Multiple drug therapy/ Combination of Antimicrobial Drug

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Multiple drug therapy/ Combination of Antimicrobial Drug:

Combine use of two or more antimicrobial drugs is occasionally required to treat certain infection. It is useful in following situations:
To broaden the spectrum of antibacterial activity
To treat mixed or obscure bacterial infections in which organism are not susceptible to single antimicrobial drug.
To achieve synergistic antimicrobial activity against some resistant strains of bacteria.
To prevent emergence of resistant strains of bacteria
To minimize the toxicity of antimicrobial drug.

Disadvantages of multiple drug therapy:

It is not useful when drugs combined in fixed dosage mixture or when two drugs interfere with each other’s action.
Increases chances of super infection
Facilitate the emergence of bacterial resistance when inadequate doses of non-synergistic drug are used.
Increase cost of therapy

Guidelines for Combination of Antimicrobial Drug:

Selection of combination of antimicrobial drug should be based on mechanism of action which are different and spectra of activity those are complimentary.
As general rule, combination of two bacteriostatic drug results in additive effect whereas combination of two bactericidal drugs often results in synergistic effect.
Some exceptions are present. Ex: combination of bactericidal streptomycin and bacteriostatic tetracycline produce synergistic action in the treatment of brucellosis.
Type of interaction between two antimicrobial drugs in combination may be evaluated from plot of activity in isobologram.
It determines whether the MIC of one drug is reduced (synergism), unchanged (additive) or increased (antagonism) in presence of another drug.
In isobologram, synergism is shown by concave curve, addition by straight line & antagonism by convex curve.
Bactericidal + Bactericidal = Synergistic effect

Bacteriostatic + Bacteriostatic = Additive effect

Bactericidal + Bacteriostatic = Antagonistic effect

Examples:

Synergism:

Combination of penicillin G and streptomycin produce synergistic lethal effect on enterococci because penicillin G enhances penetration of aminoglycoside into bacterial cell by causing bacterial cell wall damage.

Antagonism:

Combination of tetracyclines and penicillin produces reduced antibacterial activity as tetracyclines inhibit growth and multiplication of bacteria those are required for rapid cell wall damaging effect produced by β-lactam antibiotics.

Prophylactic use of Antimicrobial Agent: