TABLE 4.
MICs of various beta-lactam antibiotics alone and in combination with QPX7728 against isogenic strains of P. aeruginosa overexpressing MexAB-OprM and/or chromosomal AmpCa
| Strain | MexAB-OprM | AmpCb | MIC (μg/ml) |
||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Meropenem |
Ceftolozane |
Cefepime |
Ceftazidime |
Piperacillin |
|||||||||||||
| Alone | With QPX7728 at: |
Alone | With QPX7728 at: |
Alone | With QPX7728 at: |
Alone | With QPX7728 at: |
Alone | With QPX7728 at: |
||||||||
| 4 μg/ml | 8 μg/ml | 4 μg/ml | 8 μg/ml | 4 μg/ml | 8 μg/ml | 4 μg/ml | 8 μg/ml | 4 μg/ml | 8 μg/ml | ||||||||
| PAM1020 | BL | 1 | 0.5 | 0.5 | 0.5 | 0.5 | 0.5 | 0.5 | 0.5 | 0.5 | 0.5 | 1 | 1 | 1 | 4 | 4 | 4 |
| PAM2156 | BL | 489 | 2 | 0.5 | 0.5 | 4 | 0.5 | 0.5 | 8 | 0.5 | 0.5 | 32 | 1 | 1 | >256 | 16 | 4 |
| PAM1032 | Up | 0.8 | 2 | 2 | 2 | 0.5 | 0.5 | 0.5 | 4 | 4 | 4 | 4 | 4 | 4 | 16 | 16 | 16 |
| PAM2005 | Up | 769 | 4 | 2 | 2 | 4 | 1 | 0.5 | 16 | 4 | 4 | 64 | 8 | 8 | >256 | 128 | 32 |
QPX7728 was used at a fixed concentration of 8 μg/ml. All strains are derivatives of PAM1020 (PAO1). BL, basal level; Up, overexpressed. Overexpression of the MexAB-OprM efflux pump in PAM1032 and PAM2005 is due to the L75R amino acid substitution in the MexR protein. PAM2005 was selected from PAM1032 on piperacillin at 64 μg/ml. It has AmpC overproduced due to the D135H amino acid substitution in the AmpR protein. PAM2156 was obtained by transducing a piperacillin resistance marker from PAM1032 into PAM1020 using phage F116, as described in Materials and Methods. The QPX7728 MIC against all strains was >128 μg/ml.
The numbers correspond to the level of expression of the chromosomal ampC relative to that in PAM1020.