Table A3.
Antimicrobial combinations shown to be synergistic in checkerboard (CHBD) and/or time-kill assay (TKA) at concentrations ≤ established breakpoints of resistance.
| Antimicrobial Combinations | CHBD | CHBD: Concentration at which Synergy Was Present | TKA | TKA: Concentration at which Synergy Was Present | ||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Studies n |
Isolates n |
Synergy n (% *) |
≤Breakpoints n (% *) |
>Breakpoints n (% *) |
Unclear n (% *) |
Studies n |
Isolates n |
Synergy n (% *) |
≤Breakpoints n (% *) |
>Breakpoints n (% *) |
Unclear n (% *) |
|
| SUL-based | ||||||||||||
| SUL/CAZ | 1 | 10 | 7 (70%) | 1 (10%) | 6 (60%) | 0 (0%) | ||||||
| SUL/CIP | 1 | 10 | 8 (80%) | 2 (20%) | 6 (60%) | 0 (0%) | ||||||
| SUL/MEM | 6 | 173 | 72 (42%) | 2 (1%) | 2 (1%) | 68 (39%) | 3 | 54 | 32 (59%) | 0 (0%) | 7 (22%) | 25 (78%) |
| SUL/DOR | 1 | 17 | 4 (24%) | 4 (100%) | 0 (0%) | 0 (0%) | ||||||
| SUL/AVI | 1 | 1 | 1 (100%) | 1 (100%) | 0 (0%) | 0 (0%) | ||||||
| SUL/GEN | 1 | 10 | 8 (80%) | 2 (25%) | 6 (75%) | 0 (0%) | ||||||
| SUL/CST | 1 | 6 | 2 (33%) | 2 (100%) | 0 (0%) | 0 (0%) | ||||||
| SUL/PMB | 1 | 3 | 2 (67%) | 2 (100%) | 0 (0%) | 0 (0%) | ||||||
| SUL/FOF | 2 | 56 | 41 (73%) | 3 (7%) | 37 (90%) | 1 (2%) | 2 | 10 | 7 (70%) | 0 (0%) | 7 (100%) | 0 (0%) |
| SAM-based | ||||||||||||
| SAM/FEP | 1 | 2 | 2 (100%) | 1 (50%) | 1 (50%) | 0 (0%) | ||||||
| SAM/LVX | 1 | 7 | 7 (100%) | 5 (71%) | 2 (29%) | 0 (0%) | ||||||
| SAM/MEM | 2 | 10 | 2 (20%) | 2 (100%) | 0 (0%) | 0 (0%) | 1 | 2 | 0 (0%) | 0 (0%) | 0 (0%) | 0 (0%) |
| SAM/RIF | 1 | 7 | 7 (100%) | 4 (57%) | 1 (14%) | 2 (29%) | ||||||
| IMP-based | ||||||||||||
| IMP/CFS | 1 | 16 | 11 (69%) | 9 (82%) | 2 (18%) | 0 (0%) | ||||||
| IMP/CST | 2 | 10 | 9 (90%) | 2 (20%) | 7 (70%) | 0 (0%) | 1 | 2 | 0 (0%) | 0 (0%) | 0 (0%) | 0 (0%) |
| IMP/RIF | 2 | 28 | 16 (57%) | 11 (39%) | 3 (11%) | 2 (7%) | 5 | 13 | 6 (46%) | 0 (0%) | 6 (46%) | 0 (0%) |
| IMP/FOF | 3 | 45 | 26 (58%) | 9 (20%) | 10 (22%) | 7 (16%) | 1 | 9 | 8 (89%) | 0 (0%) | 8 (89%) | 0 (0%) |
| MEM-based | ||||||||||||
| MEM/SUL | 6 | 173 | 72 (42%) | 2 (1%) | 2 (1%) | 68 (39%) | 3 | 54 | 32 (59%) | 0 (0%) | 7 (13%) | 25 (46%) |
| MEM/SAM | 2 | 10 | 2 (20%) | 2 (20%) | 0 (0%) | 0 (0%) | 1 | 2 | 0 (0%) | 0 (0%) | 0 (0%) | 0 (0%) |
| MEM/AMK | 4 | 47 | 16 34%) | 1 (2%) | 2 (4%) | 13 (28%) | ||||||
| MEM/CST | 6 | 29 | 21 (72%) | 5 (17%) | 11 (3%) | 5 (17%) | 3 | 4 | 4 (100%) | 0 (0%) | 4 (100%) | 0 (0%) |
| MEM/PMB | 1 | 3 | 3 (100%) | 3 (100%) | 0 (0%) | 0 (0%) | 1 | 2 | 0 (0%) | 0 (0%) | 0 (0%) | 0 (0%) |
| MEM/FOF | 4 | 79 | 15 (19%) | 1 (1%) | 14 (18%) | 0 (0%) | ||||||
| MEM/VAN | 1 | 5 | 3 (60%) | 1 (20%) | 0 (0%) | 2 (40%) | ||||||
| DOR-based | ||||||||||||
| DOR/SUL | 1 | 17 | 4 (24%) | 4 (24%) | 0 (0%) | 0 (0%) | ||||||
| DOR/CST | 3 | 6 | 2 (33%) | 1 (17%) | 1 (17%) | 0 (0%) | 5 | 33 | 23 (70%) | 19 (58%) | 4 (12%) | 0 (0%) |
| DOR/TGC | 1 | 3 | 3 (100%) | 1 (33%) | 0 (0%) | 2 (67%) | 1 | 45 | 5 (11%) | 5 (11%) | 0 (0%) | 0 (0%) |
| DOR/RIF | 1 | 1 | 0 (0%) | 0 (0%) | 0 (0%) | 0 (0%) | 1 | 5 | 2 (40%) | 1 (20%) | 1 (20%) | 0 (0%) |
| CZA- or AVI-based | ||||||||||||
| AVI/SUL | 1 | 1 | 1 (100%) | 1 (100%) | 0 (0%) | 0 (0%) | ||||||
| CST-based | ||||||||||||
| CST/SUL | 1 | 6 | 2 (33%) | 2 (33%) | 0 (0%) | 0 (0%) | ||||||
| CST/LVX | 2 | 2 | 1 (50%) | 1 (50%) | 0 (0%) | 0 (0%) | 2 | 2 | 1 (50%) | 0 (0%) | 1 (50%) | 0 (0%) |
| CST/IMP | 2 | 10 | 9 (90%) | 2 (20%) | 7 (70%) | 0 (0%) | 1 | 2 | 0 (0%) | 0 (0%) | 0 (0%) | 0 (0%) |
| CST/MEM | 6 | 29 | 21 (72%) | 5 (17%) | 11 (38%) | 5 (17%) | 3 | 4 | 4 (100%) | 0 (0%) | 4 (100%) | 0 (0%) |
| CST/DOR | 3 | 6 | 2 (33%) | 1 (17%) | 1 (17%) | 0 (0%) | 5 | 33 | 23 (70%) | 19 (58%) | 4 (12%) | 0 (0%) |
| CST/TGC | 2 | 10 | 0 (0%) | 0 (0%) | 0 (0%) | 0 (0%) | 1 | 12 | 7 (100%) | 7 (100%) | 0 (0%) | 0 (0%) |
| CST/RIF | 5 | 40 | 31 (78%) | 10 (25%) | 10 (25%) | 11 (28%) | 3 | 7 | 7 (100%) | 0 (0%) | 6 (86%) | 1 (14%) |
| CST/SXT | 2 | 8 | 2 (25%) | 1 (13%) | 0 (0%) | 1 (13%) | 1 | 1 | 1 (100%) | 0 (0%) | 1 (100%) | 0 (0%) |
| CST/CHL | 1 | 2 | 2 (100%) | 1 (50%) | 1 (50%) | 0 (0%) | 1 | 2 | 2 (100%) | 0 (0%) | 2 (100%) | 0 (0%) |
| CST/FA | 2 | 6 | 6 (100%) | 1 (17%) | 2 (33%) | 3 (50%) | 2 | 4 | 3 (75%) | 0 (0%) | 3 (75%) | 0 (0%) |
| CST/VAN | 7 | 33 | 29 (88%) | 2 (6%) | 2 (6%) | 25 (67%) | 6 | 20 | 16 (80%) | 13 (65%) | 3 (15%) | 0 (0%) |
| PMB-based | ||||||||||||
| PMB/SUL | 1 | 3 | 2 (67%) | 2 (67%) | 0 (0%) | 0 (0%) | ||||||
| PMB/MEM | 1 | 3 | 3 (100%) | 3 (100%) | 0 (0%) | 0 (0%) | 1 | 2 | 0 (0%) | 0 (0%) | 0 (0%) | 0 (0%) |
| PMB/RIF | 1 | 3 | 3 (100%) | 1 (33%) | 1 (33%) | 1 (33%) | 1 | 3 | 1 (33%) | 1 (33%) | 0 (0%) | 0 (0%) |
| PMB/VAN | 1 | 3 | 3 (100%) | 3 (100%) | 0 (0%) | 0 (0%) | 1 | 3 | 2 (67%) | 0 (0%) | 2 (67%) | 0 (0%) |
| TGC-based | ||||||||||||
| TGC/DOR | 1 | 3 | 3 (100%) | 1 (33%) | 0 (0%) | 2 (67%) | 1 | 45 | 5 (11%) | 5 (11%) | 0 (0%) | 0 (0%) |
| TGC/AMK | 1 | 14 | 2 (14%) | 1 (7%) | 1 (7%) | 0 (0%) | 1 | 1 | 1 (100%) | 1 (100%) | 0 (0%) | 0 (0%) |
| TGC/CST | 2 | 10 | 0 (0%) | 0 (0%) | 0 (0%) | 0 (0%) | 1 | 12 | 7 (58%) | 7 (58%) | 0 (0%) | 0 (0%) |
| TGC/RIF | 2 | 16 | 1 (6%) | 0 (0%) | 1 (6%) | 0 (0%) | 2 | 4 | 1 (25%) | 1 (25%) | 0 (0%) | 0 (0%) |
| TGC/FOF | 1 | 4 | 3 (75%) | 1 (25%) | 2 (50%) | 0 (0%) | 1 | 1 | 1 (100%) | 0 (0%) | 1 (100%) | 0 (0%) |
| RIF-based | ||||||||||||
| RIF/SAM | 1 | 7 | 7 (100%) | 4 (57%) | 1 (14%) | 2 (29%) | ||||||
| RIF/CFS | 1 | 7 | 2 (29%) | 1 (14% | 0 (0%) | 1 (14%) | ||||||
| RIF/IMP | 2 | 28 | 16 (57%) | 11 (39%) | 3 (11%) | 2 (7%) | 5 | 13 | 6 (46%) | 0 (0%) | 6 (46%) | 0 (0%) |
| RIF/DOR | 1 | 1 | 0 (0%) | 0 (0%) | 0 (0%) | 0 (0%) | 1 | 5 | 2 (40%) | 1 (20%) | 1 (20%) | 0 (0%) |
| RIF/CST | 5 | 40 | 31 (78%) | 10 (25%) | 10 (25%) | 11 (28%) | 3 | 7 | 7 (100%) | 0 (0%) | 6 (85%) | 1 (14%) |
| RIF/PMB | 1 | 3 | 3 (100%) | 1 (33%) | 1 (33%) | 1 (33%) | 1 | 3 | 1 (33%) | 1 (33%) | 0 (0%) | 0 (0%) |
| RIF/TGC | 2 | 16 | 1 (100%) | 0 (0%) | 1 (100%) | 0 (0%) | 2 | 4 | 1 (25%) | 1 (25%) | 0 (0%) | 0 (0%) |
| FOF-based | ||||||||||||
| FOF/SUL | 2 | 56 | 41 (73%) | 3 (5%) | 37 (66%) | 1 (2%) | 2 | 10 | 7 (70%) | 0 (0%) | 7 (70%) | 0 (0%) |
| FOF/IMP | 3 | 45 | 26 (58%) | 9 (20%) | 10 (22%) | 7 (16%0 | 1 | 9 | 8 (89%) | 0 (0%) | 8 (89%) | 0 (0%) |
| FOF/MEM | 4 | 79 | 15 (19%) | 1 (1%) | 14 (18%) | 0 (0%) | ||||||
| FOF/AMK | 2 | 29 | 26 (90%) | 11 (38%) | 15 (52%) | 0 (0%) | ||||||
| FOF/GEN | 2 | 13 | 12 (92%) | 3 (32%) | 9 (69%) | 0 (0%) | ||||||
| FOF/TGC | 1 | 4 | 3 (75%) | 1 (25%) | 2 (50%) | 0 (0%) | 1 | 1 | 1 (100%) | 0 (0%) | 1 (100%) | 0 (0%) |
| Triple combinations | ||||||||||||
| PMB/FOF/MEM | 1 | 3 | 3 (100%) | 3 (100%) | 0 (0%) | 0 (0%) | ||||||
| PMB/SUL/MEM | 1 | 3 | 3 (100%) | 3 (100%) | 0 (0%) | 0 (0%) | ||||||
| CST/DOR/SUL | 1 | 6 | 6 (100%) | 6 (100%) | 0 (0%) | 0 (0%) | ||||||
| CST/VAN/DOR | 1 | 3 | 3 (100%) | 3 (100%) | 0 (0%) | 0 (0%) | ||||||
* Percentage over total number of isolates. Combinations only shown to be synergistic at concentrations > established breakpoints or at unclear concentrations are not included in this Table. A more complete (including all combinations) version of this Table as well as similar Tables for other methods are available in the Supplementary Materials File S1 Section 4. Abbreviations: AMK = amikacin, AVI = avibactam, ATM = aztreonam, AZM = azithromycin, CAZ = ceftazidime, CFS = cefoperazone/sulbactam, CHBD = checkerboard assay, CHL = chloramphenicol, CIP = ciprofloxacin, CST = colistin, CZA = ceftazidime/avibactam, DOR = doripenem, FA = fusidic acid, FEP = cefepime, FOF = fosfomycin, GEN = gentamicin, IMP = imipenem, LVX = levofloxacin, MEM = meropenem, PMB = polymyxin-B, RIF = rifampicin, SAM = ampicillin/sulbactam, SUL= sulbactam, SXT = trimethoprim/sulfamethoxazole, TEC = teicoplanin, TGC = tigecycline, TKA = time-kill assay, TMP = trimethoprim, VAN = vancomycin. In the single eligible study using multiple-combination bactericidal assay [12] (not shown in the Table) the following combinations were active at concentrations equal to breakpoints of resistance: SAM/RIF (synergistic against 1 of 8 eligible isolates), SAM/SXT (1/7), SAM/TEC (1/8), AMK/CAZ (1/6), AMK/SXT (1/6), AZM/CAZ (1/8), AZM/SXT (1/6), AZM/TEC (1/8), ATM/CAZ (1/9), ATM/SXT (1/7), ATM/TEC (1/9), CAZ/MEM (1/9), CAZ/RIF (1/9), CAZ/TGC (1/9), CAZ/SXT (1/7), CAZ/VAN (1/9), MEM/RIF (1/9), MEM/SXT (1/7), MEM/TEC (1/9), RIF/SXT (1/7), SXT/VAN (1/7), AMK/RIF (2/6), CAZ/TEC (2/9), CST/RIF (9/9), CST/TEC (9/9), CST/VAN (8/9), CST/MEM (8/9), CST/ATM (8/9), CST/CAZ (6/9), CST/SAM (5/8), CST/SXT (3/8), CST/AMK (4/6), CST/AZM (4/8).