Introduction to Antimicrobials Page 1 of 6

Introduction to Antimicrobials

Antibiotics: chemical substances produced by bacteria, fungi,

actinomyces that suppress the growth of other microorganisms and may
destroy them, e.g. penicillin, streptomycin, etc. Antimicrobial
compounds include synthetic compounds, e.g. quinolones, sulfonamides.

Why are they selectively toxic to bacteria?

1. Bacterial cell wall consists of peptidoglycans and that of humans of phospholipid.

2. Antibiotics inhibit selectively the enzymes required for synthesis of acid, mammals
use preformed folic acid.
3. Antibiotics selectively inhibit protein synthesis in bacteria which have 70S ribosomes,
whereas mammals have 80S ribosomes

Classification of antimicrobials

1. According to spectrum of activity

a. Broad spectrum: wide range of activity- both G + ve & G –ve organisms,
e.g., 3rd generation cephalosporins.
b. Narrow spectrum: limited antibacterial activity, e.g., streptomycin,
nafcillin, etc.

2. According to type of action

a. Primarily bacteriostatic: inhibit growth of organisms: e.g., sulfonamides, etc;
and body’s immune system eliminates the pathogens, if antimicrobial is stopped
before the bacteria is destroyed, relapse may occur. Not used in
immunocompromised patients or in life threatening infections.

b. Primarily bactericidal: kill microorganisms; e.g. β-lactams, quinolones, etc. Use

in the treatment of meningitis, endocarditis, and to treat bacteremia in neutropenic
patients.
Bactericidals are divided into:
i. Conc. dependent killing: aminoglycosides and quinolones.
ii. Time dependent killing: β lactams and vancomycin.

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Mechanism of action of antimicrobials

1. Inhibition of cell wall synthesis: e.g. penicillin, cephalosporin. etc.

2. Increase cell membrane permeability leading to leakage of intracellular

compounds, e.g. polymyxins, polyene antifungal agents like nystatin,
amphotericin B.

3. Inhibition of protein synthesis in a reversible way (bacteriostatic):

− Acting on 50S ribosomes: chloramphenicol, clindamycin and
erythromycin.
− Acting on 30S ribosomes: tetracyclines.
4. Inhibitors of protein synthesis acting on 30S ribosomes (bactericidal):
aminoglycosides.

5. Interfering with nucleic acid metabolism:

− Inhibitors of DNA dependent RNA polymerase: rifampin.
− Inhibitors of DNA supercoiling and DNA synthesis:
fluoroquinolones

6. Drugs affecting intermediary metabolism: inhibitors of folic acid

synthesis: trimethoprim, sulfonamides, & pyrimethamine.

Mechanisms of bacterial resistance to antimicrobials

1. Production of enzymes that destroy the drug, examples:

β -lactamase by Staph, resistant to penicillin.

2. Change in permeability to the drug:

Increased efflux: e.g. quinolones, tetracyclines
dec.influx: e.g. tetracyclines, aminoglycosides.

3. Development of an altered structural target:

o Altered 30S ribosome- for aminoglycosides
o Altered 50S ribosome- for erythromycin.
o Low affinity for PBP (Penicillin binding protein) by MRSA (Methicillin-
resistant Staphylococcus aureus).

4. Development of altered metabolic pathway that bypasses the reaction

inhibited by the drug: Sulfonamide-resistant bacteria may utilize preformed folic
acid.

How to delay emergence of resistance

• Prescribe only when necessary

• Prescribe narrow spectrum where possible.
• Limit use of newer drugs

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• Minimise giving antibiotics to livestock.

Selection of antimicrobial agents

Antibiotics are used in 2 ways:

A. Empiric or initial therapy: which covers all likely microorganisms, broad spectrum
combination of antibiotics used.

Approach to empiric therapy:

– Formulate a clinical diagnosis.
– Obtain specimens for laboratory exam.
– Formulate a microbiologic diagnosis.
– Determine the necessity for empiric therapy
– Institute treatment.

B. Definitive therapy: After infectious organism is identified, narrow spectrum and drug
with low toxicity preferred

Factors affecting Selection of antimicrobial agent:

A. Organism and microbial sensitivity to antimicrobial agent

tested by i. disc diffusion, serial dilution.
B. Drug factors: pharmacokinetic factors
C. Host factors.

B. Drug factors (pharmacokinetic factors)

• Kinetics of ADME:
– Route of administration
– Physicochemical properties (polar drugs may not penetrate CNS)
– Protein binding (highly protein bound drug penetrate less)
– Presence or absence of inflammation
– Antimicrobial binding to exudates or tissues
– Pathways of excretion of antimicrobial.
• The potential toxicity of an agent
• Pharmacokinetic or pharmacodynamic interactions with other drugs
• Potency
• Cost

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A. Host factors

• Host defense mechanism: Both humoral and cellular immunity are

important.
o Bacteriostatic drugs are not useful if host defense mechanisms are
compromised.
o Bactericidal drugs are used for bacterial endocarditis and
meningitis and disseminated gram-negative bacillary infections
especially pseudomonas in neutropenic patients.
• Local factors: pus, abscess (aminoglycosides less effective)
• Age: with chloramphenicol: gray baby syndrome in new born,
accumulation of tetracyclines in milk and teeth in children.
• Genetic factors: hemolysis of RBC with certain drugs in patients with
G6PD deficiency.
• Pregnancy: deafness in children on use of streptomycin during pregnancy.
• Lactating female: hemolysis of RBC in G6PD deficient baby on
administration of sulfonamides to lactating women.
• Prior drug adverse effects: drug allergy with β lactams.
• Renal function: adjust dose of aminoglycosides, vancomycin in renal
impairment.
• Hepatic function: adjust dosage of erythromycin in hepatic disease.

Therapy with combined antimicrobial agents

• Two bacteriostatic drugs often show additive effect.

• Two bactericidal agents are additive if the organism is sensitive to both e.g. INH
and rifampin in TB. (INH= isonicotinyl hydrazine = isoniazid).
• Combination of bactericidal with bacteriostatic drug is additive if the organism
has low sensitivity to cidal drug, e.g. streptomycin and tuberculosis for
brucellosis.
• Combination of cidal with static agent is antagonistic if the organism has high
sensitivity to cidal drug, penicillin and tetracycline/chloramphenicol for
pneumococci.

Mechanisms of drug synergism:

• Blockade of sequential steps in a metabolic sequence: cotrimoxazole.

• Inhibition of enzymatic inactivation: β-lactams with β-lactamase inhibitor.
• Enhancement of antimicrobial agent uptake: Penicillin and other cell wall
active agents increase the uptake of aminoglycosides. Amphotericin B enhances
the uptake of flucytosine by fungi.

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Indications for use of antibiotic drug combinations

1. Treatment of polymicrobial bacterial infections: like intra-

abdominal abscess.
2. Therapy of severe infection in which a specific cause is
unknown.
3. Enhancement of antibacterial activity in the treatment of
specific infection: enterococcal endocarditis: β lactams and
aminoglycosides.
4. To decrease dose related toxicity by decreasing dose of one or
more components: amphotericin B and flucytosine.
5. Prevention of emergence of resistant microorganism:
tuberculosis, leprosy.

The drugs should have different mechanisms of action and different side effect profiles.

Disadvantages of combination of antimicrobial agents

1. Increased risk of toxicity

2. Increased cost
3. Selection of microorganisms that are resistant to antibiotic
4. Increased chances of superinfection.
5. Antagonism of antibacterial effect with the combined use of bactericidal and
bacteriostatic drugs- bacteriostatic effect is obtained

Misuses of antibiotics

1. Treatment of untreatable infections: viral infections: mumps, measles, upper

respiratory tract infection.
2. Therapy of fever of undetermined origin.
3. Improper dosage: dose, duration, frequency
4. Reliance on chemotherapy with omission of surgical drainage
5. Lack of adequate bacteriological information

The prophylaxis of infection with antibiotics

Chemoprophylaxis is of value: if a single effective drug is used to prevent infection by

a specific microorganism or to eradicate infection immediately or soon after it has
become established.
It often fails if the aim of prophylaxis is to prevent colonization or infection by any or all
microorganisms in environment of a patient.

Prophylaxis:
A. Surgical
B. Nonsurgical

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Superinfections

Means appearance of bacterial and clinical evidence of a new infection during the
chemotherapy of a primary one.

• More common when host defense is compromised as in: corticosteroid therapy,

leukemia or other malignancies, especially treated with anticancer drugs, AIDS,
neutropenia, agranulocytosis, diabetes.
• Occurs due to alteration of microbial flora of host in intestine, respiratory
and genitourinary tract. Microorganisms are mostly Enterobacteriaceae,
Pseudomonas, Candida or other fungi.
• The broader the spectrum of antibiotics, greater is the risk. It is lowest with
penicillin G, higher with tetracycline and highest with combination of broad-
spectrum antimicrobials and extended spectrum 3rd generation cephalosporins.
• Incidence also increases with prolonged administration of antibiotics.

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