymerase), and cell membrane inhibitors. Cell membrane Folate synthesis RNA polymerase inhibitors inhibitors inhibitor Amphotericin Sulfonamides Ketoconazole Trimethoprim Rifampin Polymyxin Protein Ribosome Folate synthesis mRNA DNA mRNA Protein synthesis Cell wall synthesis DNA gyrase Protein synthesis inhibitors inhibitors inhibitors -Lactam antibiotics: Aminoglycosides carbapenems, Fluoroquinolones Chloramphenicol cephalosporins, Clindamycin monobactams, and Macrolides penicillins Mupirocin Other antibiotics: Streptogramins bacitracin, Fosfomycin, Tetracyclines 10 and vancomycin Antimicrobial Activity of a chemotherapeutic drug The drug’s bactericidal or bacteriostatic effect The spectrum of activity against important groups of pathogens Its concentration- and time-dependent effects on sensitive organisms 11 Effect: Bactericidal or Bacteriostatic A bactericidal drug kills sensitive organisms so that the number of viable organisms falls rapidly after exposure to the drug. A bacteriostatic drug inhibits the growth of bacteria but does not kill them. For this reason, the number of bacteria remains relatively constant in the presence of a bacteriostatic drug, and immunologic mechanisms are required to eliminate organisms during treatment of an infection with this type of drug. The same principle applies to antifungal drugs: fungicidal drug fungistatic drug 12 In vitro effects of bactericidal and bacteriostatic drugs No drug given (the control) # of viable bacteria per milliliter Bacteriostatic drug (e.g., tetracycline) Bactericidal drug (e.g., penicillin)  Time Drug Added 13 Bactericidal or Bacteriostatic Drugs Bactericidal drugs have actions that induce lethal changes in microbial metabolism or block essential activities for microbial viability. They typically produce a more rapid microbiologic response and more clinical improvement and are less likely to elicit microbial resistance. For example, drugs that inhibit the synthesis of the bacterial cell wall (e.g., penicillins ) prevent the formation of a structure required for the survival of bacteria. Bacteriostatic drugs usually inhibit a metabolic reaction needed for bacterial growth but is not necessary for survival. E.g., sulfonamides block the synthesis of folic acid, a cofactor for enzymes that synthesize DNA components and amino acids. 14 Bactericidal or Bacteriostatic Drugs Drugs that reversibly inhibit bacterial protein synthesis (e.g., tetracyclines ) are also bacteriostatic, whereas drugs that irreversibly inhibit protein synthesis (e.g., streptomycin ) are usually bactericidal. Some antibiotics, such as erythromycin, can be either bactericidal or bacteriostatic, depending on their concentration and the bacterial species against which they are used. 15 Antimicrobial Spectrum narrow-spectrum drugs extended-spectrum drugs broad-spectrum drugs 16 Concentration- and Time-Dependent Effects The minimal inhibitory concentration (MIC): the lowest concentration of a drug that inhibits bacterial growth. Based on the MIC, a particular strain of bacteria can be classified as susceptible or resistant to a particular drug. The concentration-dependent killing rate (CDKR): The post-antibiotic effect (PAE): 17 Some aminoglycosides (e.g., tobramycin) and some fluoroquinolones (e.g., ciprofloxacin) exhibit a CDKR against a large group of gram-negative bacteria, including Pseudomonas aeruginosa and members of the family Enterobacteriaceae. In contrast, penicillins and other -lactam antibiotics usually do not exhibit a CDKR. A Concentration-dependent killing rate B Post-antibiotic effect # of viable bacteria # of viable bacteria per milliliter per milliliter  Hours   Hours Hours Drug Drug Drug added added removed 18  Most bactericidal antibiotics exhibit a PAE against susceptible pathogens. For example, penicillins and macrolide antibiotics show a PAE against gram-positive cocci, and aminoglycosides show a PAE against gram-negative bacilli. Because aminoglycosides exhibit both a CDKR and a PAE, treatment regimens have been developed in which the entire daily dose of an aminoglycoside is given at one time. Theoretically, the high rate of bacterial killing produced by these regimens would more rapidly eliminate bacteria, and the PAE would prevent any remaining bacteria from replicating for several hours after the drug has been eliminated from the body. 19 Microbial Sensitivity and Resistance Laboratory Tests for Microbial Sensitivity ▪ Broth dilution test ▪ Disk diffusion method (Kirby-Bauer test) ▪ E-test method 20 Broth Dilution Test Tubes that contain a nutrient broth are inoculated with equal numbers of bacteria and serially diluted concentrations of an antibiotic. After incubation, the minimal inhibitory concentration (MIC) is identified as the lowest antibiotic concentration that prevents visible growth of bacteria. Visible growth No visible growth of bacteria Antibiotic concentration (g/mL) What concentration is the MIC in this test? 21  Disk Diffusion Method (Kirby-Bauer Test) Each disk used in the disk diffusion method is impregnated with a different antibiotic. The disks are placed on agar plates seeded with the test organism. After incubation, the zone inhibited by each antibiotic is measured. The zone diameter for each antibiotic is compared with standard values for that particular antibiotic. Susceptible Resistant Organisms for the test Intermediate 22 E-Test Method. The E-test strip is a proprietary device that uses a diffusion method to determine the MIC of an organism. The device is a plastic strip that is impregnated with a gradient of antibiotic concentrations. After the strip is placed on an agar culture of the organism, the culture is incubated. The E-test Zone of strip inhibition Agar plate with growing organisms MIC 23  The organism is classified as having susceptibility, intermediate sensitivity, or resistance to the drug tested. These categories are based on the relationship between the MIC and the peak serum concentration of the drug after administration of typical doses. In general, the peak serum concentration of a drug should be 4 to 10 times greater than the MIC for a pathogen to be susceptible to a drug. 24 Microbial Resistance to Drugs Innate Acquired Acquired drug resistance arises from: ▪ spontaneous mutation Microbes can spontaneously mutate to form resistant to a particular antimicrobial drug at a relatively constant rate, such as in 1 in 1012 organisms per unit of time. ▪ transfer of plasmids 25 Mutation and Selection A Spontaneous mutation B Transferable resistance and selection and selection R factor Recipient Donor cell plasmid cell Chromosome Sensitive strain with resistant mutant Bacterial conjugation Antibiotic added to culture Transfer of R factor plasmid Selection of Expression of R factor 26 resistant mutant Transferable Resistance Transferable resistance usually results from bacterial conjugation and the transfer of plasmids (extrachromosomal DNA) that confer drug resistance. Transferable resistance, however, can also be mediated by transformation (uptake of naked DNA) or transduction (transfer of bacterial DNA by a bacteriophage). Bacterial conjugation enables a bacterium to donate a plasmid containing genes that encode proteins responsible for resistance to an antibiotic. These genes are called resistance factors (R factors). The resistance factors can be transferred both within a particular species and between different species, so they often confer multidrug resistance. 27 Primary Mechanisms of Microbial Resistance 1. Inactivation of the drug by microbial enzymes 2. Decreased accumulation of the drug by the microbe 3. Reduced affinity of the target macromolecule for the drug 28  Mechanisms of Microbial Resistance Mechanism Examples Inactivation of the drug by Inactivation of aminoglycosides by acetylase, adenylate synthetase, and microbial enzymes phosphorylase enzymes Inactivation of penicillins and other β-lactam antibiotics by β-lactamase enzymes Decreased accumulation of Decreased uptake of β-lactam antibiotics owing to altered porins in gram-negative the drug by the microbe bacteria Decreased uptake and increased efflux of fluoroquinolones Decreased uptake and increased efflux of tetracyclines Reduced affinity of the Reduced affinity of DNA gyrase for fluoroquinolones target macromolecule for Reduced affinity of folate synthesis enzymes for sulfonamides and trimethoprim the drug Reduced affinity of ribosomes for aminoglycosides, chloramphenicol, clindamycin, macrolides, or tetracyclines Reduced affinity of RNA polymerase for rifampin Reduced affinity of transpeptidase and other penicillin-binding proteins for 29 penicillins and other β-lactam antibiotics  Some of these transport proteins are similar to human permeability glycoprotein (i.e., P-glycoprotein), which transports antineoplastic drugs out of human cancer cells and thereby confers resistance to the drugs 30 The Selection of Antimicrobial Drugs is largely based on: The cause, location, and severity of an infection The age, physiologic status, and immune competency of the patient The pharmacologic properties of antimicrobial drugs 31 Host Factors Pregnancy drug allergies age and immune status the presence of renal impairment the presence of hepatic insufficiency the presence of abscesses the presence of indwelling catheters and similar devices 32 Antimicrobial Activity laboratory tests described earlier or based on knowledge of the most common organisms causing various types of infections and the preferred drugs for these organisms (empiric selection). Empiric therapy may be used to treat serious infections until test results are available or to treat minor upper respiratory and urinary tract infections because of the predictability of causative organisms and their sensitivity to drugs. For the following table: a: Recommended drug(s) listed first, followed by alternates in no particular order. 2 or 3: refers to second or third generation cephalosporin. 33 Bacteria Antimicrobial Drugs Gram-Positive Cocci Enterococcus species Penicillin G or ampicillin plus gentamicin; vancomycin plus gentamicin; quinupristin + dalfopristin, linezolid, daptomycin, tigecycline Staphylococcus aureus Penicillin G (if sensitive), nafcillin, oxacillin, vancomycin, trimethoprim-sulfamethoxazole, linezolid, daptomycin, tigecycline Streptococcus pyogenes Penicillin G or V, a cephalosporin, a macrolide, clindamycin Viridans group streptococci Penicillin G ± gentamicin; a cephalosporin, vancomycin Streptococcus pneumoniae Penicillin G (if sensitive), a cephalosporin 2 or 3, amoxicillin + clavulanate, antipneumococcal fluoroquinolone, azithromycin, telithromycin Gram-Positive Bacilli Bacillus anthracis (anthrax) Ciprofloxacin or doxycycline, + clindamycin or rifampin Clostridiodes difficile (diarrhea, pseudomembranous Metronidazole, oral vancomycin colitis) Clostridiodes perfringens, Clostridiodes tetani Penicillin G ± clindamycin, doxycycline Corynebacterium diphtheriae Erythromycin or clindamycin Listeria monocytogenes Ampicillin (± aminoglycoside), trimethoprim-sulfamethoxazole Nocardia asteroides and other species Trimethoprim-sulfamethoxazole, minocycline, imipenem, amikacin, linezolid Gram-Negative Cocci Moraxella catarrhalis Amoxicillin + clavulanate, a cephalosporin 2 or 3, a macrolide, a fluoroquinolone Neisseria gonorrheae Ceftriaxone, cefixime, cefpodoxime 34 Neisseria meningitides Penicillin G, ceftriaxone or other cephalosporin 2 or 3, chloramphenicol Gram-Negative Bacilli Bacteroides species (anaerobes) Metronidazole, cefoxitin, carbapenem, penicillin + β - lactamase inhibitor Bordetella pertussis (whooping cough) A macrolide (azithromycin), trimethoprim-sulfamethoxazole Helicobacter pylori (peptic ulcer disease) Clarithromycin, amoxicillin, metronidazole, bismuth compounds, tinidazole, proton pump inhibitors Haemophilus influenzae Upper respiratory infections: amoxicillin + clavulanate, oral cephalosporin 2 or 3, azithromycin; serious infections: cefotaxime or ceftriaxone Pseudomonas aeruginosa Tobramycin, ceftazidime, a carbapenem, aztreonam, piperacillin + tazobactam or quinolone Most Enterobacteriaceae ( Escherichia coli; Parenteral cephalosporin 2 or 3, an aminoglycoside, piperacillin + tazobactam, a Klebsiella, Proteus, Serratia, Enterobacter, carbapenem, aztreonam, a fluoroquinolone, trimethoprim + sulfamethoxazole (urinary Citrobacter, Providencia species, and others) tract infections) Salmonella and Shigella species A fluoroquinolone; ceftriaxone (Salmonella), azithromycin (Shigella ) Campylobacter jejuni Azithromycin or erythromycin, quinolone Yersinia pestis (plague); Francisella Gentamicin, doxycycline tularensis (tularemia) Actinomycetes Chlamydiae, Ehrlichia, rickettsiae Doxycycline (all); azithromycin (chlamydiae) Spirochetes Borrelia burgdorferi (Lyme disease) Doxycycline, amoxicillin, parenteral cephalosporin 2 or 3 Borrelia recurrentis (relapsing fever) Doxycycline, penicillin G 35 Treponema pallidum (syphilis, yaws) Benzathine penicillin G, doxycycline Pharmacokinetic Properties that influence antibiotic selection Oral bioavailability, peak serum concentration, distribution to particular sites of infection, routes of elimination, and elimination half-life. An ideal antimicrobial drug for ambulatory patients would have good oral bioavailability and a long plasma half-life so that it would need to be taken only once a day. Azithromycin is an example of an antibiotic that meets these criteria. 36 Why should the peak serum concentration of an antimicrobial drug be several times greater than the MIC of the pathogenic organism for the drug to eliminate the organism? The tissue concentrations of a drug are sometimes lower than the plasma concentration. The urine concentration of an antimicrobial drug can be 10 to 50 times the peak serum concentration. For this reason, infections of the urinary tract can be easier to treat than are infections at other sites. 37  Relationship between the plasma concentration of a typical antimicrobial drug and the drug’s minimal inhibitory concentration (MIC) for five bacterial organisms (A) Streptococcuas pneumoniae Plasma drug concentration (g/mL) E (B) Staphylococcus aureus (C) Escherichia coli (D) Enterobacter cloacae (E) Pseudomonas aeruginosa D B C A  A, B, C : susceptible Drug D: intermediate in sensitivity administered E: resistant 38 The sites and routes Sites of infection that are not readily penetrated by many antimicrobial drugs include the central nervous system, bone, prostate gland, and ocular tissues. The treatment of meningitis requires that drugs achieve adequate concentrations in the cerebrospinal fluid. Some antibiotics (e.g., penicillin G) penetrate the blood-cerebrospinal fluid barrier when the meninges are inflamed, but the aminoglycosides do not. For this reason, aminoglycosides can be given intrathecally for the treatment of meningitis. Because antimicrobial drug concentrations are low in bone, patients with osteomyelitis must usually be treated with antibiotics for several weeks to produce a cure. 39 The sites and routes The prostate gland restricts the entry of some antimicrobial drugs because the drugs have difficulty crossing the prostatic epithelium and because prostatic fluid has a low pH. These characteristics favor the entry and accumulation of weak bases (e.g., trimethoprim) and tend to exclude the entry of weak acids (e.g., penicillin). Drugs that are eliminated by renal excretion (e.g., fluoroquinolones) are more effective for urinary tract infections than drugs that are largely metabolized or undergo biliary excretion (e.g., erythromycin). Antibiotics that are eliminated by the kidneys (e.g., the aminoglycosides) can accumulate in patients whose renal function is compromised, however, and their dosage must be reduced in these patients. 40 Adverse Effect Profile Consider the probable risk-to-benefit ratio when selecting drugs for treatment. The β-lactam (e.g., penicillins and cephalosporins) and macrolide (e.g., erythromycin) antibiotics cause a relatively low incidence of organ system toxicity and are often used to treat minor infections, including infections in pregnant women. The aminoglycosides (e.g., gentamicin) cause a relatively high incidence of adverse effects and are reserved for the treatment of more serious or life-threatening infections. Fluoroquinolones and tetracyclines are intermediate in their adverse effect profile. 41 Combination Drug Therapy Drug combinations are used to treat: infections that are known or suspected to be caused by more than one pathogen (mixed infections), such as intraabdominal infections caused by both aerobic and anaerobic organisms derived from the intestinal tract. life-threatening infections, such as hospital- acquired (nosocomial) pneumonia, are treated with a combination of antibiotics until the causative organism can be identified. 42 The relationship between two drugs and their combined effect: Antagonistic: the combined effect is less than the effect of either drug alone. Additive: the combined effect is equal to the sum of the independent effects. Synergistic: the combined effect is greater than the sum of the independent effects. Indifferent: the combined effect is similar to the greatest effect produced by either drug alone. 43  Bactericidal drugs are usually more effective against rapidly dividing bacteria, and their effect may be reduced if bacterial growth is slowed by a bacteriostatic drug (e.g., chloramphenicol or tetracycline). 44 Several possible interactions of two antimicrobial drugs combined in vitro No drug Drugs X and Y: Mutual antagonism # of viable bacteria per milliliter Drugs X and Y: Antagonism of Y by X Drugs X and Y: Indefference Drugs X and Y: Synergism Where is the curve  showing additive effect? Drugs Added 45 If two bactericidal drugs that target different microbial functions are given in combination, they can exert additive or synergistic effects against susceptible bacteria penicillins can have additive or synergistic effects with aminoglycosides, which inhibit protein synthesis, against gram-negative bacilli such as P. aeruginosa, and against gram-positive enterococci and staphylococci. sulfamethoxazole and trimethoprim inhibit sequential steps in bacterial folate synthesis and have synergistic activity against organisms that may be resistant to either drug alone. 46 Combination therapy may also serve to reduce the emergence of resistant organisms e.g., about 1 in 106 Mycobacterium tuberculosis organisms will mutate to a resistant form during treatment with any single drug. The rate of mutation to form resistant to two drugs is the product of the individual drug resistance rates, or about 1 in 1012 organisms. Because fewer than 1012 organisms are usually present in a patient with tuberculosis, it is unlikely that a resistant mutant will emerge during combination therapy. In the case of tuberculosis, combination therapy can delay emergence of resistance even though the drugs may not exhibit a synergistic effect against the microbe. 47 Prophylactic Therapy The prevention of infections requires: the sterilization of diagnostic and surgical instruments the use of disinfectants to reduce environmental pathogens in hospitals and clinics the disinfection of skin and mucous membranes before invasive procedures antimicrobial drugs are also administered prophylactically ▪ to reduce the incidence of infections associated with surgical and other invasive procedures ▪ to prevent disease transmission to close contacts of infected persons 48  Prevention of Infection during Surgical and Invasive Procedures Infection Pathogens Preferred Drugs Endocarditis in persons with valvular Amoxicillin or heart disease undergoing oral, dental clindamycin or upper respiratory procedures Surgical wound infections Staphylococcus aureus , Cefazolin enteric gram-negative rods Surgical abdominal infections Enteric gram-negative Cefoxitin, cefotetan, bacilli and anaerobes ertapenem, or cefazolin + metronidazole 49  Prevention of Disease Transmission in Persons at Increased Risk Infection Preferred Drugs Genital or perinatal herpes Acyclovir simplex HIV infection in newborns Highly active antiretroviral therapy (HAART) Influenza, type A and B Oseltamivir or zanamivir Malaria Chloroquine, or atovaquone + proguanil, doxycycline, or mefloquine Meningococcal disease Rifampin, ciprofloxacin, or ceftriaxone Tuberculosis Isoniazid or rifampin; isoniazid + rifapentine 50 Summary of Important Points Antibiotics are substances produced by one microbe that inhibit the growth or viability of pathogenic organisms. These include cell wall synthesis inhibitors, protein synthesis inhibitors, metabolic and nucleic acid inhibitors, and cell membrane inhibitors. Antimicrobial drugs can be characterized as bactericidal (able to kill microbes) or bacteriostatic (able to slow the growth of microbes). They can also be characterized as narrow-spectrum, broad-spectrum, or extended-spectrum based on their range of antimicrobial activity. Laboratory tests used to determine microbial sensitivity to drugs include the broth dilution test, the disk diffusion method (Kirby-Bauer test), and the E-test method. The broth dilution test and E-test method are used to determine the MIC, which is the lowest drug concentration that inhibits microbial growth in vitro. 51  Acquired microbial resistance arises by mutation and selection or by transfer of genes encoding resistance factors. The most common mechanism of transferable resistance is bacterial conjugation followed by the exchange of plasmids containing resistance genes. The mechanisms responsible for microbial resistance to a drug include inactivation of the drug by microbial enzymes, decreased uptake or increased efflux of the drug by the microbe, and reduced affinity of the target macromolecule for the drug. The selection of an antimicrobial drug for treating a particular infection requires consideration of host factors (pregnancy, drug allergies, age and immune status, and the presence of concomitant diseases) and drug characteristics (antimicrobial activity, pharmacokinetic properties, adverse effect profile, cost, and convenience). 52  Combinations of antimicrobial agents can be used for the treatment of infections caused by more than one organism, the empiric treatment of serious infections, and the prevention of antibiotic resistance. A combination of two synergistic drugs is sometimes employed to treat an infection caused by a single microbe. Antibiotic prophylaxis is used to prevent infections during surgical and other invasive procedures and to prevent the transmission of infectious diseases to persons at risk The summary and the three tables are from Brenner and Stevens’ Pharmacology, 6th Ed. 53