TABLE 1.
Overview of the 9 days ciprofloxacin sub-MIC selective windows of P. aeruginosa PA14 and 12 clinical isolatesa
| Strain (ST) | Sample type | Mutational resistome | MIC (μg/mL) | MSb (μg/mL) | Maximum fold-change MIC | Sub-MIC selective concentrationsc | Cross-resistance | Collateral sensitivity |
|---|---|---|---|---|---|---|---|---|
| PA14 | 0.5 | 0.005 | 681 | 1/100 MIC | LEV, CAZ, AMK, ATM, | FOF | ||
| 1/50 MIC | LEV, CAZ, AMK, ATM, | FOF | ||||||
| 1/25 MIC | LEV | FOF | ||||||
| 1/10 MIC | LEV, CAZ, AMK, | FOF | ||||||
| 1/5/MIC | LEV | FOF | ||||||
| 1/2 MIC | LEV | ATM, FOF | ||||||
| CAN01-002 (111) | Sputum | MexB Q319X, MexY G530S, MexZ Q140K, MexT G276D | 0.25 | 0.005 | 16 | 1/50 MIC | LEV, ATM | AMK |
| 1/25 MIC | LEV, ATM | |||||||
| 1/10 MIC | LEV | AMK | ||||||
| 1/5/MIC | LEV | AMK | ||||||
| 1/2 MIC | LEV | AMK, IPM | ||||||
| AND04-004A (244) | Tracheal aspirate | 0.25 | 0.005 | 94 | 1/50 MIC | LEV, IPM | ||
| 1/25 MIC | LEV, IPM | |||||||
| 1/10 MIC | LEV, IPM | AMK | ||||||
| 1/5/MIC | LEV, IPM | AMK, CAZ, ATM | ||||||
| 1/2 MIC | LEV, IPM | AMK, ATM | ||||||
| FQSE06-0403 (274) | CF sputum | MexA L338P, MexZ S9P, Mpl S257L, FusA1 Y552C and T671I, FtsI P215L | 0.125 | 0.0125 | 11 | 1/10 MIC | LEV, AMK, FOF | |
| 1/5/MIC | LEV | |||||||
| 1/2 MIC | LEV, FOF | |||||||
| BAL04-002 (1816) | Blood | MexA K86E, AmpR G295R, AmpC A278G, ParE E215Q | 0.4 | 0.004 | 85 | 1/100 MIC | LEV, ATM | |
| 1/50 MIC | LEV, CAZ, ATM | |||||||
| 1/25 MIC | LEV, CAZ, ATM | |||||||
| 1/10 MIC | LEV | AMK | ||||||
| 1/5/MIC | LEV | AMK, CAZ, ATM | ||||||
| 1/2 MIC | LEV | AMK, cAT, aTM | ||||||
| CAT02-004 (244) | Blood | MexR S88fs, DacB A340G | 0.4 | 0.016 | 32 | 1/25 MIC | LEV, CAZ, AMK | - |
| 1/10 MIC | LEV, AMK | - | ||||||
| 1/5/MIC | LEV, AMK | - | ||||||
| 1/2 MIC | LEV, AMK | - | ||||||
| GAL02-004 (217) | Sputum | GyrA A908T, GyrB R22C, MexS P225L, Mpl H109Y, AmpC V239A, FusA1 T671A | 1 | 0.1 | 16 | 1/10 MIC | LEV | ATM |
| 1/5 MIC | LEV | CAZ, ATM | ||||||
| 1/2 MIC | LEV | ATM | ||||||
| GAL02-002 (3342) | Sputum | MexZ Y204X, MexS G76S, GalU C242X, OprJ D303V, PmrB A467V | 0.125 | 0.025 | 4 | 1/5/MIC | LEV | AMK |
| 1/2 MIC | LEV | AMK, ATM, FOF | ||||||
| FQSE110603 (701) | CF sputum | MexX A38P, MexY N709H and A568T, OprN R363H, AmpDh2 P116S | 0.4 | 0.004 | 192 | 1/100 MIC | LEV, FOF | |
| 1/50 MIC | LEV, ATM, FOF | AMK | ||||||
| 1/25 MIC | LEV, IPM, FOF | AMK | ||||||
| 1/10 MIC | LEV, ATM, IPM, FOF | AMK | ||||||
| 1/5/MIC | LEV, IPM, FOF | AMK | ||||||
| 1/2 MIC | LEV, IPM, FOF | CAZ, AMK | ||||||
| ICA01-004 (698) | Sputum | MexE V156A, AmpR E162Q, ArmZ V266M | 0.25 | 0.01 | 188 | 1/25 MIC | LEV, CAZ, ATM | |
| 1/10 MIC | LEV, CAZ, ATM, FOF | AMK | ||||||
| 1/5 MIC | LEV, CAZ, ATM, FOF | AMK | ||||||
| 1/2 MIC | LEV, IPM | AMK, ATM | ||||||
| AND04-003 (1227) | Tracheal aspirate | GyrA T83I and K162R, NalD Q97X, MexS L32Q and V333M, MexT R334C | 2 | 0.4 | 8 | 1/5 MIC | LEV, CAZ | |
| 1/2 MIC | LEV, CAZ | |||||||
| CLE03-004 (381) | Tracheal aspirate | MexZ L23fs, AmpC S173N | 0.25 | 0.005 | 43 | 1/50 MIC | LEV, AMK, ATM, FOF | |
| 1/25 MIC | LEV, CAZ, AMK, ATM, FOF | |||||||
| 1/10 MIC | LEV, AMK, FOF | |||||||
| 1/5 MIC | LEV, FOF | ATM | ||||||
| 1/2 MIC | LEV | AMK, ATM | ||||||
| FQSE111010 (701) | CF sputum | GyrA Y267N, GyrB R138L, MexX A38P, MexY N709H and A568T, NfxB E75K, OprD Q424E and S403A, OprN R363H, AmpDh2 P116S | 0.4 | 0.04 | 24 | 1/10 MIC | LEV, ATM, FOF | |
| 1/5 MIC | LEV, ATM | |||||||
| 1/2 MIC | LEV | ATM, FOF |
The table encloses the information about the strains used in this study, their MIC and MSC values to ciprofloxacin, the maximum fold-change of their MICs to this drug (with respect to the one of the parental strains) observed within their 9 days sub-MIC selective windows, and the cross-resistance and collateral sensitivity phenotypes that each concentration within said windows selects for (at least half the replicates must show ≤1/2 or ≥2-fold of the parental strain MIC to be subsumed, as determined using MIC test strips that allow discrimination of small differences in MICs). All clinical isolates had been sequenced and characterized in previous studies (89–91).
MSCs of ciprofloxacin for all the strains are lower than the highest concentration of this compound found in nature (31 μg/mL) (32).
Sub-MIC concentrations that selected for at least one population resistant to ciprofloxacin with MIC values ≥EUCAST breakpoint (0.5 μg/mL) are presented in bold. The same applies to the name of the drugs to which at least one population acquired cross-resistance above EUCAST breakpoints. The mutations in the resistomes that are known to be linked to quinolones resistance are underlined (95, 96). The data on PA14 strain come from reference 10. ST, sequence type; CF, cystic fibrosis; fs, frameshift; LEV, levofloxacin; CAZ, ceftazidime; AMK, amikacin; ATM, aztreonam; IPM, imipenem; FOF, fosfomycin.