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Introduction to Chemotherapy
By:
Mr. Shivsharan B. Dhadde
Chemotherapy:
• Treatment of systemic infections or cancer with specific drugs that
selectively suppress the infecting microorganism/malignant cells without
significantly affecting the host.
• Antibacterial:
Eg. Penicillins, Aminoglycosides, Erythromycin, etc.
• Antifungal:
Eg. Griseofulvin, Amphotericin B, Ketoconazole, etc.
• Antiviral:
Eg. Acyclovir, Amantadine, Zidovudine, etc.
• Antiprotozoal:
Eg. Chloroquine, Pyrimethamine, Metronidazole, Diloxanide, etc.
• Anthelmintic:
Eg. Mebendazole, Pyrantel, Niclosamide, Diethyl carbamazine, etc.
D. Spectrum of activity
• Narrow-spectrum
Penicillin G
Streptomycin
Erythromycin
• Broad-spectrum
Tetracyclines
Chloramphenicol
The initial distinction between narrow and broad-spectrum antibiotics is no longer
clearcut. Drugs with all ranges of intermediate band width, e.g. extended spectrum
penicillins, newer cephalosporins, aminoglycosides, fluoroquinolones are now
available. However, the terms ‘narrowspectrum’ and ‘broad-spectrum’ are still applied.
E. Type of action
• Primarily bacteriostatic
Sulfonamides , Erythromycin
Tetracyclines, Ethambutol
Chloramphenicol, Clindamycin
Linezolid
• Primarily bactericidal
Penicillins, Cephalosporins
Aminoglycosides ,Vancomycin
Polypeptides, Nalidixic acid
Rifampin, Ciprofloxacin
Isoniazid, Metronidazole
Pyrazinamide, Cotrimoxazole
Some primarily static drugs may become cidal at higher concentrations (as
attained in the urinary tract), e.g. sulfonamides, erythromycin, nitrofurantoin.
On the other hand, some cidal drugs, e.g. cotrimoxazole, streptomycin may
only be static under certain circumstances.
F. Antibiotics are obtained from:
• Fungi
Penicillin, Griseofulvin,Cephalosporin
• Bacteria
Polymyxin B, Tyrothricin, Colistin, Aztreonam Bacitracin
• Actinomycetes
Aminoglycosides, Macrolides,Tetracyclines Polyenes, Chloramphenicol
PROBLEMS THAT ARISE WITH THE USE OF AMAs
Toxicity
a) Local irritancy:
• This is exerted at the site of administration. Gastric irritation, pain and abscess formation at
the site of i.m. injection, thrombophlebitis of the injected vein are the complications.
b) Systemic toxicity:
• Almost all AMAs produce dose related and predictable organ toxicities.
• Some AMAs have a high therapeutic index—doses up to 100-fold range may be given
without apparent damage to host cells, Eg. penicillins, some cephalosporins and
erythromycin.
Still others have a very low therapeutic index—use is highly restricted to conditions
where no suitable alternative is available, e.g.:
• Polymyxin B: Neurological and renal toxicity.
Hypersensitivity reactions
• Practically all AMAs are capable of causing hypersensitivity reactions.These are
unpredictable and unrelated to dose.
• The whole range of reactions from rashes to anaphylactic shock can be produced.
• This phenomenon is relatively common and potentially very dangerous because the
microorganisms responsible for the new infection can be drug-resistant strains.
• The broader the antibacterial spectrum and the longer the period of antibiotic
treatment, the greater is the alteration in the normal microflora, and the greater is the
possibility that a single, typically drug-resistant microorganism will become
predominant, invade the host, and produce infection.
• The most specific and narrowest spectrum antimicrobial agent should be chosen to
treat infections whenever feasible
CHOICE OF AN ANTIMICROBIAL AGENT
i) Patient factors, ii) Organism-related considerations iii) Drug factor
Patient factors
Age:
• Age may affect kinetics of many AMAs.
• Sulfonamides displace bilirubin from protein binding sites—can cause kernicterus in the
neonate because their bloodbrain barrier is more permeable.
• The t½ of aminoglycosides is prolonged in the elderly and they are more prone to
develop VIII nerve toxicity.
• Tetracyclines deposit in the developing teeth and bone—discolour and weaken them—
are contraindicated below the age of 6 years.
• Renal and hepatic function
Cautious use and modification of the dose of an AMA (with low safety margin) becomes
necessary when the organ of its disposal is defective
Local factors
The conditions prevailing at the site of infection greatly affect the action of AMAs.
(a) Presence of pus and secretions decrease the efficacy of most AMAs,
especially sulfonamides and aminoglycosides. Drainage of the abscess
reduces the population of the causative bacteria, suppresses anaerobes by
exposure to oxygen, and improves diffusion of the antibiotic into the abscess.
(f) Penetration barriers may hamper the access of the AMA to the site of infection in
subacute bacterial endocarditis (SABE), endophthalmitis, prostatitis. However,
trimethoprim and fluoroquinolones attain high concentration in prostate due to ion
trapping.
Genetic factors
Primaquine, nitrofurantoin, sulfonamides, chloramphenicol and
fluoroquinolones are likely to produce haemolysis in G-6-PD deficient
patient.
• Drug allergy
History of previous exposure to an AMA should be obtained. If a drug has
caused allergic reaction —it has to be avoided in that patient, e.g. drug of choice
for syphilis in a patient allergic to penicillin is tetracycline. β-lactams,
sulfonamides, fluoroquinolones and nitrofurantoin frequently cause allergy.
• Impaired host defence
Integrity of host defence plays a crucial role in overcoming an infection.
Pyogenic infections occur readily in neutropenic patients, while if cell-mediated
immunity is impaired (e.g. AIDS), infections by low grade pathogens and
intracellular organisms abound.
• A clinical diagnosis should first be made, at least tentatively, and the likely
pathogen guessed.
1. Clinical diagnosis itself directs choice of the AMA
The infecting organism and its sensitivity are not variable, e.g. syphilis,
chancroid, diphtheria, tetanus, plague, cholera, trachoma thrush,
tuberculosis, lobar pneumonia, leprosy, amoebiasis, herpes simplex, etc.
2. A good guess can be made from the clinical features and local experience
about the type of organism and its sensitivity: tonsillitis, otitis media, boils,
vaginitis, urethritis; the most appropriate specific AMA should be
prescribed and the response watched for. A gram stained smear
examination of infected material may help to aid the choice.
3. Choice to be based on bacteriological examination
No guess can be made about the infecting organism or its sensitivity, e.g.
bronchopneumonia, empyema, meningitis, osteomyelitis, urinary tract
infection, wound infection, etc. In these situations, an AMA should be
selected on the basis of culture and sensitivity testing; but this may not be
always possible.
Drug factors
When any one of a number of AMAs could be used to treat an infection,
choice among them is based upon specific properties of these AMAs:
1. Spectrum of activity: For definitive therapy, a narrow-spectrum drug which
selectively affects the concerned organism is preferred, because it is
generally more effective than a broad-spectrum AMA, and is less likely to
disturb the normal
2. Sensitivity of the organism: assessed on the basis of MIC values (if
available) and consideration of postantibiotic effect.
3. Relative toxicity: Obviously, a less toxic antibiotic is preferred, e.g. a β-
lactam over an aminoglycoside or erythromycin over clindamycin.
4. Route of administration: Many AMAs can be given orally as well as
parenterally, but aminoglycosides, penicillin G, carbenicillin, many
cephalosporins, vancomycin, etc. have to be given by injection only. For
less severe infections, an oral antibiotic is preferable; but for serious
infections, e.g. meningitis, spreading cellulitis, septicaemias, a parenteral
antibiotic may be chosen.
5. Pharmacokinetic profile:
For optimum action the antibiotic has to be present at the site of infection in
sufficient concentration for an adequate length of time. This depends on their
pharmacokinetic characteristics. Most antibiotics are given at 2 to 4 half-life
intervals—thus attaining therapeutic concentrations only intermittently.
6. Evidence of clinical efficacy: Relative value of different AMAs in treating
an infection is decided on the basis of comparative clinical trials. Optimum
dosage regimens and duration of treatment are also determined on the basis
of such trials. Reliable clinical trial data, if available, is the final guide for
choice of the antibiotic.
8. Cost: Less expensive drugs are to be preferred.
COMBINED USE OF ANTIMICROBIALS
More than one AMAs are frequently used concurrently. This should be done
only with a specific purpose and not blindly in the hope that if one is good,
two should be better and three should cure almost any infection. The
objectives of using antimicrobial combinations are:
1. To achieve synergism
3. Failure to take necessary adjuvant measures, e.g. drainage of abscesses, empyema, etc.;
removal of renal stones, other foreign bodies or infected gall bladder, adjustment of
proper urinary pH in case of urinary tract infection; cavity closure; control of diabetes,
etc.
5. Infecting organism present behind barriers, such as vegetation on heart valves (SABE),
inside the eyeball, blood brain-barrier.
6. Trying to treat untreatable (viral) infections or other causes of fever (malignancy, collagen
diseases).