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. Author manuscript; available in PMC: 2020 May 7.
Published in final edited form as: Nat Microbiol. 2019 Jun 17;4(10):1627–1635. doi: 10.1038/s41564-019-0480-z

Figure 3. Efficacy of antibiotic combinations is largely dependent on multiple heteroresistance.

Figure 3.

a, Schematic of the antibiotic combination screen. Eight representative clinical isolates of CRE (4 K. pneumoniae, 3 E. cloacae, 1 E. coli) were treated with 16 antibiotics at the clinical breakpoint concentration alone, or in all 120 possible combinations. Amk, amikacin; Gen, gentamicin; Tob, tobramycin; Amp, ampicillin; Azt, aztreonam; Cfz, cefazolin; Cpm, cefepime; Cft, ceftazidime; Mer, meropenem; PTz, piperacillin/tazobactam; Cip, ciprofloxacin; Col, colistin; Fos, fosfomycin; Tet, tetracycline; Tig, tigecycline; SXT, trimethoprim/sulfamethoxazole, b, Graph of the number of antibiotic combination/isolate interactions resulting in the indicated number of logs of killing for the subset of cases in which an isolate was classified by clinical testing as resistant to both drugs (RxR)(n=313). c,e, Isolates classified as resistant by clinical testing, and designated by PAP as either resistant (RxR) or heteroresistant (HRxHR) to both drugs, categorized by the number of logs killing observed compared to antibiotic-free control (percentages are shown). In (e), only combinations including both an aminoglycoside and beta-lactam are shown. d,f, Antibiotic combinations designated as resistant by clinical testing, and either resistant (RxR; n=l 17) or heteroresistant (HRxHR; n=36) to both drugs by PAP, categorized by the number of logs of killing when compared to an antibiotic free control, expressed in number of total treatments. In (f), only combinations including both an aminoglycoside and beta-lactam are shown (RxR, n=22; HRxHR, n=10). **** p < 0.0001, two-sided Mann-Whitney U test of logs killing, binned in 1 log increments.