Principles of chemotherapy

Principles of chemotherapy

1. I ntroduction to C hemotherapy G Vijay Narasimha Kumar Asst. Professor, Dept . of . Pharmacology Sri P admavathi S chool of Pharmacy

2. Overview Objectives History Definitions Important concepts References

3. Objectives To bring awareness in students regarding the significant contributions of scientists in the emergence of Chemotherapy. To impart knowledge concerning key terms and concepts in chemotherapy.

4. History Humankind has been subject to infection by microorganisms since before the dawn of recorded history 3 . Infectious diseases and cancers are among the most deadly afflictions plaguing human societies 1 . Antibiotics are the most frequently prescribed medications today to treat infections although microbial resistance due to evolutionary pressures and misuse threatens their continued efficacy 3 .

5. Centuries earlier humans had learned to use crude preparations empirically for the topical treatment of infections. Chinese used soya bean curd and moldy bread for carbuncles & boils. Greeks (Hippocrates) used wine to treat wounds 2 .

6. Bacteria Antony Leeuwenhoek was the first person to see bacteria and he is often regarded as the “ Father of Microbiology”. Van Leeuwenhoek discovered " protozoa " - the single-celled organisms and he called them " animalcules ". He also improved the microscope and laid foundation for microbiology. He is often cited as the first microbiologist to study muscle fibers, bacteria and spermatozoa 5 .

7. Specific infectious disease – Specific microorganism Robert Heinrich Herman Koch , was a celebrated German physician, pioneering microbiologist and founder of modern  bacteriology. H e is known for his role in identifying the specific causative agents  and for giving experimental support for the concept of infectious disease. He showed that specific microorganisms could always be isolated from the excreta and tissues of people with particular infectious diseases and that these same microorganisms were usually absent in healthy individuals 3,6 .

8. Figure: Koch’s Postulates 3

9. He is well known for his role in identifying the specific causative agents of  tuberculosis, cholera, and  anthrax . As a result of his groundbreaking research on tuberculosis , Koch received the  Nobel Prize in Physiology or Medicine in 1905 3,6 .  

10. Antibiosis Antibiosis  is a biological interaction between two or more organisms that is detrimental to at least one of them; it can also be an antagonistic association between an organism and the metabolic substances produced by another . Louis Pasteur reported in 1877 that when common bacteria are introduced into a pure culture of anthrax bacilli, the bacilli died and that an injection of deadly anthrax bacillus into a laboratory animal was harmless if common bacteria are injected with them 3 .

11. Figure: Harposporium ( centre ) showing antibiosis against Paecilomyces varioti 7

12. Paul Ehlrich – Father of Chemotherapy Paul Ehrlich  was a German physician and scientist who worked in the fields of hematology, immunology, and  antimicrobial chemotherapy . The methods he developed for staining tissue made it possible to distinguish between different types of blood cells, which led to the capability to diagnose numerous blood diseases. His laboratory discovered   arsphenamine  ( Salvarsan ), the first effective medicinal treatment for  syphilis , thereby initiating and also naming the concept of chemotherapy. Ehrlich popularized the concept of a  magic bullet . In 1908, he received the  Nobel Prize  in Physiology or Medicine for his contributions to immunology 8 .

13. Alexander Fleming Sir Alexander Fleming   was a Scottish  biologist, pharmacologist and botan is t . Following World War I, Fleming actively searched for anti-bacterial agents, having witnessed the death of many soldiers from sepsis  resulting from infected  wounds 9 .   .

14. Testing the nasal secretions from a patient with a heavy cold, he found that nasal mucus had an inhibitory effect on bacterial growth . This was the first recorded discovery of  lysozyme , an enzyme present in many secretions including tears, saliva, human milk as well as mucus. Lysozyme degrades the bonds in bacterial peptidoglycan cell walls, particularly in Gram-positive organisms. Unfortunately, lysozyme had little therapeutic potential 9 . Alexander Fleming - Lysozyme

15. Alexander Fleming - Penicillins Due to difficulties in cultivation and purification of penicillins , Fleming finally abandoned penicillin. N ot long after he did,  Howard Florey  and  Ernst Boris Chain  at the Radcliffe Infirmary in Oxford took up researching and mass-producing it 9 . "When I woke up just after dawn on September 28, 1928, I certainly didn't plan to revolutionize all medicine by discovering the world's first antibiotic, or bacteria killer," Fleming would later say, "But I suppose that was exactly what I did.“

16. They started mass production after the bombing of  Pearl Harbor . By   D-Day in 1944, enough penicillin had been produced to treat all the wounded in 2 nd world war 9 . They were awarded Nobel prize in Physiology and Medicine for the year 1945.

17. Gerhard Domagk - Sulphonamides Gerhard Johannes Paul Domagk   was a   German  pathologist and bacteriologist. He is credited with the discovery of Sulfonamidochrysoidine (KI-730 )– the first commercially available antibiotic (marketed under the brand name Prontosil ) – for which he received the 193 9   Nobel Prize in Physiology or Medicine.  Domagk's work on sulfonamides eventually led to the development of the antituberculosis drugs thiosemicarbazone and  isoniazid , which helped to curb the epidemic of tuberculosis which swept Europe after World War II 10 .

18. Selman Abraham Waksman  was a Russian-born, Jewish-American inventor, biochemist and microbiologist whose research into organic substances, largely into organisms that live in  soil and their decomposition  promoted the discovery of  Streptomycin , and several other  antibiotics such as   actinomycin ,  clavacin ,   streptothricin ,  grisein ,  neomycin,  fradicin ,  candicidin ,  candidin etc., Selman Abraham Waksman - Streptomycin Waksman was awarded the Nobel Prize in 1952 "for his discovery of streptomycin, the first antibiotic effective against tuberculosis ."

19. In rapid succession, deliberate searches of the metabolic products of wide variety of soil microbes led to the discovery of --- Trythricin – 1939 Streptomycin – 1943 Chloramphenicol – 1947 Chlortetracycline – 1948 Neomycin – 1949 Erythromycin – 1952 These drugs ushered in the age of so called “ miracle drugs ”. Hence 1940-60 is called “ Golden age of Anti- Microbials ” 3 .

20. Key Terms Infection  is the invasion of an organism's body tissues by disease-causing agents, their multiplication, and the reaction of host tissues to these organisms and the toxins they produce . Infectious disease , also known as transmissible disease  or communicable disease, is illness resulting from an infection . Disease causing agent is also called infectious agent. A disease  is a particular abnormal condition, a disorder of a structure or function, that affects part or all of an organism. Disease is often construed as a medical condition associated with specific symptoms and  signs. Illness  and  sickness  are generally used as synonyms for  disease 12 .

21. If the infectious agent produces no clinical evidence of disease, the infection is called subclinical or asymptomatic. A detectable alteration in normal tissue function is called disease . Pathogenicity is the ability to produce disease; thus a pathogen is a microorgnism that causes disease. True pathogen causes disease or infection in a healthy individual. Opportunistic pathogen causes disease only in a susceptible individuals. Communicable disease is the ability of the infectious agent to be transmitted to an individual by direct or indirect contact or as an airborne infection 12 . Key Terms

22. Key Terms A  medical sign  is an  objective  indication of some medical fact or characteristic that may be detected and still or video photographed or audio-recorded by a patient or anyone, especially a  physician , before or during a physical examination of a patient. A  symptom   is a departure from normal function or feeling which is noticed by a  patient , reflecting the presence of an unusual state, or of a disease. A symptom is subjective , observed by the patient ,  and cannot be measured directly . For example , whereas a tingling paresthesia  is a symptom (only the person experiencing it can directly observe their own tingling feeling),  erythema  is a sign (anyone can confirm that the skin is redder than usual ) 12 .

23. Key Terms Morbidity  (from Latin  morbidus , meaning "sick, unhealthy") is a diseased state, disability, or poor health due to any cause. A  syndrome   is the association of several medical signs, symptoms, and or other characteristics that often occur together . Incubation period   is the time between infection and the appearance of symptoms . L atency period   is the time between infection and the ability of the disease to spread to another person, which may precede, follow, or be simultaneous with the appearance of symptoms 12 .

24. Figure: Incubation and Latent period

25. Disease – Stages An  acute disease  is a short-lived disease, like the common cold . A  chronic disease  is one that lasts for a long time, usually at least six months. During that time, it may be constantly present, or it may go into remission and periodically relapse. A flare-up can refer to either the recurrence of symptoms or an onset of more severe symptoms . A refractory disease is a disease that resists treatment, especially an individual case that resists treatment more than is normal for the specific disease in question 12 .

26. Progressive disease  is a disease whose typical natural course is the worsening of the disease until death, serious debility, or organ failure occurs.  A   cure  is the end of a medical condition or a treatment that is very likely to end it. R emission  refers to the disappearance, possibly temporarily, of symptoms 12 .

27. Key Terms Antimicrobial chemotherapy involves treatment  of  systemic/topical infection  using chemical agents or drugs that  are   selectively toxic to the causative  ag-ent  of the disease, such as  a virus , bacterium, or other  microorganism without harming the host cells 11 .

28. Figure: Venn diagram showing Relationship between antimicrobial agents

29.   Antibiotics are a broader range of antimicrobial compounds which can act on fungi, bacteria, and other compounds. Although  antibacterials come under antibiotics,  antibacterials  can kill only bacteria. There are four types of antimicrobial chemotherapy: Antibacterial chemotherapy , the use of antibacterial drugs to treat bacterial infection. Antifungal chemotherapy , the use of antifungal drugs to treat fungal infection. Antiprotozoal chemotherapy , the use of antiprotozoal drugs to treat protozoan infection. Antiviral chemotherapy , the use of antiviral drugs to treat viral infection 11 .

30. Antiseptics: Agents that kill or inhibit growth of microorganisms when applied to tissues. Disinfectants: Agents killing or inhibiting growth of microorganisms when applied to nonliving objects. Cidal (Irreversible inhibition of growth) An agent that kills microorganisms. Bactericidal , fungicidal, viricidal … etc e.g . Penicillin’s, Cephalosporin’s, Aminoglycosides… etc Static (Reversible inhibition of growth) An agent that inhibits growth of microorganism. Bacteriostatic , fungistatic , Viristatic etc., e.g . Sulfonamides, Tetracyclines, Macrolide antibiotics… etc 11 .

31. A static agent in large doses becomes cidal and cidal agents in low doses become static. One drug ( chloramphenicol) could be bacteriostatic for one organism (gram negative rods), & cidal for another (S. pneumoniae ) 1 .

32. Principles of Antimicrobial therapy Antimicrobial therapy takes advantage of the biochemical differences that exist between microorganisms and human beings. Antimicrobial drugs are effective in the treatment of infections because of their selective toxicity; that is, they have the ability to injure or kill an invading microorganism without harming the cells of the host 1,4 .

33. Mechanism of Selective Targeting The goal of antimicrobial therapy is selective toxicity , i.e., inhibiting pathways or targets that are critical to pathogen at concentrations of drug lower than those required to affect host pathways. Selectivity can be realized by attacking: Targets unique to pathogen and that are not present in the host. Targets in the pathogen that are similar but not identical to the host. Targets in the pathogen that are shared by the host but that vary in importance between pathogen and host and thus impart selectivity 1,4 .

34. S.no Type of Targeting Mechanism Example 1 Unique Drug targets genetic or biochemical pathways that is unique to pathogen Bacterial cell wall synthesis inhibitor, Fungal cell wall and membrane damagers 2 Selective Drug targets protein isoform that is unique in pathogen Dihydrofolate reductase inhibitors, Protein synthesis inhibitors 3 Common Drug targets metabolic requirements that is specific to pathogen Antimetabolites Ex: 5-Flourouracil 1,4 Mechanism of Selective Targeting

35. Therapeutic Index (TI) The ratio of toxic dose to therapeutic dose of a drug is called therapeutic index of a drug. A lso referred to as  therapeutic window  or  safety window  or sometimes as  therapeutic ratio 11 . TD 50 T herapeutic I ndex = ED 50

36. The TI is therefore an indication how selective the drug is in producing the desired effects. A highly selective drug can often be prescribed safely because of the large difference between its therapeutic and toxic concentrations. The margin of safety is less in less selective drug , because of its low therapeutic index 11 .

37. Selection of Antimicrobial agent Selection of the most appropriate antimicrobial agent requires knowing 4 -- T he organism’s identity. T he organism’s susceptibility to a particular agent. T he site of the infection. P atient factors. T he safety of the agent. T he cost of therapy.

38. Identification of the infecting organism Characterizing the organism is central to selection of the proper drug. Body fluids that are normally sterile are taken for identification are -- B lood S erum C erebrospinal fluid [ CSF] P leural fluid S ynovial fluid P eritoneal fluid U rine 4 . Generally it is necessary to culture the infective organism to arrive at a conclusive diagnosis and determine the susceptibility to antimicrobial agents. Thus, it is essential to obtain a sample culture of the organism prior to initiating treatment.

39. Figure: Some laboratory techniques that are useful in the diagnosis of microbial diseases 4 .

40. Empiric therapy prior to identification of the organism Ideally , the antimicrobial agent used to treat an infection is selected after the organism has been identified and its drug susceptibility established . However, in the critically ill patient, such a delay could prove fatal , and immediate empiric therapy is indicated 4 .

41. Acutely ill patients with infections of unknown origin require immediate treatment. Ex: A neutropenic patient (one who is predisposed to infections due to a reduction in neutrophils ) A patient with meningitis If possible, therapy should be initiated after specimens for laboratory analysis have been obtained but before the results of the culture and sensitivity are available 4 . Timing:

42. Drug choice in the absence of susceptibility data is influenced by the site of infection and the patient’s history. For example: Previous infections Age Recent travel history recent Antimicrobial therapy Immune status Whether the infection was hospital- or community-acquired Broad-spectrum therapy may be indicated initially when the organism is unknown or polymicrobial infections are likely 4 . Selecting a drug:

43. The choice of agent(s ) may also be guided by known association of particular organisms in a given clinical setting. For example, A gram-positive cocci in the spinal fluid of a newborn infant is unlikely to be Streptococcus pneumonia and most likely to be Streptococcus agalactiae (a group B streptococci ), which is sensitive to penicillin G . By contrast, gram-positive cocci in the spinal fluid of a 40-year-old patient are most likely to be S. pneumoniae . This organism is frequently resistant to penicillin G and often requires treatment with a high-dose third generation cephalosporin (such as ceftriaxone ) or vancomycin 4 .

44. After a pathogen is cultured, its susceptibility to specific antibiotics serves as a guide in choosing antimicrobial therapy. Some pathogens, such as Streptococcus pyogenes and Neisseria meningitidis , usually have predictable susceptibility patterns to certain antibiotics . In contrast, most gram-negative bacilli , enterococci, and staphylococcal species often show unpredictable susceptibility patterns and require susceptibility testing to determine appropriate antimicrobial therapy 4 . Determining antimicrobial susceptibility of infective organisms:

45. The minimum inhibitory concentration (MIC) is the lowest antimicrobial concentration that prevents visible growth of an organism after 24 hours of incubation. This serves as a quantitative measure of in vitro susceptibility and is commonly used in practice to streamline therapy . Computer automation has improved the accuracy and decreased the turnaround time for determining MIC results and is the most common approach used by clinical laboratories 4 . Minimum inhibitory concentration:

46. Figure: Determination of minimum inhibitory concentration (MIC ) 4

47. Bacteriostatic versus bactericidal drugs 4 Bacteriostatic drugs Arrest the growth and replication of bacteria Limits the spread of infection until the immune system attacks, immobilizes, and eliminates the pathogen If the drug is removed before the immune system has scavenged the organisms, enough viable organisms may remain to begin a second cycle of infection. Bactericidal drugs Kill bacteria Eliminates infection before the activation of the immune system D rugs of choice in seriously ill and immunocompromised patients.

48. Effect of the site of infection on therapy: Adequate levels of an antibiotic must reach the site of infection for the invading microorganisms to be effectively eradicated. Capillaries with varying degrees of permeability carry drugs to the body tissues. Natural barriers to drug delivery are created by the structures of the capillaries of some tissues, such as the Prostate Testes Placenta The vitreous body of the eye Central nervous system ( CNS) 4 .

49. Figure: Structure of a Capillary 13

50. Figure: Types of Capillaries 13

51. Figure: Types of Capillaries 13

52. CNS: Blood Brain Barrier

53. Figure: Transport mechanisms through BBB 13

54. The penetration and concentration of an antibacterial agent in the CSF are particularly influenced by the following: Lipid solubility of the drug. Molecular weight of the drug. Protein binding of the drug 13

55. Patient F actors: In selecting an antibiotic, attention must be paid to the condition of the patient. 1. Immune System : Elimination of infecting organisms from the body depends on an intact immune system, and the host defense system must ultimately eliminate the invading organisms. Alcoholism, diabetes , HIV infection, malnutrition, autoimmune diseases , pregnancy , or advanced age can affect a patient’s immunocompetence , as can immunosuppressive drugs. High doses of bactericidal agents or longer courses of treatment may be required to eliminate infective organisms in these individuals 13

56. 2.Renal dysfunction: Poor kidney function may cause accumulation of certain antibiotics . The number of functional nephrons decreases with ag e . Thus, elderly patients are particularly vulnerable to accumulation of drugs eliminated by the kidneys . Dosage adjustment prevents drug accumulation and therefore adverse effects. Serum creatinine levels are frequently used as an index of renal function for adjustment of drug regimens 13 .

57. 3.Hepatic dysfunction : Antibiotics that are concentrated or eliminated by the liver must be used with caution when treating patients with liver dysfunction 13 . Ex: Erythromycin and Doxycycline .

58. 4 . Poor Perfusion : Decreased circulation to an anatomic area, such as the lower limbs of a diabetic patient , reduces the amount of antibiotic that reaches that area, making these infections difficult to treat 13 .

59. 5.Age : Renal or hepatic elimination processes are often poorly developed in newborns, making neonates particularly vulnerable to the toxic effects of chloramphenicol and sulfonamides. Young children should not be treated with tetracyclines or quinolones , which affect bone growth and joints, respectively. Elderly patients may have decreased renal or liver function , which may alter the pharmacokinetics of certain antibiotics 13 .

60. 6. Pregnancy and lactation : Many antibiotics cross the placental barrier or enter the nursing infant via the breast milk. Although the concentration of an antibiotic in breast milk is usually low, the total dose to the infant may be sufficient to produce detrimental effects 13 .

61. Figure: Maternal Intake of Drug 13

62. Figure: FDA categories of antimicrobials and fetal risk. 13

63. 7. Risk factors for multidrug-resistant organisms: Infections with multidrug-resistant pathogens need broader antibiotic coverage when initiating empiric therapy. Common risk factors for infection with these pathogens include -- P rior antimicrobial therapy in the preceding 90 days. H ospitalization for greater than 2 days within the preceding 90 days. C urrent hospitalization exceeding 5 days . High frequency of resistance in the community or local hospital unit. Immunosuppressive diseases and/or therapies 13 .

64. Safety of the agent : Antibiotics such as the penicillins are among the least toxic of all drugs because they interfere with a site or function unique to the growth of microorganisms. Other antimicrobial agents (for example, chloramphenicol ) have less specificity and are reserved for life-threatening infections because of the potential for serious toxicity to the patient 13 .

65. Cost of therapy : Often several drugs may show similar efficacy in treating an infection but vary widely in cost. For example, treatment of methicillin -resistant Staphylococcus aureus (MRSA) generally includes one of the following: vancomycin , clindamycin , daptomycin , or linezolid . Although choice of therapy usually centers on the site of infection, severity of the illness, and ability to take oral medications, it is also important to consider the cost of the medication 13 .

66. Figure: Relative cost of some drugs used for the treatment of Staphylococcus aureus 13 .

67. DETERMINANTS OF RATIONAL DOSING: Rational dosing of antimicrobial agents is based on their pharmacodynamic and pharmacokinetic properties. Three important properties that have a significant influence on the frequency of dosing are -- Concentration dependent killing. Time-dependent killing. Post antibiotic effect (PAE ). Utilizing these properties to optimize antibiotic dosing regimens can improve clinical outcomes and possibly decrease the development of resistance 13 .

68. Concentration-dependent killing Certain antimicrobial agents, including aminoglycosides and daptomycin , show a significant increase in the rate of bacterial killing as the concentration of antibiotic increases from 4- to 64-fold the MIC of the drug for the infecting organism. Giving drugs that exhibit this concentration-dependent killing by a once-a-day bolus infusion achieves high peak levels, favoring rapid killing of the infecting pathogen 13 .

69. Figure: Significant dose dependent killing effect shown by tobramycin . 13

70. Time-dependent (or) Concentration-independent killing: The clinical efficacy of some antimicrobials is best predicted by the percentage of time that blood concentrations of a drug remain above the MIC 13 . Figure: Non significant dose-dependent killing effect shown by ticarcillin 13

71. Ex: β- lactams, glycopeptides, macrolides, clindamycin , and linezolid. D osing schedules for the penicillins and cephalosporins that ensure blood levels greater than the MIC for 50% and 60% of the time, respectively, provide the most clinical efficacy . Therefore , extended (generally 3 to 4 hours) or continuous (24 hours) infusions can be utilized instead of intermittent dosing (generally 30 minutes) to achieve prolonged time above the MIC and kill more bacteria 13 .

72. Postantibiotic effect (PAE): The PAE is a persistent suppression of microbial growth that occurs after levels of antibiotic have fallen below the MIC . Antimicrobial drugs exhibiting a long PAE (for example, aminoglycosides and fluoroquinolones ) often require only one dose per day, particularly against gram negative bacteria 13 .

73. CHEMOTHERAPEUTIC SPECTRA : Narrow-spectrum antibiotics Extended-spectrum antibiotics Broad-spectrum antibiotics

74. Narrow-spectrum antibiotics: Chemotherapeutic agents acting only on a single or a limited group of microorganisms are said to have a narrow spectrum. For example, isoniazid is active only against Mycobacterium tuberculosis 13 .

75. Extended-spectrum antibiotics Extended spectrum is the term applied to antibiotics that are modified to be effective against gram-positive organisms and also against a significant number of gram-negative bacteria. For example, ampicillin is considered to have an extended spectrum because it acts against gram-positive and some gram-negative bacteria 13 .

76. Broad-spectrum antibiotics: Drugs such as tetracycline, fluoroquinolones and carbapenems affect a wide variety of microbial species and are referred to as broad-spectrum antibiotics. Administration of broad-spectrum antibiotics can drastically alter the nature of the normal bacterial flora and precipitate a super infection due to organisms such as Clostridium difficile, the growth of which is normally kept in check by the presence of other colonizing microorganisms . Ex: Tetracyclines 13

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