Objectives:

The standard method of assessing antibiotic combinations is the measurement of fractional inhibitory concentration indices (FICIs). The FIC however, gives no indication of the breakpoints (BPs) of the antibiotics. With the well established role of the MIC and BP in determining outcome of antibiotic therapy, we have developed a new measurement of antibiotic combinations, the breakpoint index (BPI), which takes into account both the minimum inhibitory concentrations (MICs) and BPs of antibiotics in combination.

Methods:

FICIs for antibiotic combinations against Gram-negative isolates from cystic fibrosis patients, as measured by Etest, were compared against the MICs alone and in combination, expressed as a ratio to the relevant antibiotic BPs. The BPI = [(BP antibiotic 1/combination MIC of antibiotic 1) + (BP antibiotic 2/combination MIC of antibiotic 2)].

Results:

A total of 120 strains of Pseudomonas aeruginosa (PA) were tested against 38 different antibiotic combinations, 69 strains of Burkholderia cepacia (BC) against 60 combinations and 27 strains of Stenotrophomonas maltophilia (SM) against 37 combinations. The number of organism/antibiotic combinations tested for PA was 740, for BC was 462 and for SM was 172. The BPI bore no relationship to the FICI (r² = 6.9 to -0.4). High BPIs were present in combination with low FICIs (synergistic combinations) and those with high FICIs (antagonistic combinations). The mean BPIs (±SD) for the synergistic combinations (FICI <= 0.5) for PA, BC and SM were 55.3 (±102), 25.5 (±55) and 29.1 (±41.1), respectively. The mean BPIs (±SD) for the additive combinations (FICI > 0.5 and <=1.0) for PA, BC and SM were 8.7 (±132), 17.9 (±25.1) and 44.5 (±43.6) respectively. The mean BPIs (±SD) for the indifferent combinations (FICI 1.0 and <=2.0) for PA, BC and SM were 68.1 (±112), 25.1 (±38.2) and 67.1 (±69.4), respectively. The mean BPIs for the antagonistic combinations of PA, BC and SM were 20 (±-20.6), 15.5 (±22.1) and 53.5 (±60.2), respectively.

Conclusions:

The higher the BPI the greater the difference between the tissue levels and the MIC ensuring maximum clinical effect. It is apparent that the FICI can give quite misleading data, underestimating the pharmacodynamic benefits of additive and indifferent antibiotic combinations.