antibiotics are necessary to treat infections and chemotherapeutic agents are also used for this purpose. Chemotherapeutic agents are also used in the treatment of cancers. These therapeutic agents have limitations, specific action and a set mode of action. We can say that they are selective. The antibiotics are natural as well as synthetic in nature and have specificity for action against the microorganisms. Chemotherapeutic agents are chemical in nature and are synthesised in labs. They are less selective in action.

1. CHEMOTHERAPY AND
ANTIBIOTICS
ANJU RANA

2. HISTORY
The term was used in the early 1900s by Paul Ehrlich for use
of chemicals to treat any disease (chemo+therapy), such as
the use of antibiotics (antibacterial chemotherapy).
First modern chemotherapeutic agent was arsphenamine,
an arsenic compound discovered in 1907 and used to
treat syphilis and was later followed by sulfonamides (sulfa
drugs) and penicillin. Nowadays the term ‘any treatment of
disease with drugs’ is expressed by a word
pharmacotherapy.

3. Chemotherapy is the use of chemical substances having property to
inhibit the growth of microorganism in treatment of diseases.
The chemical compounds that are used to kill or inhibit the growth of
microorganisms already established in the tissues of the body are known
as chemotherapeutic agents.
It may be given to prolong life or to reduce symptoms of a disease. The
first use of drugs to treat cancer was reported in the early 20th century,
although it was not originally intended for that purpose.

4. Goodman & Gilman used mustard gas as therapy
Mustard gas was used as a chemical warfare agent
during World War I and was discovered to be a potent
suppressor of hematopoiesis (blood production). The
accidental discovery that the mustard gas led to slow
progression of cancer cells in body encouraged Goodman
and Gilman to use it in patients with Hodgkin’s disease in
1943. From here chemotherapy began.

6. The chemotherapeutic agents are non-specific in action and are
cytotoxic.
One of the side effects of chemotherapy is damage to the normal cells
that divide rapidly and are sensitive to the anti-mitotic drugs like cells
in the bone marrow, digestive tract and hair follicles. This induces
decreased production of blood cells, inflammation of the lining of the
digestive tract and hair loss.
Chemotherapy damage or stress cells, which may lead to cell death if
apoptosis is initiated.

7. Commonly used chemotherapeutic drugs

8. Alkylating agents: These are one of the earliest and
commonly used drugs. They damage DNA and stops
cancer cells to replicate.

9. Fig. Antimetabolites inhibit the DNA synthesis

10. Anthracyclines: These are drugs used for treatment of cancer and thy act
by interfering with enzymes that are necessary for replication of DNA but
are not cell cycle specific, e.g. doxorubicin, mitimycin-C and bleomycin.
These are derived from Streptomyces percetus.
Plant alkaloids: These are derived from plants and are found to inhibit
cell division or interfere with necessary enzymes needed for cell division.
They can affect at any phase of cell division. They produce toxic effects
like haematopoesis or neurological toxicities. Examples of plant
alkaloides are: vinca alkaloid, vincristine, paclitaxel and docetaxel.

11. Antibiotics
Antibiotics were known by their activities long before they were given this
specific name that means ‘against life’.
Many years ago the Chinese used moldy curd to treat boils and controlled foot
infections by wearing sandals with layer of mold.
Pasteur and Joubert realised that growth of anthrax bacillus was inhibited by
certain other microorganisms growing in the culture plate.
In 1929, Alexander Fleming observed that Staphylococcus aureus growth was
inhibited when a mold accidently grew in it.

12. Later on this accidental drug was known as wonder drug – Penicillin and was
found to be produced by Penicillium notatum.
Streptomycin produced by Streptomyces griseus was the second antibiotic
invented by Dr. Selman Waksman in 1948.
Fig. Dr. Selman Waksman and structure of
Streptomycin

13. Antibiotics belong to the broader group of antimicrobial compounds
that are used to treat infections caused by microorganisms including
fungi and protozoa.
Antibiotics were originally produced by natural living organisms like
aminoglycosides produced by Streptomyces genus, but some are
semisynthetic like cephalosporins, carbapenems or synthetic like the
sulphonamides, quinolone and oxazolidinones.

14. Principles of antibiotic therapy
• The antibiotic therapy is based on theory of selective toxicity
that is antibiotic can kill microorganism without causing harm to body of
patient.
• Various antibiotics either inhibit or destroy the metabolic properties
of bacteria.
For example, penicillin inhibits the peptidoglycan in the cell wall of bacter
• For an antibiotic to be effective a fixed dose has to be given to a
patient otherwise it could harm him/her.
• This difference between a dose necessary for treatment of a disease
and the one that may harm a person is large and is called as
therapeutic index.

16.  Antibiotics may be divided into two broad categories according to their
effect on microorganisms: bactericidal agents, those that kill bacteria and
bacteriostatic agents, those that inhibit bacterial growth.
 Antimicrobial agents are called as broad spectrum when they act against a
wide range of Gram-positive and Gram-negative bacteria like tetracyclin,
erythromycin and cephalisporins.
 They can be narrow spectrum with limited action like penicillin to Gram
positive bacteria. Metronidazole is also a narrow spectrum antibiotic
because of its activity against strict anaerobes and some protozoa.

17. 1.Competition with a natural substance for the active site of the
enzyme, e.g. action of sulphonamides to interfere competitively
with the utilization of PABA or action of PABA with para-
aminosalicylic acid.
2.Combination with an enzyme at a site sufficiently close to the
active site so as to interfere with its enzymatic function, like
vancomycin, ristocetin and bacitracin.
3.Combination with non-enzymatic structural components, like
drugs which inhibit protein synthesis and which act by damaging
cytoplasmic membranes.

19. The antibiotic chosen for treatment of a disease depends on following factors:
 Location of infection: The site or location of infection is important in choosing
an antibiotic because to treat an infection antibiotic must be in sufficient
concentration at that particular site. For example, the sites with insufficient
supply of blood. Some sites with low pH inhibit certain antibiotics.
 Organism: Specific identification of the organism predicts the natural history of
the infection and allows treatment strategy and choice of drug to be given.
 Pattern of susceptibility: Some organisms may show good susceptibility
towards an antibiotic but other bacteria may not. For example penicillin is
effective for treating infection of Streptococcus pyogenes although Acinetobacter
and Pseudomonas show resistance. Antibiotics should be chosen to cover the
resistance pattern of all the potential pathogens.

20.  Severity of infection: In general, oral therapy is used when it is well tolerated and
provides an adequate therapeutic effect, the parenteral route being reserved for
patients who have difficulty taking oral medications or when it is desired to
provide prompter or greater antimicrobial activity. In case of severe infections
antibiotics are given by parenteral route.
 History of allergy: If a person has previous allergic history, the antibiotic’s
choice to be selected for treatment is limited.
 Side effects: Some antibiotics may be associated with harmful side effects and
must be given carefully to a patient. For example, in patients who are already
suffering from renal disease, antibiotic like aminoglycoside should e given
carefully.
 Likelihood of unwanted effects: for example, aminoglycosides should be used
with care in patients with pre-existing renal disease.
 The cost of therapy also affects the choice of antibiotic to be used for treatment.

21. Mechanism of antibiotic action

23. The antibiotic treatment causes some side effects also. The effects on human body
are:
Gastrointestinal tract - Antibiotic activity can upset the balance of the normal flora
within the gut, e.g. β-lactams drugs. The commensal bacteria like Candida species,
overgrow and may lead to pseudomembrane colitis.
Skin - Skin may be affected with adverse range of manifestations like mild
urticarial to erythematous lesions or Stevens-Johnson syndrome which could be life
threatening. Generally, discontinuation of antibiotic therapy resolve these issues.
Haemopoietic system -Chloremphenicol produces dose dependant suppression of
bone marrow, granulocytopaenia, thrombocytopaenia and sometimes haemolytic
anaemia.
Renal system - Tetracyclines and aminoglycoside antibiotics may be the cause of
renal toxicity and damage to the convoluted tubules. This antibiotic is given under
medical guidance in patients already suffering from renal diseases.

24. Some commonly used antibiotics

25. Beta-lactam antibiotics like penicillin
Penicillins work by inhibiting peptidoglycan cross-linkage. Modifications to the
penicillins have extended their antibacterial spectrum and improved absorption.
Penicillins now include:
 natural penicillins e.g. benzylpenicillin and penicillin V
 penicillinase-resistant penicillin e.g. flucloxacillin
 aminopenicillins e.g. ampicillin-like agents
 expanded-spectrum penicillins e.g. piperacillin
 penicillins combined with β-lactamase inhibitors e.g. amoxicillin and clavulanate
or co-amoxiclav.
Penicillins are secreted by the kidney and have a short half-life. They are
distributed in extracellular fluid, but do not cross the blood-brain barrier unless the
meninges are inflamed.

26. Cephalosporins
Cephalosporins are closely related to penicillins. They are all active
against Gram-positive organisms and later compounds have activity
against Gram-negative bacteria including Pseudomonas.
Monobactams
They have a broad spectrum of activity, including against anaerobes.
Imipenem and meropenem have antipseudomonal effects and must be
given intravenously.

27. Aminoglycosides
Aminoglycosides act by preventing translation of mRNA into proteins. They are
given parenterally. They are limited to the extracellular fluid and are excreted in the
urine. Aminoglycosides are toxic to the kidney, which necessitates careful
monitoring of serum concentrations.
Glycopeptides
The glycopeptides such as vancomycin and teicoplanin inhibit peptidoglycan cross-
linking in Gram-positive organisms only. Resistance to them is rare but sometimes
glycopeptide-resistant enterococci - GRE and Staphylococcus aureus are found.
Administration of the drug is intravenous or intraperitoneal because they are not
absorbed orally. The exception is the oral use of vancomycin to treat
pseudomembranous colitis.
They are distributed in the extracellular fluid, but do not cross the blood-brain
barrier unless there is meningeal inflammation. Excretion is via the kidney.

28. Quinolones
Quinolones act by inhibiting bacterial DNA gyrase. The early
quinolones did not attain high tissue levels and were used only for
UTIs. Fluorine modification (fluoroquinolones) has made them
active against Gram-negative pathogens including Chlamydia.
Ciprofloxacin has activity against Pseudomonas spp. Quinolones
are well absorbed orally, are widely distributed and penetrate cell
well.

29. Macrolides and Oxazolidinones
The macrolides (erythromycin, azithromycin and clarithromycin) and
oxazolidinones e.g. linezolid bind to the 50S ribosome, interfering with
protein synthesis. Linezolid is well absorbed orally and concentrated in
the skin.
They are active against Gram-positive cocci, many anaerobes (but not
Bacteroides), Mycoplasma and Chlamydia. They are absorbed orally,
distributed in the total body water, cross the placenta, are concentrated in
macrophages, polymorphs and the liver and are excreted in the bile.
Erythromycin may cause nausea. The newer macrolides e.g.
azithromycin is well tolerated and is less toxic.

30. Streptogramins
Pristinamycin is a bactericidal semisynthetic streptogramin
consisting of quinupristin and dalfopristin. It acts by preventing
peptide bond formation, which results in release of incomplete
polypeptide chains from the donor site. It is active against a broad
range of Gram-positive pathogens and some Gram-negatives, such as
Moraxella, Legionella, Neisseria meningitidis and Mycoplasma. It is
used mainly for the treatment of resistant Gram-positive infections
like GRE and glycopeptide-intermediate S. aureus or GISA.

31. Metronidazole
The main features of metronidazole are that it is;
 active against all anaerobic organisms;
 a receiver of electrons under anaerobic conditions, so forms toxic
metabolites that damage bacterial DNA;
 also active against some species of protozoa, including Giardia, Entamoeba
histolytica and Trichomonas vaginalis;
 absorbed orally and can be administered parenterally;
 widely distributed in the tissues, crossing the blood-brain barrier and
penetrating into abscesses;
 metabolized in the liver and excreted in the urine;
 well tolerated, except that it cannot be taken with alcohol.

32. Tetracyclines
Tetracyclines act by inhibition of protein synthesis by locking tRNA
to the septal site of mRNA. They are active against many Gram-
positive and some Gram-negative
pathogens, Chlamydia, Mycoplasma, Rickettsia and
Treponemes, Plasmodium and Entamoeba histolytica. Doxycycline
is absorbed orally, has a long half-life and is widely distributed.
Adequate therapeutic levels may be obtained by a once-daily dosage.
The newer tetracyclines such as tigecycline are used to treat
multiresistant Gram-negative infections.

33. Sulphonamides and trimethoprim
Sulphonamides and trimethoprim act by inhibiting the synthesis of
tetrahydrofolate. They are now rarely used in the treatment of bacterial
infections but have an important role in the management of
Pneumocystis jiroveci and protozoan infections including malaria.
Sulphonamides can be given intravenously and are well absorbed when
given orally. They are widely distributed in the tissues and cross the
blood-brain barrier. They are metabolized in the liver and excreted via
the kidney.

34. Resistance against drugs

35. Resistance can develop quickly because:
 bacteria multiply rapidly & mutations arise regularly
 segments of DNA can be transferred by transformation
 genetic information can be transferred rapidly by bacteriophages,
plasmids or other mobile genetic elements.
 Antibiotic’s overuse, misuse and abuse favours the emergence and
survival of resistant organisms. The misuse of antibiotics includes
failure to take the prescribed course of the antibiotics or to take the
course of treatment at incorrect daily intervals.

36. Avoiding development of drug resistance
Development of drug resistance can be avoided or minimised by:
1.Using correct dosage of the proper antibiotics to overcome an infection
quickly.
2.Using combination of antibiotics.
3.Avoiding indiscriminate use of antibiotics in unnecessary situations.
4.Using a different antibiotic when an organism shows evidence of
becoming resistant.
5.Not to use antibiotics without physician’s prescription.