2. 2
Chemotherapy/Anti-infectives
• Chemotherapy of TB, leprosy, enteric fever (Antibacterials)
• Chemotherapy of malaria, filaria, amoebiasis, Leishmaniasis
(Antiprotozoals)
• Antihelminthic drugs (worm and fluke infections)
• Antiviral drugs
• Antifungal drugs
• Anticancer drugs
• Antiseptics and disinfectants
3. 3
1. Classify antimicrobials using mode of action/
chemical class/ with examples.
2.Describe the mechanism of action of common
antimicrobial class.
TLOs
4. 4
• Chemotherapy: Treatment with specific drugs that selectively
suppress infecting microorganism/cancer cells without
significantly affecting the host (selective microbial toxicity).
• Antibiotics: Natural substances produced by microorganisms,
that selectively suppress growth/kill other microorganisms
• Antimicrobials: synthetic (manmade) antibacterial drugs and
not obtained from microorganisms.
• Antibacterial spectrum: Bacteria susceptible to antibacterial
actions of a particular drug.
• Broad spectrum: antibacterial effective against a wide variety of
both Gram+ve and Gram-ve pathogenic bacteria.
• Chemoprophylaxis: Use of antibiotics/antimicrobials to prevent
infection. Ex. before a surgical procedure or in patients with an
increased risk of infection.
Important Terms
5. 5
Classification of antimicrobials
1. Mechanism of Action
2. Type of organisms against which primarily active
3. Spectrum of activity
4. Type of action
5. Chemical structure
6. 6
1. Classification of antimicrobials based on mechanism of action
• Inhibit cell wall synthesis: Penicillins, Cephalosporins, Cycloserine,
Vancomycin.
• Leakage from cell membranes: Polymyxin, Amphotericin B, Nystatin.
• Inhibit protein synthesis: Tetracycline, Chloramphenicol,
Erythromycin, Clindamycin, Linezolid.
• Misreading of mRNA code and affect permeability: Strepto, Genta
• Inhibit DNA gyrase: Ciprofloxacin
• Interfere with DNA function: Rifampin, Metronidazole
• Interfere with DNA synthesis: Acyclovir, Zidovudine
• Interfere with intermediary metabolism: Sulphonamides, PAS,
Trimethoprim, Pyrimethamine, Ethambutol
7. 7
2. Classification of antimicrobials based on activity
on specific organism
• Antibacterials: Penicillins, Aminoglycosides, Erythromycin.
• Antifungal: Griseofulvin, Amphotericin B, Ketoconazole.
• Antiviral: Acyclovir, Amantadine, Zidovudine.
• Antiprotozoal: Chloroquine, Pyrimethamine, Metronidazole.
• Antihelminthic: Mebendazole, Pyrantel, Niclosamide.
8. 8
3. Classification of antimicrobials based on
spectrum of activity
• Narrow spectrum: Penicillin G, Streptomycin, Erythromycin
• Broad-spectrum: Tetracyclines, Chloramphenicol,
Fluoroquinolones,
12. 12
General Principles of Antimicrobial
chemotherapy
• Infections and its complications are the most
common type of condition seen in clinical practice
by general physicians.
• A decision to treat with antimicrobials , delay or not
to treat is taken based on patient presenting
condition.
• Hence patients treated/not to be treated with
antimicrobials/delayed use of antimicrobials
depends on the sound reasoning of physician.
13. 13
Selection of antimicrobial agent
I. Patient factors
II. Microorganism-related factors
III. Drug-related factors
I. Patient factors:
a. Age- age affects PK of many antimicrobials. Not all
antimicrobials can be prescribed to paediatric and
geriatric patients.
Ex. Conjugation and excretion of chloramphenicol is low in
newborn causing Gray baby syndrome in large doses.
AG have to be used with caution in elderly patients (↓GFR).
Sulfonamides may displace bilirubin from protein binding
sites and cause kernicterus in the neonates.
14. 14
b. Renal and hepatic function: Dose should be adjusted in
reduced organ function.
In mild renal failure, dose reduction is recommended for
aminoglycosides, and Vancomycin.
Reduce dose in moderate to severe failure. Ex. Metronidazole,
Fluoroquinolones, Clarithromycin.
Reduce dose in hepatic failure: metronidazole, and rifampin
Drugs to be avoided- Erythromycin, Pyrazinamide
c. Local factors:
1. Pus and secretions decrease efficacy during use of sulphonamides
and aminoglycosides.
2. Presence of necrotic material/foreign body makes eradication of
infection impossible.
3. Haematomas foster bacterial growth and drugs like TC, penicillins,
cephalosporins bind to degrade haemoglobin in the haematomas.
15. 15
d. Drug allergy: patient’s previous exposure to antimicrobial should
be obtained. Ex. Drug of choice for syphilis in a patient
allergic to penicillin is TC.
e. Impaired host defence: In a subject with normal host defence a
bacteriostatic antimicrobial may cure the condition. But in patients
with impaired immune systems, it is important to use intensive
therapy with cidal drugs.
f. Pregnancy: Antimicrobials to be avoided in pregnancy due to
risk to fetus. Ex. Tetracycline cause yellow atrophy of liver,
pancreatitis, and nephrotoxicity to mother.
Tooth and bone deformities to foetus.
Aminoglycosides cause fetal ototoxicity and nephrotoxicity.
g. Genetic factors: Primaquine, Pamaquine, Chloroquine,
Isoniazid, Sulfonamides, chloramphenicol, fluoroquinolones
and aspirin, cause hemolysis in G-6PD deficiency.
16. 16
II. Microorganism-related factors:
a. Clinical diagnosis directs choice of antimicrobials:
Usually the microorganism and its sensitivity to a
particular antimicrobial is always constant.
b. A good clinical judgement can be made: The
clinical features, type of microorganism,
sensitivity along with experience should help in
the selection of antimicrobial.
c. Bacteriological examination: If its difficult to
identify the microorganism or its sensitivity,
antimicrobial selected based on culture/sensitivity
testing. Empirical treatment with broad spectrum
antimicrobial can be started.
17. 17
III. Drug-related factors:
When antimicrobials are used to treat an infection preferred choice is
based on specific properties of drug:
(a) Spectrum of activity: a narrow-spectrum drug which
selectively kills organism preferred, due to high efficacy than
broad spectrum antimicrobial and do not disturb normal microbial
flora. Empirical treatment uses a broad spectrum drug that covers
all pathogens.
(b) Type of activity: infections in patients with normal immune
system respond well with cidal/static drugs.
bacteriCidal bacterioStatic
1. Acute infections respond well
with Cidal drugs.(↓ number of
bacteria at site of infection).
2. Cidal drug exhibit post-
antibiotic effect and no need to
maintain drug levels above MIC.
1.Takes time to resolve with static
drugs (prevents bacterial
multiplication).
2. Static drug level should be
maintained above MIC levels to
prevent bacterial multiplication and
chances of relapse.
18. 18
(c). Sensitivity of organism: depends on MIC and post antibiotic effect.
(d). Relative toxicity: A less toxic antimicrobial is preferred. (ex). A beta
lactam selected over an aminoglycoside.
(e). PK profile: antimicrobial activity depends on drug conc at site of
infection for adequate time period which depends on PK profile of drug.
1. Conc dependent inhibition: inhibitory effect depends on ratio of peak
conc to MIC. (Ex) amino glycosides and fluroquinolones. Single dose
has better effect.
2. Time-dependent inhibition: inhibitory effect depends on length of
time conc remains above MIC. Ex. Beta lactams, macrolides, etc.
Division of daily dose has better effect.
Drugs which penetrate better and attains high conc at site of infection
usually is highly efficacious. Ex fluoroquinolones. Penicillins and
aminoglycosides poor CSF penetration unless meninges inflammed.
19. 19
(f). Route of administration: for some antimicrobials like
aminoglycosides, penicillin G, carbenicillin, cephalosporins,
vancomycin it is usually preferable to give injection form. In serious
infections like meningitis, cellulitis, septicaemias parenteral
anitibiotic may be given. For less serious oral antibiotic given.
(g). Clinical efficacy: results of clinical trials also give an idea of efficacy
of antibiotic. Dosage regimens, duration of treatment info are also
available.
(h). Cost: Treatment depends on cost.
Antimicrobial Combinations: Objectives
1. To achieve synergism
2. To reduce severity of adverse effects
3. To prevent emergence of resistance
4. To broaden spectrum of antimicrobial action
20. 20
1. To achieve synergy (supra-additive): synergism
cause lowering of MIC. If MIC of each drug reduced to
25% or less then the pair considered synergistic.
Ex. Sulfamethoxazole+ trimethoprim (co-
trimoxazole) due to sequential block of folate
metabolism. Combination yields cidal whereas
individual drugs have static effect.
beta lactamase inhibitor clavulanic acid /sulbactam
+amoxicillin/ampicillin in H.inflenzae, N.gonorrheae
infections producing Beta lactamase enzymes.
penicillin/ampicillin+streptomycin/gentamycin or
vancomycin+gentamycin for enterococcal,
subacute bacterial endocarditis. Combo of
bactericidal drugs produce faster cure and reduces
chances of relapse.
21. 21
Failure of antimicrobial therapy
Success of antimicrobial therapy measured by clinical improvement /
eradication of infecting organism.
Causes of failure:
1. Improper selection of drug, dose, route of administration,
duration of treatment.
2. Treatment started too late.
3. Failure to take necessary adjuvant measures. Ex. Drainage of
abscesses, empyema, removal of stones, foreign bodies,
infected gall bladder, adjustment of urinary pH in UTI,
control of diabetes etc.
4. Poor host defence- Immuno compromised states like
leukaemias, neutropenia, HIV and TB.
5. Infecting organism present behind barriers such as behind
heart valves (SABE), inside eye ball, brain etc.
6. Presence of dormant/altered organisms giving rise to
relapses.
23. 23
1. Inhibit cell wall synthesis (CWSI): Beta lactams (Penicillins,
Cephalosporins) Vancomycin.
2. Inhibit protein synthesis (PSI): Tetracycline, Chloramphenicol,
Erythromycin, Clindamycin, Linezolid.
Misreading of mRNA code and affect permeability: Strepto, Genta.
3. Inhibit DNA gyrase: Ciprofloxacin
4. Interfere with intermediary metabolism: Sulphonamides, PAS,
Trimethoprim, Pyrimethamine, Ethambutol
Classification of antimicrobials based on mechanism of action
24. 1.CWSI
Beta-lactam inhibit cell wall synthesis by:
(1) binding of the drug to specific enzymes (penicillin-
binding proteins[PBPs]) located in the bacterial
cytoplasmic membrane.
(2) inhibition of the transpeptidation reaction that cross-
links the linear peptidoglycan chain constituents of the cell
wall.
(3) activation of autolytic enzymes that cause lesions in
the bacterial cell wall cause bactericidal effects.
24
27. Drugs Mechanism of action
Tetracycline (BS) Binds reversibly to the 30S subunit of the bacterial
ribosome, blocking access of the amino acyl-tRNA to the
mRNA-ribosome complex at the acceptor site.
Aminoglycosides
(BCD)
Bind to the 30S ribosomal subunit and interfere with
protein synthesis in at least 3 ways: (1) block formation of
the initiation complex; (2) cause misreading of the code
on the mRNA template; and (3) inhibit translocation.
Chloramphenicol
(BS)
Binds to the bacterial 50S ribosomal subunit and inhibits
protein synthesis at the peptidyl transferase reaction
Macrolides (BS) Bind irreversibly to a site on the 50S subunit of the
bacterial ribosome, thus inhibiting the translocation steps
of protein synthesis.
Clindamycin (BS) Same as macrolides.
Linezolid (BS) Binds to a site on the bacterial 23S ribosomal RNA of the
50S subunit and prevents the formation of a functional
70S initiation complex. 27
28. 3. Inhibitors of DNA gyrase
MOA: Fluoroquinolones (Ciprofloxacin) interfere with bacterial
DNA synthesis by inhibiting topoisomerase II (DNA gyrase) in
gram-negative organisms, and topoisomerase IV, in gram-
positive organisms.
Block the relaxation of supercoiled DNA catalyzed by
topoisomerase II (DNA gyrase), required for normal
transcription and duplication.
Inhibition of topoisomerase IV by fluoroquinolones
interferes with the separation of replicated chromosomal
DNA during cell division leading to BCD effects.
28
29. 4. Interfere with intermediary metabolism
Enzymes requiring folate-derived cofactors are essential for
the synthesis of purines and pyrimidines (precursors of
RNA and DNA) and other compounds necessary for
cellular growth and replication.
In the absence of folate, cells cannot grow or divide. To
synthesize the critical folate derivative, tetrahydrofolic acid,
humans must obtain preformed folate in the form of folic
acid as a vitamin from the diet.
In contrast, bacteria must synthesize folate de novo.
29
30. Sulfonamides (sulfa drugs) are antimicrobials that inhibit
this de novo synthesis of folate.
Trimethoprim prevents microorganisms from converting
dihydrofolic acid to tetrahydrofolic acid, with minimal effect
on a human cell's ability to make this conversion.
Thus, both sulphonamides (sulphamethoxazole) and
trimethoprim (COMBO COTRIMOXAZOLE IS
SYNERGISTIC COMBO; BCD) interfere with the ability of
an infecting bacterium to divide.
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