Warren Combination Therapy

Rationale for the use of antimicrobial combinations

Decreased emergence of resistance
Decrease dose related toxicity
Polymicrobial indections
Virulence suppression
Synergy

Synergy- Checkerboard assay

 two or more antibiotics tested in combo in concentrations equal to, above, and below their MIC

<0.5 synergy
<1 additivity

>2 antagonism

Synergy- Agar solution

this technique involves incorporating antibiotics into agar plates at various concentrations and assessing bacterial growth inhibition.

Dynamic kill curve- synergy

Dynamic kill curve- indifference

Dynamic kill curve- antagoinsm

Serial Inhibition of metabolic pathway

• Serial inhibition of folate synthesis

• Both TMP and SMX are bacteriostatic as single agents but bactericcidal when used in combo

Inhibition of protective enzymes

Combination targets of cell wall or cell membrane antibiotics

Drug targets within cell wall or membrane function to synergize antibiotic effect

Phosphonic acid derivates + B-lactams/vanco
Daptomycin + B lactams

what vanco combo causes less nephrotoxicity ?

Vacno + Hydrophillic B lactams (ampicillin, most cephalosporins)

Use of cell wall agents to enhance uptake

Aminoglycosides + B lactams
Daptomycin + B lactams

Recognize mechanisms for and potential clinical implications of antagonistic combinations

Static agents used with cidal agents —> Induction of resistance, competitive binding