Article Figures & Data
Figures
- FIG 1
Time-kill synergy graphs. The activities of colistin (CST) in combination with minocycline (MIN) (A), linezolid (LZD) (B), fusidic acid (FA) (C), and levofloxacin (LVX) (D) were tested against strain BIDMC 32 (K. pneumoniae). Red bars and numbers indicate differences in the bacterial concentration between the starting inoculum and the drug combination at 24 h. Blue bars and numbers indicate differences in the bacterial concentration between the combination and the most active single agent at 24 h. The green dashed lines mark the lower limit of detection.
Tables
- TABLE 1
Strain characterization, including MICs
aBIDMC strains are from the CRE genome initiative. FDA-CDC strains are from FDA-CDC Antimicrobial Resistance Isolate Bank. The ARLG strain is from the Antibiotic Resistance Leadership Group Laboratory Center Virtual Repository.
bConcentrations are expressed as the trimethoprim concentration/sulfamethoxazole concentration.
cConcentrations are expressed as ceftazidime concentration/avibactam concentration.
dInterpretive criteria for these drugs have not been established for Enterobacteriaceae.
eST, sequence type.
fDark shading indicates an MIC classified as resistant; light shading indicates an MIC classified as intermediate; no shading indicates an MIC classified as susceptible (for those drugs for which interpretive criteria for Enterobacteriaceae exist) (see the text for definitions). CST, colistin; MIN, minocycline; DOX, doxycycline; TET, tetracycline; TGC, tigecycline; CHL, chloramphenicol; LVX, levofloxacin; AMK, amikacin; SXT, trimethoprim-sulfamethoxazole; MEM, meropenem; CZA, ceftazidime-avibactam; AZM, azithromycin; ERY, erythromycin; RIF, rifampin; APR, apramycin; NA, no result, as two separate trials for this combination had ≥2 skipped wells.
gThe isolate has been sequenced, but the cause of carbapenem resistance has not been elucidated (57).
hMultilocus sequence typing schemes are not available for these species.
iIsolate not yet sequenced.
- TABLE 2
Rates of synergy by drug using checkerboard array
Drug tested in combination with colistin % synergya (95% confidence interval) for: All strains Strains excluding species intrinsically resistant to colistin Linezolid 95.0 (73.1–99.7) 100 (78.1–100.0) Rifampin 94.7 (71.9–99.7) 100 (77.1–100.0) Azithromycin 90.0 (66.9–98.2) 100 (78.1–100.0) Fusidic acid 90.0 (66.9–98.2) 94.4 (70.6–99.7) Minocycline 85.0 (61.1–96.0) 88.9 (63.9–98.1) Clindamycin 80.0 (55.7–93.4) 88.9 (63.9–98.1) Erythromycin 80.0 (55.7–93.4) 88.9 (63.9–98.1) Chloramphenicol 75.0 (50.6–90.4) 77.8 (51.9–92.6) Levofloxacin 70.0 (36.4–80.0) 66.7 (41.2–85.6) Doxycycline 60.0 (36.4–80.0) 66.7 (41.2–85.6) Ceftazidime-avibactam 41.2 (19.4–66.5) 46.7 (22.3–72.6) Tigecycline 25.0 (9.6–49.4) 27.8 (10.7–53.6) Vancomycin 25.0 (9.6–49.4) 27.8 (10.7–53.6) Tetracycline 20.0 (6.6–44.3) 22.2 (7.4–48.1) Meropenem 15.0 (4.0–38.9) 11.1 (1.9–36.1) Amikacin 15.0 (4.0–38.9) 16.7 (4.4–42.3) Trimethoprim-sulfamethoxazole 15.0 (4.0–38.9) 11.1 (1.9–36.1) Apramycin 10.0 (1.8–33.1) 11.1 (1.9–36.1) Daptomycin 0.0 (0–22.9) 0.0 (0.0–25.3) ↵a Synergy percentages represent the results of testing of 20 isolates for each combination, except rifampin (results of testing of 19 isolates were used because 1 trial had skipped wells), daptomycin (results for testing of 17 isolates were used because 1 trial had skipped wells and 2 trials had colistin MICs >±1 2-fold dilution from the modal MIC), and ceftazidime-avibactam (results for 17 isolates were used because 3 trials had colistin MICs >±1 2-fold dilution from the modal MIC).
- TABLE 3
Time-kill synergy results
Drug combination (concn [μg/ml])c Strain Difference in bacterial concn (no. of log10 CFU/ml) between: Combination at 24 h and starting inoculuma Combination and most active single agent at 24 hb MIN (1) + CST (1) BIDMC 32 −3.30 −6.43 DOX (1) + CST (1) BIDMC 32 −3.48 −6.52 TET (4) + CST (1) BIDMC 32 −1.62 −3.84 TGC (0.5) + CST (1) BIDMC 32 −3.22 −5.88 AZM (0.5) + CST (1) BIDMC 32 −1.56 −4.56 ERY (4) + CST (1) BIDMC 32 2.76 0.31 AMK (16) + CST (4) FDA-CDC 0125 −2.84 −5.62 APR (8) + CST (1) FDA-CDC 0097 −1.32 −3.39 RIF (0.125) + CST (1) BIDMC 32 −0.82 −3.82 CHL (128) + CST (1 BIDMC 32 −1.24 −4.18 LVX (64) + CST (1) BIDMC 32 −3.64 −6.22 MEM (16) + CST (1) BIDMC 44 −3.67 −7.16 CZA (2/4) + CST (1) BIDMC 32 −2.10 −4.18 SXT (0.125/2.375) + CST (1) BIDMC 91 0.07 −2.59 LZD (64) + CST (1) BIDMC 32 −3.10 −5.88 CLI (16) + CST (1) BIDMC 32 0.18 −3.05 FA (16) + CST (1) BIDMC 32 −1.22 −4.52 VAN (64) + CST (4) FDA-CDC 0125 1.73 −1.06 ↵a Calculated as (number of log10 CFU per milliliter after 24 h of incubation) − (number of log10 CFU per milliliter of starting inoculum). Negative values indicate a decrease in the colony count from the starting inoculum. Bactericidal combinations are shaded.
↵b Calculated as (number of log10 CFU per milliliter of culture grown with both antibiotics after 24 h of incubation) − (number of log10 CFU per milliliter of culture grown with the single most active antibiotic after 24 h of incubation). Negative values indicate a lower final colony count with the combination than with the most active single agent. Synergistic combinations are shaded.
↵c MIN, minocycline; CST, colistin; DOX, doxycycline; TET, tetracycline; TGC, tigecycline; AZM, azithromycin; ERY, erythromycin; AMK, amikacin; APR, apramycin; RIF, rifampin; CHL, chloramphenicol; LVX, levofloxacin; MEM, meropenem; CZA, ceftazidime-avibactam; SXT, trimethoprim-sulfamethoxazole; LZD, linezolid; CLI, clindamycin; FA, fusidic acid; VAN, vancomycin. For ceftazidime-avibactam, the concentrations are expressed as the ceftazidime concentration/avibactam concentration, and for trimethoprim-sulfamethoxazole, the concentrations are expressed as the trimethoprim concentration/sulfamethoxazole concentration.
Supplemental material
- Supplemental file 1 -
Supplemental Tables S1 to S3
PDF, 157K
- Supplemental file 2 -
Supplemental Data Set S1
XLSX, 67K
- Supplemental file 1 -
