Download - Principles of chemotherapy
Introduction to Chemotherapy
G Vijay Narasimha KumarAsst. Professor,
Dept. of. PharmacologySri Padmavathi School of
Pharmacy
Overview
Objectives History Definitions Important concepts References
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.
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.
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.
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.
Specific infectious disease – Specific microorganism Robert Heinrich Herman Koch, was a
celebrated German physician, pioneering microbiologist and founder of modern bacteriology.
He 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.
Figure: Koch’s
Postulates3
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 .
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.
Figure: Harposporium (centre) showing antibiosis against Paecilomyces varioti 7
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.
Alexander Fleming
Sir Alexander Fleming was a Scottish biologist, pharmacologist and botanist.
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.
.
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
Alexander Fleming - Penicillins
Due to difficulties in cultivation and purification of penicillins, Fleming finally abandoned penicillin.
Not 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.“
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 2nd world war 9. They were awarded Nobel prize in
Physiology and Medicine for the year 1945.
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 1939 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.
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."
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.
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 disease12.
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 infection12.
Key Terms
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.
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. Latency 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 symptoms12.
Figure: Incubation and Latent period
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 question12.
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.
Remission refers to the disappearance, possibly temporarily, of
symptoms12.
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.Antimicrobial Agent
Antibacterials(Synthetic)
Antibiotics(Microorganisms)
Figure:Venn
diagram showing
Relationship between antimicrobial agents
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.
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.
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.
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 .
Mechanism of Selective TargetingThe 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.
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
AntimetabolitesEx: 5-
Flourouracil1,4
Mechanism of Selective Targeting
Therapeutic Index (TI)
The ratio of toxic dose to therapeutic dose of a drug is called therapeutic index of a drug.
Also referred to as therapeutic window or safety window or sometimes as therapeutic ratio 11.
TD 50
Therapeutic Index = ED 50
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.
Selection of Antimicrobial agentSelection of the most appropriate antimicrobial agent requires
knowing 4 --
1)The organism’s identity.
2)The organism’s susceptibility to a particular agent.
3)The site of the infection.
4)Patient factors.
5)The safety of the agent.
6)The cost of therapy.
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 --
Blood Serum Cerebrospinal fluid [CSF] Pleural fluid Synovial fluid Peritoneal fluid Urine4.
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.
Figure: Some laboratory techniques that are useful in the diagnosis of microbial diseases 4.
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.
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:
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:
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.
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:
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:
Figure: Determination of minimum inhibitory concentration (MIC) 4
Bacteriostatic versus bactericidal drugs 4
Bacteriostatic drugsArrest the growth and replication of bacteriaLimits the spread of
infection until the immune system attacks,
immobilizes, and eliminates
the pathogenIf the drug is removed before the immune system
has scavenged the organisms, enough viable
organisms mayremain to begin a second
cycle of infection.
Bactericidal drugs
Kill bacteria
Eliminates infection before the activation of
the immune system
Drugs of choice in seriously ill and
immunocompromisedpatients.
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.
Figure: Structure of a Capillary 13
Figure: Types of Capillaries 13
Figure: Types of Capillaries 13
CNS: Blood Brain Barrier
Figure: Transport mechanisms through BBB 13
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
Patient Factors: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 individuals13
2.Renal dysfunction: Poor kidney function may cause accumulation of certain
antibiotics.
The number of functional nephrons decreases with age. 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.
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.
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.
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.
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.
Figure: Maternal Intake of Drug13
Figure: FDA categories of antimicrobials and fetal risk.13
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 --
Prior antimicrobial therapy in the preceding 90 days. Hospitalization for greater than 2 days within the preceding 90 days. Current hospitalization exceeding 5 days. High frequency of resistance in the community or local hospital unit.
Immunosuppressive diseases and/or therapies 13.
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.
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.
Figure: Relative cost of some drugs used for the treatment of Staphylococcus aureus13.
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
resistance13.
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 pathogen13.
Figure: Significant dose dependent
killing effect shown by tobramycin.13
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 MIC13. Figure: Non
significant dose-dependent killing effect shown by
ticarcillin13
Ex: β-lactams, glycopeptides, macrolides, clindamycin, and linezolid. Dosing 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 bacteria13.
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 bacteria13.
CHEMOTHERAPEUTIC SPECTRA:
Narrow-spectrum antibiotics
Extended-spectrum antibiotics
Broad-spectrum antibiotics
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 tuberculosis13.
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
bacteria13.
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: Tetracyclines13
References
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2006.4. Karen Whalen. Illustrated reviews in Pharmacology. 6th ed. Wolters Kluwer; 2015.5. https://explorable.com/discovery-of-bacteria6. Brock, Thomas. Robert Koch: A life in medicine and bacteriology. ASM Press: Washington DC,
1999. 7. https://atrium.lib.uoguelph.ca/xmlui/handle/10214/69688. The Nobel Prize in Physiology or Medicine 1908, Paul Erlich – Biography.9. Hugh TB (2002). "Howard Florey, Alexander Fleming and the fairy tale of penicillin". The
Medical journal of Australia 177 (1): 52–53.10.Otten, H. (1986). "Domagk and the development of the sulphonamides". The Journal of
antimicrobial chemotherapy 17 (6): 689–696.11.Sharma HL, Sharma KK. Principles of Pharmacology. 2nd ed. Paras medical publisher; 2013.12.BMA dictionary.13. Toratora