Antibiotic Synergy (FIC) Calculator

Calculate fractional inhibitory concentration (FIC) index to determine antibiotic synergy or antagonism.

MIC of antibiotic A alone (μg/mL) (μg/mL)

MIC of antibiotic B alone (μg/mL) (μg/mL)

MIC of A in combination (μg/mL) (μg/mL)

MIC of B in combination (μg/mL) (μg/mL)

Please check your inputs and try again.

How FIC Is Interpreted

The fractional inhibitory concentration index sums how much of each drug's own MIC is still needed when the two are combined. If a drug works at a quarter of its solo MIC, its fractional contribution is 0.25.

FIC index = (MIC_{A combo} / MIC_{A alone}) + (MIC_{B combo} / MIC_{B alone})

FIC index	Interpretation
≤ 0.5	Synergy
> 0.5 to 4	Indifference (no interaction)
> 4	Antagonism

The thresholds are wider than intuition suggests. A FIC of 1.0 means the drugs are simply additive, contributing exactly their proportional share — that is indifference, not synergy. Older literature using narrower bands overreported synergy considerably.

Why Some Combinations Synergise

Mechanism	Example
One drug lets the other in	Ampicillin breaches the wall so gentamicin can reach the ribosome
Sequential blockade of a pathway	Trimethoprim and sulfamethoxazole in folate synthesis
Inhibiting a resistance enzyme	Clavulanate protecting amoxicillin from beta-lactamase
Preventing resistance emergence	Rifampin combinations in tuberculosis

The ampicillin–gentamicin case is the classic. Enterococci are intrinsically resistant to aminoglycosides because the drug cannot cross the cell wall efficiently. Cell wall disruption by ampicillin allows entry, and the combination is bactericidal where neither drug alone is — which is why it remains standard for enterococcal endocarditis.

Antagonism and Its Limits

Antagonism is less common but real. A bacteriostatic drug that halts growth can protect bacteria from a beta-lactam that requires active cell wall synthesis to kill.

In vitro synergy frequently fails to translate clinically. The checkerboard assay uses a fixed inoculum, a single timepoint and no host immune system, whereas real infections involve varying bacterial density, tissue penetration differences and immune contribution. Time-kill curves give a more dynamic picture, and clinical outcome data remains the only real evidence.

Worked Examples

Example 1: Ampicillin + gentamicin for endocarditis

MIC_amp=8, MIC_gent=4, combo: amp=2, gent=0.5

Result: FIC=2/8+0.5/4=0.25+0.125=0.375

FIC≤0.5: SYNERGY — classic combination

Example 2: Fluoroquinolone + rifampin: antagonism risk

FIC often >2

Result: Rifampin single mutations induced

Rifampin used alone → resistance; add second drug

Example 3: Why the FIC threshold is 0.5

Two drugs each at half their solo MIC

Result: FIC = 1.0, indifference

Each contributes exactly its proportional share, which is what independent action predicts. Genuine synergy needs a greater reduction than that.

Example 4: Overcoming intrinsic resistance

Enterococcus, ampicillin plus gentamicin

Result: Bactericidal where neither is alone

The aminoglycoside cannot cross the intact cell wall. Ampicillin breaches it, and the pair achieves killing that neither drug can produce independently.

Common Mistakes

⚠️

Treating FIC 1.0 as synergy

That value means the drugs are exactly additive, which is classified as indifference. Synergy requires 0.5 or below.

⚠️

Assuming in vitro synergy predicts clinical benefit

The checkerboard uses fixed inoculum, one timepoint and no immune system. Many combinations synergistic in vitro show no clinical advantage.

⚠️

Ignoring the possibility of antagonism

A bacteriostatic drug can protect organisms from a beta-lactam requiring active growth to kill. Combinations need justification, not assumption.

⚠️

Using a single method to claim synergy

Checkerboard and time-kill assays frequently disagree. Confirming across methods is standard before drawing conclusions.

Frequently Asked Questions

Checkerboard assay?

Serial dilutions of both antibiotics in a grid. Incubate bacteria. Read MIC at each combination point. Plot FIC isobologram. Concave curve (toward origin): synergy. Convex: antagonism. Straight line: additive. Labor-intensive but informative.

Clinical synergy examples?

Beta-lactam + aminoglycoside: Enterococcal endocarditis. Amphotericin + flucytosine: cryptococcal meningitis. Penicillin + clavulanate: beta-lactamase inhibition (not true synergy but similar principle). TMP-SMX: sequential DHFR inhibition is true synergy.

What FIC value indicates synergy?

0.5 or below. Values between 0.5 and 4 indicate indifference, and above 4 indicates antagonism.

Why is FIC 1.0 not synergy?

Because it means each drug contributes exactly its proportional share, which is what independent action predicts. That is additive, not synergistic.

Why does ampicillin plus gentamicin work for enterococci?

Enterococci resist aminoglycosides because the drug cannot cross the cell wall. Ampicillin disrupts the wall, allowing gentamicin to reach the ribosome.

Does in vitro synergy predict clinical benefit?

Often not. The assay lacks immune contribution, varying inoculum and tissue penetration. Clinical outcome data is the only reliable evidence.