Supplement to Book…………….

CHEMOTHERAPY
Antibiotic:
Antibiotics are the chemical substances produced by micro-organism which have the Property of
inhibiting the growth or suppress the growth of other micro-organisms; e.g. penicillin, amoxicillin.
Anti-microbial agents
Anti-microbial is defined as any agents or substances produced by natural, synthetic and semi-synthetic,
able to kill or inhibit the growth of micro-organisms.
Chemotherapeutic agents:
 Chemotherapeutic agents are chemicals used for the treatment of infection, caused by microorganisms
like bacteria, virus, fungi etc.
 A chemotherapeutic agent may act by destroying the organism (bactericidal) or by inhibiting its
growth (bacteriostatic).the selective toxic action of the infection organism is the key to beneficial
actions of antibiotics. These drugs can hit multiple targets in bacteria such as:
 the cell wall
 the cytoplasmic membrane
 the ribosomes
 the RNA molecules involved in transcription of genetic information
 enzymes required for RNA synthesis or replication
 metabolic pathways
 The other potential targets ate the formed structures such as microtubules (targets in fungi and cancer
cells) and muscle tissues in helminthes.
 Chemotherapy means treatment of systemic infection and malignant cells.

Problems encountered during antimicrobial therapy

Selective toxicity of the chemotherapeutic agent to the invading organism does not insure the host against
adverse effects. Since the drug may produce an allergic response or be toxic in ways un-related to the
drugs anti-microbial activity.
1. Toxicity
2. Hypersensitivity
3. Super infection
4. Nutritional deficiencies
5. Drug resistance

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Prevention of drug resistance:

It is very clinically important to prevent the development of drug resistance .measures that are to be taken
to prevent drug resistance are.
a) Chemotherapeutic agents should not be used indiscriminately, inadequately or prolonged.
b) Rapidly and selectively acting anti-microbial should be used. Broad-spectrum drugs should be used
only when a specific one cannot be determined or is not suitable .e.g.
Tetracycline, chloramphenicol.
c) Combinations of drugs are to be used in prolonged treatment. E.g. Tuberculosis.
d) Infection by organisms which can develop resistance must be treated intensively. e.g. S.aureus, E.coli,
M.tuberculosis

Selection of anti-microbial agents

The selection of the most appropriate anti-microbial agents is based on the knowledge of:
1 .The identity of the organism and its sensitivity to a particular agent.
2. The safety of the agents
3. The site of infection
4. Patient factors
5. The cost factors

Combination of antimicrobial drugs

It is advisable to treat the infection organism with a single agent to reduce the possibility of super-
infection, decrease the emergence of resistant organism and minimize toxicity of superinfection. However
combination of drugs is frequently used for treatment of infections such as tuberculosis.

The objectives of using combination of drugs are:

 To achieve synergism.
 To reduce severity of incidence of adverse effects.
 To prevent emergence of resistance.
 To broaden the spectrum of anti-microbial activity.

Rationale for Combination Therapy

1) Infection Severity and Polymicrobial Infections
 Although combination therapy is often required to treat a variety of infections, we might argue the
logic for combination antibiotics on the basis of infection severity alone. Even in cases of

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 Supplement to Book…………….
overwhelming sepsis or life-threatening meningitis, monotherapy is justifiable in the
immunocompetent patient when the offending pathogen has been identified.
 Combination therapy is often required, however, for empirical coverage of acute infection before the
micro-organisms responsible have been identified. Examples include community-acquired and
nosocomial pneumonia including aspiration pneumonia, sepsis, meningitis and endocarditis.
 Although the patient's history and demographic profile are crucial in making these decisions, these
types of infections often involve a variety of pathogens ranging from Gram-positive and Gram
negative to the atypical and fastidious organisms.

2 Pharmacodynamic/Synergy
 Combination of 2 different classes of compounds may result in bactericidal activity which is
significantly greater than the sum of either agent alone. When this phenomenon is demonstrated, the
combination is said to be synergistic. If the combination results in a worsening effect, it is said to be
antagonistic. A result which is less than synergistic but not antagonistic is said to be indifferent or
additive.
 There are currently 2 laboratory methods utilized to evaluate the combination of 2 antimicrobials
potentially exhibiting synergism.
 Although the combination of an aminoglycoside and a third generation cephalosporin has been
suggested for the treatment of Enterobacter aerogenes and E. cloacae infections due to their inherent
multidrug-resistant nature, this combination is not always effective in preventing the emergence of
resistance to one or both of these agents.
 The addition of rifampicin to quinolone therapy may decrease the emergence of resistance

Disadvantages of Combination Therapy

1) Antagonism
 The combination of two or more antibiotics can result in negative interactions as well as the previously
described positive interactions, i.e. synergy.
 An antagonist effect is defined as less antimicrobial activity with a combination of drugs than with the
use of either agent alone. This effect can be easily demonstrated in the laboratory setting.
 It is now recognized that clinically apparent antagonism is usually the result of one drug inducing β-
lactamase while a second drug is β-lactamase unstable
 Cefoxitin and imipenem are two well documented examples of antimicrobial agents capable of
inducing β-lactamase in organisms including E. cloacae, Serratia marcescens and P. aeruginosa.

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Cefoxitin and imipenem remain unaffected by the inducible β- lactamase while a concomitant β-
lactam antibiotic is then subject to hydrolysis.
 In situations where synergy is relied upon (e.g. treatment of P. aeruginosa in an immunocompromised
patient) strong inducers of β-lactamase should not be combined with other β-lactam antibiotics.

2) Adverse Effects
 It is obvious that the administration of more than one antibiotic may increase the chance of an adverse
drug reaction. Accordingly, it is often difficult to distinguish which antibiotic is the offending agent.
 Well described adverse effects of antimicrobial combinations include nephrotoxicity, coagulopathy,
diarrhoea (including diarrhoea secondary to Clostridium difficile infection), seizures and
hypersensitivity reactions. Vancomycin and aminoglycosides have been associated with an increased
incidence of nephrotoxicity when the treatment duration is >21 days)
 It should be noted, however, that these studies evaluated patients receiving conventional dosage
regimens of aminoglycosides (every 8 to 12 hours).
 It would be interesting to re-evaluate this potential, toxicity with aminoglycosides administered at,
higher doses and less frequent dosage intervals. Although double β-lactam combinations may avoid
aminoglycoside associated nephrotoxicity, latamoxef and piperacillin resulted in prolonged
granulocytopenia compared with latamoxef plus amikacin in a study treating febrile granulocytopenic
patients.
3 Superinfection
 Superinfection is common following broad-spectrum antimicrobial therapy. Secondary infection is
often caused by resistant bacteria and fungi. In one landmark study, broadspectrum antibiotic therapy
compared with narrow-spectrum therapy was noted to be 5 times as likely to result in superinfection
with a mortality of >90%
4 Costs
 Combination therapy is not uniformly more expensive than monotherapy, based on acquisition costs
alone.
 However, when combining the cost of administering several antibiotics (preparation of fluids, nursing
time and associated monitoring costs), further analysis must be performed.

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Classification of antimicrobial drugs

A) Based on mechanism of action

1. Inhibit cell wall synthesis: E.g. Penicillin, cephalosporin, cycloserin, vancommycin, bacitracin

2 .Cause leakage from cell membrane: E.g. Polypeptides-polymyxins, colistins, bacitracin, Polylenes-
amphotericin B, nystatin, hamycin

3. Inhibit protein synthesis: E.g. Tetracycline, chloramphenicol, erythromycin clindamycin

4. Cause misreading of m-RNA code and affect permeability: E.g. Amino glycosides:-streptomycin,
gentamycin

5. Inhibit DNA gyrase: e.g. ciprofloxacin, ofloxacin, norfloxacin, and others

6. Interfere with DNA functions: E.g. Rifampicin, metronidazole

7. Interfere with DNA synthesis: E.g. Acyclovir, zidovudine

8. Interfere with intermediatory metabolism: E.g. Sulfonamide, methotrexate

B) Based on spectrum of activity

1. Narrow spectrum e.g. penicillin G, Streptomycin, erythromycin

2. Broad spectrum e.g. tetracycline, chloramphenicol

C) Based on type of action

1. Primarily bacteriostatic e.g. sulphonamides, tertacyclines, chloramphenicol, erythromycin.

2. Primarily bacteriocidal e.g. penicillin, cephalosporin, aminoglycosides, vancomycin

Note: for the details of anti-neoplastic agents, folate antagonist, cell wall synthesis inhibitors, protein
synthesis inhibitors, DNA synthesis inhibitors, antiseptics and disinfectants please refer the class
note and assignment.

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