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PRINCIPLES TO CHEMOTHERAPY
BIETE LUNDAU LUKE
DipPharm, Bpharm, Mclinpharm
INTRODUCTION TO CHEMOTHERAPY 2
 Chemotherapy is the form of treatment where drugs are used to eradicate
pathogenic organisms or neoplastic cell in treatment of infectious diseases and
cancer respectively

 One great principle on which chemotherapy is based is that of selective toxicity

 Selective toxicity entails that the chemotherapeutic drug inhibits the vital function of
invading microorganism or neoplastic cells

 The chemotherapeutic agent therefore, becomes toxic to the microorganism

without harming the host

 This is dependent on the presence of the biochemical difference between the

parasite and the host (qualitative and quantitative functional differences)
Classes of chemotherapeutic agents
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The chemotherapeutic agents include the following;
i. Antimicrobial agents
a). Antibacterial and antibiotics
b). Antiviral drugs
c). Anti-fungal drugs
d). Anti parasitic drugs
- Anti malaria drugs
- Anti amoebic drugs
- Anti helminthic drugs (Worm treatment)

ii. Antineoplastic drugs (Drugs used in cancer treatments)

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ANTI-MICROBIAL DRUGS

 As one of the classes of chemotherapeutic agents, antimicrobial drugs

are sub-classified as anti-bacterial, anti-fungal and anti-viral agents

 These agents include both natural ones called antibiotics and

synthetic ones

 An antibiotic is a substance produced from or by one microbe which

subsequently affects the growth or viability of another microbe
CLASSIFICATION OF ANTIMICROBIAL DRUGS
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 Antimicrobial drugs are usually classified based on the following;
i. Site
ii. Mechanism of action

 Then they are further sub-classified based on the chemical structure

 Overaly, these drugs include

i. Cell wall synthesis inhibitors
ii. Protein synthesis inhibitor
iii. Metabolic and nucleic acid synthesis inhibitors
iv. Cell membrane inhibitors
ANTIMICROBIAL ACTIVITY
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The antimicrobial activity of a drug is characterized in the following way;
i. Being either bactericidal or bacteriostatic against microorganism
ii. Spectrum of activity against important groups of pathogens
iii. Concentration time dependent effects on sensitive organisms

 Bactericidal drugs kill sensitive organism so as to rapidly lower the viable

organisms after exposure to the drug

 Bacteriostatic drugs inhibits the growth but does not kill them leading to
relatively and thus calling for the host immunological system to
eliminate constant number of bacteria

 This also applies to drugs that which kill or inhibits the growth of fungi
which are referred to as fungicidal and fungistatic drugs respectively
BACTERICIDAL VS BACTERIOSTATIC EFFECT 7
 Bactericidal drugs are mostly preferable when treating most bacteria
infections

 This is because bactericidal typically produce a more rapid biological

response, more clinical improvement and are less likely to elicit microbial
resistance

 Bactericidal drugs have actions that induce lethal changes in microbial

metabolism or block the activities that are essential for microbial viability
(Here actually lies the basis for their mechanism of action) e.g. peniciliins
inhibiting bacterial cell wall synthesis

 In contrast, Bacteriostatic drugs usually inhibit the metabolic reaction that is

needed for bacterial growth but is not necessary for survival e.g.
sulphonamides inhibiting folate synthesis, an enzymatic co factor in
synthesis of DNA components and amino acids
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Bactericidal or bacteriostatic Cont’d

 Drugs like tetracyclines that reversibly inhibit bacterial protein synthesis

are bacteriostatic

 Drugs that irreversibly inhibit bacterial protein synthesis like

aminoglycosides are bactericidal

 Depending on the concentration of the drug and the bacterial species

against which they are used, some drugs can either be bactericidal or
bacteriostatic
ANTI-MICROBIAL SPECTRUM
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Antimicrobial spectrum of activity is the primary determinant of the drug’s
clinical use

1. Narrow spectrum drugs antimicrobials

 These are antimicrobial which a re active against a single species or
a limited group of pathogens e.g. gram-positive bacteria

2. Broad spectrum antimicrobials

 These are antimicrobial drugs which are active against a wide range
of pathogens

3. Extended spectrum antimicrobials

 These antimicrobial drugs have an intermediate range of activity
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Considerations for Suitable use of a drug spectrum

 Narrow spectrum antimicrobial drugs are sometimes preferred

because they target the specific pathogen without disturbing the
normal flora of the gut or respiratory tract

 Broad spectrum antimicrobial drugs are sometimes preferred for initial

treatment of an infection when the causative pathogen is not yet
identified
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CONCENTRATION AND TIME DEPENDENT EFFECTS
 Antimicrobial drugs exhibit various concentration time dependent
effects which influence their clinical efficacy, dosage and frequency
of administration

 Examples of concentration time dependent effects are

i. Minimum inhibitory concentration (MIC)
 This is the minimum concentration of the drug that inhibits bacteria
growth and using it, a particular strain of bacteria can be classified as
susceptible or resistant to a particular drug

ii. Concentration dependent killing rate (CDKR)

iii. Post antibiotic effect (PAE)
Application of Concentration and time dependent effects
 Some aminoglycosides like tobramycin and some fluoroquinolones like ciprofloxacin 12
exhibit a Concentration dependent killing rate (CDKR) against a large group of gram
negative bacteria including Pseudomonas aeruginosa while Penicillins and other β-
lactam antibiotics usually do not exhibit a CDKR

 After an antibacterial drug has been removed from the bacterial culture, evidence
of a persistent effect on bacteria growth may exist, this effect being known as
Postantibiotic effect (PAE) which many bactericidal antibiotics are known to exhibit
against susceptible pathogens

 Penicllins show a PAE against gram positive cocci while aminoglycosides show PAE
against gram negative bacilli

 Aminoglycosides exhibit both CDKR and PAE and hence the established treatment
regimen where the entire daily dose is administered at one time which rapidly
eliminates the bacteria while the PAE prevents any remaining bacteria from
replicating for several hours after the drug has been eliminated from the body
MICROBIAL SENSITIVITY AND RESISTANCE
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 Microbial sensitivity to antimicrobial drugs can be determined by various methods
i.e. the broth dilution test (Test tube), the disk diffusion (Kirby – Bauer test) and the E –
test method

 The broth and the E – test can be used to determine the MIC of a drug

 It is on the basis of MIC that the micro-organism can be classified as having,

susceptibility, intermediate sensitivity or resistance to the tested drug

 These categories in terms of susceptibility are based on the relationship between the
MIC and the peak serum concentration of the drug after administration of typical
doses
 Generally, the peak serum concentration of the drug should be 4 – 10 times greater
than the MIC in order for the pathogen to be susceptible

 It is worth noting that pathogens with intermediate sensitivity may respond to

treatment with maximum doses of an antimicrobial agent
MICROBIAL RESISTANCE TO DRUGS
 Antimicrobial resistance (AMR) is the ability of a micro-organism to resist the 14
effects of an antimicrobial medication that could previously treat the
microbe successfully

 AMR has been proved a challenge to infectious disease management and

has been documented to cause an estimated 700,000 deaths annually
world wide (UN,2019)

Origin of resistance
 Resistance to antimicrobial agents can either be innate or acquired

Acquired resistance
This arises from the following;
- Mutation and selection
- Transfer of plasmids that confer drug resistance

NB: It is the micro-organisms which become resistant to drugs and not drugs to micro-organisms
Mutation and Selection 15
 Microbes can undergo spontaneous mutation to a form that is resistant to
antimicrobial drugs

 These mutations occur at a constant rate per unit time i.e. if the organisms
are exposed to antimicrobial drug the susceptible ones may be eradicated
leaving the resistant mutant to multiply and become the dominant strain

 Mutations and selection of resistant mutant is increased by;

- Exposure of a microorganism to sub-optimal drug concentrations
- Prolonged exposure to the antimicrobial drug

 A successful outcome therefore, calls for the laboratory tests to guide the
selection of antimicrobial drug while ensuring that the dosage and duration
of therapy are adequate for the type of infection

 Additionally and whenever possible, bacteriological response to drug

therapy should be verified by culturing samples of appropriate body fluids
Transferable resistance
 This usually results from bacterial conjugation and the transfer of 16
plasmids(Extrachromosomal DNA) that confer drug resistance

 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 which can either be transferred
within the same species and between different species and thus mostly
conferring what is termed Multi-drug resistance

 It is evidenced that the resident microflora (Normal flora) of human body

can serve as reservoirs for resistant genes which they transfer to organisms
that later invade or colonise the host

 Based on this transferable resistance principle, the various microorganism

species need not to be present during the period in which the antibiotic is
administered for resistance to ensue
Mechanisms of resistance
There are three major mechanisms by which resistance is actualized namely;
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i. Inactivation of drug by microorganism

ii. Decreased accumulation of the drug by the microorganism
iii. Reduced affinity for the drug by the target macromolecules

i. Inactivation of drug by microorganism

 This involves the production of enzymes by microorganism which destroy
an important structural component of the drug e.g. beta lactamase
destroying the lactam ring of penicillins

 This is an important mechanism of resistance to β-lactam antibiotics like

penicillins and cephalosporins

 Resistance to aminoglycosides like gentamycin is partly caused by the

production of drug inactivating enzymes that acetylate, adenylate or
phosphorylates these antibiotics
ii. Decreased accumulation of an antibiotic by the microbe 18
 This occurs in two ways which is either by increased efflux (ejection or
removal) or the decreased uptake of the drug

 Both these mechanisms contribute to the resistance of microbes to

tetracyclines and fluoroquinolones

 Increased efflux of drug is mediated by membrane proteins that transport

antimicrobial that transport antimicrobial out of the bacterial cell

 Decreased uptake of antimicrobial drugs can result from altered bacterial

porins which are membrane proteins containing channels through which
drugs and compounds enter bacteria

 Resistance to penicillins by gram negative bacilli is partly caused by

altered porin channels that do not permit penicillin entry
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iii. Reduced affinity of target molecule for antimicrobial drugs

 This is a common mechanism of microbial resistance to most classes of

antibiotics

 This resistance often results from bacteria mutation followed by the

selection of resistant mutants during exposure to antimicrobial drugs
Table showing mechanism of microbial resistance
MECHANISM EXAMPLES 20
Inactivation of the drug by microbial Inactivation of aminoglycosides by
enzymes acetylase, adenylate synthetase and
phosphorylase enzymes
Inactivation of penicillins and other Beta
lactam antibiotics by β-lactamase enzymes

Decreased accumulation of the drug by Decreased uptake of β-lactam antibiotics

the microbe due to altered porins in gram negative
bacteria
Decreased uptake and increased efflux of
fluoroquinolones and tetracyclines

Reduced affinity of the target Reduced affinity for DNA gyrase for
macromolecule for the drug fluoroquinolones
Reduced affinity of folate synthesis
enzymes for sulphonamides and
trimethoprim
Reduced affinity of ribosomes for
aminoglycosides, chloramphenicol,
clindamycin, tetracycline, macrolides
SELECTION OF ANTIMICROBIAL DRUGS
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Selection of an antimicrobial drug to be used for the treatment of a particular infection
will significantly depend on the following:
1. Host factors
 The age of the patient
 Physiological status
 Immune competence of the patient

2. Drug factors
 Pharmacologic properties and antimicrobial activity
 Pharmacokinetic properties
 Adverse effect profile

3. Disease factors
 Causative of the infection
 Location and severity of infection
Host factors in drug selection
There are a number of the host factors that influence the choice of antimicrobial drugs as highlighted below;
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 Most of the antimicrobials do cross the placenta e.g. tetracyline in pregnancy can lead to permanent
discoloration of teeth of the child even as it is contraindicated in breastfeeding mothers and those below
the age of twelve
 Many individuals are allergic to one or more antimicrobials, penicillins being the common cause of drug
allergy

 The immune status is an important factor in determining the treatment success of which advanced age,
diabetes, cancer chemotherapy and HIV are among the common causes of impaired immunity

 Therefore, patients with immune compromised state should be receive large doses and be on long
duration of treatment

 Foreign bodies like the indwelling catheters may provide sites where microbes may be covered by a
biofilm (Glycocalyx coating)

 Renal impairment may call for lower doses of antibiotics which renally excreted and similarly dose
adjustment may be required in hepatic insufficiency e.g. chloramphenicol cannot be metabolized by
neonates and hence the dosage per body weight should be lower than the adult ones
Antimicrobial activity
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Antimicrobial agents can be selected based on the following;
 Laboratory tests in terms of culture, susceptibility and sensitivity tests

 Empiric selection – based on Knowledge of common organisms causing

various infections and the preferred drugs for these organisms

 This Empiric therapy is used to treat serious infections until the results are
available and is also used in treatment of minor upper respiratory and
urinary tract infections based on the predictability of causative
microorganism and their sensitivity to drugs, the situations in which the cost
of microbial and drug sensitivity tests may not be justified

 Most infections are caused by a single microbial pathogen and thus may
only need a single drug the approach called monotherapy

 The advantages of monotherapy are that it is less expensive, less toxic and
has less effect on the host normal flora
Pharmacokinetic properties
 The pharmacokinetic properties that influence antibiotic selection include oral bioavailability, peak 24
serum concentration, distribution to particular site of infection, routes of elimination and elimination half
life

 An ideal antimicrobial drug for an ambulatory patient should have a good oral bioavailability with a long
elimination half life e.g. Azithromycin

 Sites of infection that are not readily penetrated are the CNS, the prostate grand, the bone and the
ocular tissues

 Penicillins can cross the blood brain barrier (BBB) when its inflamed while aminoglycosides do not whether
the BBB is inflamed or not while chloramphenicol crosses the BBB with or without inflammation

 Because of the low pH of the prostatic fluid and the prostatic epithelium, some antimicrobial drugs are
restricted entry into the prostate

 The route of elimination affects both the selection and use of antimicrobials i.e. fluoroquinolones which
are renally excreted are more effective in treatment of urinary tract infections than the biliary
metabolized or excreted drugs like erythromycin

 Drugs that are eliminated renally like aminoglycosides tends to accumulate in patients with renal
impairment
Adverse effects profile
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 All antimicrobial drugs can cause mild to severe adverse effects but the
incidence and intensity varies among different classes of drugs

 It is therefore, important to weigh the risk benefit ratio when selecting drugs
for treatment

 The β-lactam antibiotics like penicillins and cephalosporins cause a

relatively low incidence of organ system toxicity and are often used in
treatment of minor and common infections including those in pregnancy

 In contrast, aminoglycosides cause a relatively higher incidence and thus

are reserved for treatment of more serious and life threatening conditions

 Fluoroquinolones and tetracyclines are intermediate in their adverse effect

profile
COMBINATION DRUG THERAPY
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Combination drug therapy are used in the following instances;

 Treatment of infections known or suspected to be caused by more than

one pathogen (Mixed infections) e.g. intra-abdominal infections caused
by both the aerobic and anaerobic micro-oganisms from the GIT

 Treatment of life threatening infections like the hospital acquired

(Nosocomial) infections like pneumonia till the causative organism is
identified

 Treatment of infections where there is a likelihood of developing microbial

resistance on monotherapy treatment e.g. T.B, HIV

 Administering antimicrobial in combination can result in any for the

following; antagonistic, additive, synergistic or indifferent effects
Effects of Antimicrobial combination therapy
 Antagonistic effect – this is when the combined effect is less than the effect of either
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drug alone

 Additive effect – this is when the combined effect is the sum of the independent
effects

 Synergistic effect - this is when the combined effect is greater than the sum of
independent effects

 Indifferent effects – this is when the combined effect is similar to the greatest effect
of either of the drugs

 Bacteriostatic drugs like chloramphenicol and tetracycline are antagonistic to

bactericidal in that bactericidal drugs are usually more effective against rapidly
dividing or growing bacteria

 Two bactericidal drugs targeting different bacteria function often exhibit additive or
synergistic effects e.g. penicillins which inhibit cell wall synthesis often show additive
or synergistic effects with aminoglycosides which inhibit protein synthesis
PROPHYLACTIC THERAPY
 The term prophylaxis means preventative or to prevent coming from the
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Greek word “Phylax,” meaning “to guard” and “Watching”

 Prophylactic treatment is frequently used in healthcare to minimize illness

and disease

 Prevention of infections requires the sterilization of diagnostic and surgical

tools, use of disinfectants to reduce environmental pathogens in hospitals
and the disinfection of the skin and mucous membranes before invasive
procedures

 Antimicrobial drugs are also administered to achieve prophylaxis in the

following ways;
I. Prevent the occurrence of some infections in certain groups of patients
e.g. immune compromised patients like HIV, Cancer etc
II. Reduce the incidence of infections associated with surgical and other
invasive procedures
III. Prevent the disease transmission to close contacts of infected persons
Examples of prophylaxis treatment
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1. Prevention of infection occurance in immunocompromised
patients
 Cotrimoxazole is used to prevent pneumocystis jiroveci pneumonia in HIV
patients
 Isoniazid presumptive treatment is given to prevent T.B infection

2. Prevention of infection caused by invasive procedures

 Antibiotics are used to prevent endocarditis in persons with a history of
vulvular heart disease who are at risk of infection by viridans streptococci
acquired during dental or oral procedures or in upper respiratory tract
infections

 Antibiotics are routinely used to prevent tissue infection that can be

acquired during a wide range of surgical procedures

 The selection of antimicrobials is dependent on the likely sources of

bacteria, the skin being the major source of these bacteria during surgical
procedures e.g. staphylococci
Examples of prophylaxis treatment cont’d
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3. Prevention of Disease transmission
 Antimicrobial drugs are sometimes used to prevent the transmission of a
highly contagious disease from an infected person or vector to an
exposed person

 Antimicrobial drugs are also used to prevent malaria in persons who are
travelling to regions where malaria is endemic

 Drugs are also used in preventing influenza type A in populations at

increased risk for these diseases
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Assignment
Question:
Discuss antimicrobial stewardship, stating its significance, the different
approaches and the role of a biomedical scientists

 Due date:
 It should be typed, not less than 3 pages and not more than 5
pages excluding cover and reference pages
 Submission method: via email - lundsb82@gmail.com
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