Activity of cefiderocol (CFDC), ceftazidime-avibactam (CZA), and eravacycline (ERV)

against carbapenem-resistant (CR) E. coli isolates from the US: Clonal Background,

Resistance Genes, and Co-Resistance

• 203 U.S. clinical E. coli isolates, confirmed as non-susceptible to ≥ 1 carbapenem (2012-2017; median year, 2014), were obtained from JMI Laboratories (n = 62; diverse U.S. locales; median year, 2013) and MN Department of Health (MDH) (n = 141; diverse counties; median year, 2015). Sources divided evenly between urine (50%) and “other” (50%), i.e., blood (17%), respiratory (12%), abdominal (13%), and wound (8%).

• Broth microdilution MICs were determined according to CLSI for CFDC, CZA, and ERV, 3 carbapenems (MEM, IPM, and ETM), and 8 non-carbapenem comparators (AMK, CAZ, CST, GEN, LVX, MIN, TGC, and TZP). For CFDC, iron-depleted broth was used. For TGC and ERV, FDA breakpoints were used.

• Phylogroups, sequence types (STs), clonal subsets, and resistance genotypes (KPC, NDM, OXA-48, VIM, IMP, CTX-M, CMY-2) were defined using PCR-based assays.

• Categorical susceptibility (per FDA [TGC and ERV] or CLSI [other agents] breakpoints) and MICs were compared statistically.

Methods

J. Johnson1, B. D. Johnston2, M. Castanheira3, P. Thuras1, B. VonBank4, M. Witwer5, P. Snippes Vagnone4

1VA Med. Ctr., Minneapolis, MN, 2Univ. of MN, 3JMI Labs, North Liberty, IA, 4MN Dept. of Health, St. Paul, MN, 5Fairview Health System, St. Paul, MN

Updated AbstractBackground: Carbapenem resistance is emerging in E. coli, including its multidrug-resistant ST131-H30R lineage. New agents CFDC, CZA, and ERV have distinctive mechanisms that inhibit/kill many CR organisms. Accordingly, we tested these agents against CR E. coli clinical isolates, from surveillance systems encompassing multiple sites across the U.S. and Minnesota (MN), in relation to phylogenetic and clonal origin and key resistance genes.

Methods: 203 U.S. clinical E. coli isolates, non-susceptible to ≥ 1 carbapenem (isolated 2012-2017; median 2014), from JMI Laboratories (n = 62; diverse U.S. locales; median, 2013) and MN Dept. of Health (MDH) (n = 141; diverse counties; median, 2015), underwent broth microdilution MIC determinations with CFDC, CZA, and ERV; 3 carbs (MEM, IPM, ETP); and 8 non-carbapenem comparators (AMK, CAZ, CST, GEN, LVX, MIN, TGC, TZP). Susceptibility data (using CLSI/FDA-approved breakpoints) were compared with PCR-defined phylogroups, sequence types (STs), clonal subsets, and resistance genotypes (KPC, NDM, OXA-48, VIM, IMP, CTX-M, CMY-2).

Results: Overall, the percent susceptible was higher for CFDC (96%), CZA (92%), and ERV (97%) than for any carbapenem (MEM, 75%, IPM, 44%, ETP, 3%: P < 0.05 for each) and for all other comparators except TGC and CST (99% for each). Percent susceptible varied by phylogroup for 2 agents: CFDC (group A, 81% [P < 0.001]; CZA (group A, 74%[P < 0.001]; group B2, 99% [P = 0.003], group C, % [P = 0.01]) ); and by clonal group for CFDC (ST131: 100% [P 0.03]) and CZA (ST131 and H30R: 100% [P < 0.01]). Percent susceptible was lower for all 3 agents among isolates containing NDM (CFDC, 62% vs. 98% [P < 0.001]; CZA, 6% vs. 98% [P < 0.001]; ERV, 87% vs. 98% [P = 0.03]).

Conclusions: Among 203 molecularly characterized CR E. coli clinical isolates from the U.S., CFDC, CZA, and ERV were highly active overall, notwithstanding significant variation by phylogroup, clonal group, and NDM genotype. Thus, these agents are promising new treatment options for infections caused by CR, multidrug-resistant E. coli. Ongoing resistance monitoring is needed.

Session AAR09

Saturday

AAR-768

IntroductionCarbapenem resistance is emerging in E. coli, including its multidrug-resistant ST131-H30R lineage. New agents CFDC, CZA, and ERV have distinctive mechanisms that inhibit/kill many CR organisms. Accordingly, we tested these agents against CR E. coli clinical isolates in relation to phylogenetic, clonal origin, and key resistance genes.

Presented at ASM 2019, San Francisco, CA June 2019

• CFDC, CZA, and ERV were highly active overall, more so than all other agents except TGC and CST.

• Percent susceptible varied by phylogroup.• CFDC, CZA, and ERV percent susceptible was 100%

against ST131-H30R and H30Rx; percent susceptible was lower against NDM vs. other resistance genotypes.

Conclusions

• CFDC, CZA, and ERV are promising new treatment options in the U.S. for infections caused by CR E. coli –including several multidrug-resistant STs, notably ST131-H30R and H30Rx.

• ERV was highly active against NDM isolates (87%), exceeded only by CST (100%) and TGC (94%).

Implications

1. Clinical and Laboratory Standards Institute. 2018. Performance standards for antimicrobial susceptibility testing; twenty-sixth informational supplement. CLSI document M100-S26. Clinical and Laboratory Standards Institute, Wayne, PA

2. Colpan A, et al. Escherichia coli sequence type 131 (ST131) subclone H30 as an emergent multidrug-resistant pathogen among US veterans. Clin Infect Dis.2013; 57(9):1256-65.

3. Johnson JR et al. Abrupt emergence of a single dominant multidrug-resistant strain of Escherichia coli. J Infect Dis. 2013; 207(6) 919-928.

4. Poirel L, Walsh TR, Cuvillier V, Nordmann P. Multiplex PCR for detection of acquired carbapenemase genes. Diagn Microbiol Infect Dis. 2011;70:119–23I

References

• Work supported in part by Shionogi & Co., Ltd; Tetraphase Pharmaceuticals, Inc; and Office of Research and Development, Medical Research Service, Department of Veterans Affairs, grant #2I01CX000920-04 (JRJ)

• Test agents were provided by the following companies:• Cefiderocol: Shionogi • Eravacycline: Tetraphase• Avibactam: Allergan

Acknowledgements

• Overall, percent susceptible was higher for CFDC (96%), CZA (92%), and ERV (97%) than for any carbapenem (MEM, 75%; IPM, 44%; ETP, 3% [P < 0.05 for each]) and all other comparators except TGC and CST (each, 99%) (Table 1)

• By phylogroup, percent susceptible varied for 2 agents, i.e., CFDC (group A, 81% [vs. all others, P < 0.001]) and CZA (group A, 74% [vs. all others, P < 0.001]; group B2, 99% [vs. all others, P = 0.003]; group C, 64% [vs. all others, P = 0.01]) (Figure 1).

• CFDC, CZA and ERV were all highly active vs. ST131 and its clonal subgroups (100% susceptible).• Susceptible (%) was lower if NDM-positive (for CFDC, 62% vs. 98% [P < 0.001]; for CZA, 6% vs. 98% [P < 0.001]; for ERV, 87% vs. 98% [P = 0.03]) (Table 2).

Results

James R. Johnson, MDVA Medical CenterOne Veterans DriveMinneapolis, MN 55417612-467-4188johns007@umn.edu

Agent Susc n (%) MICmin MIC50 MIC90 MICmax

CFDC 194 (96) ≤ 0.004 0.5 > 64 > 64CZA 186 (92) ≤ 0.125 0.5 > 256 > 256ERV 197 (97) 0.06 0.25 2 2IPM 90 (44) 0.125 2 > 256 > 256MEM 153 (75) ≤ 0.03 0.5 > 4 > 4ETP 7 (3) ≤ 0.016 > 2 > 2 > 2GEN 132 (65) 0.25 1 > 16 > 16TZP 56 (28) ≤ 1 128 > 128 > 128AMK 163 (80) ≤ 0.5 4 > 64 > 64LVX 47 (23) ≤ 0.06 > 8 > 8 > 8TGC 200 (99) 0.25 0.5 8 8CAZ 19 (9) ≤ 0.125 32 > 256 > 16CST 201 (99) ≤ 0.06 0.125 8 8MIN 141 (69) 0.5 4 > 16 > 16

AgentST131 (n=68) P

H30R (n=62) P

H30Rx (n=40) P

ST405(n=15) P

ST648(n=15) P

KPC(n=35) P

NDM(n=16) P

OXA-48 (n=9) P

CTX-M (n=84) P

CMY-2 (n=58) P

CFDC 68 (100) ** 62 (100) 40 (100) 15 (100) 15 (100) 34 (97) 10 (62) *** 9 (100) 82 (98) 57 (98)

CZA 68 (100) ** 62 (100) ** 40 (100) ** 13 (87) 14 (93) 34 (97) 1 (6) *** 8 (89) 76 (90) 52 (90)

ERV 68 (100) 62 (100) 40 (100) 14 (93) 15 (100) 34 (97) 14 (87) 9 (100) 84 (100) ** 56 (97)

IPM 36 (53) 34 (55) * 26 (65) ** 11 (73) ** 11 (73) ** 0 (0) *** 0 (0) *** 1 (11) ** 51 (60) *** 25 (43)

MEM 51 (75) 47 (76) 32 (80) 12 (80) 14 (93) 19 (54) ** 1 (6) *** 7 (78) 64 (76) 49 (84)

ETP 1 (1.5) 1 (2) 1 (2) 0 (0) 0 (0) 0 (0) 1 (6) 0 (0) 3 (4) 4 (7)

GEN 47 (69) 42 (68) 29 (72) 7 (47) 10 (67) 17 (49) ** 4 (25) ** 6 (67) 45 (54) ** 47 (81) **

TZP 22 (33) 22 (35) 18 (45) ** 5 (33) 5 (33) 2 (6) ** 1 (6) 0 (0) 31 (37) ** 13 (22)

AMK 47 (69) ** 42 (68) ** 22 (55) *** 13 (87) 12 (80) 27 (77) 10 (63) 7 (78) 59 (70) ** 56 (97) ***

LVX 5 (7) *** 0 (0) *** 0 (0) *** 1 (7) 3 (20) 12 (33) 1 (6) 1 (11) 3 (4) *** 25 (43) ***

TGC 68 (100) 62 (100) 40 (100) 14 (93) 15 (100) 35 (100) 15 (94) 9 (100) 84 (100) 57 (98)

CAZ 8 (12) 7 (11) 2 (5) 2 (13) 0 (0) 1 (3) 1 (6) 2 (22) 2 (2) ** 0 (0) **

CST 67 (99) 62 (100) 40 (100) 15 (100) 15 (100) 33 (94) ** 16 (100) 9 (100) 84 (100) 58 (100)

MIN 58 (85) ** 53 (85) ** 33 (82) * 5 (33) ** 10 (67) 28 (80) 6 (37) ** 5 (56) 51 (60) ** 38 (65)

CFDC, cefiderocol; CZA, ceftazidime-avibactam; ERV, eravacycline; IPM, imipenem; MEM, meropenem; ETP, ertapenem; GEN, gentamicin; TZP, piperacillin/tazobactam; AMK, amikacin; LVX, levofloxacin; TGC, tigecycline; CAZ, ceftazidime; CST, colistin; MIN, minocycline. P value symbols (vs. all others): * P < 0.05; ** P < 0.01; *** P ≤ 0.001.

Table 2: Susceptible (%) by clonal group and resistance genes for CFDC, CZA, ERV, and comparator agents

Table 1. Overall susceptible (%), MICmin, MIC50 , MIC90, and MICmax Figure 1. Susceptible (%) by phylogroup for CFDC, CZA, and ERV

0

10

20

30

40

50

60

70

80

90

100

A B1 B2 C D F

CFDC

CZA

ERV

phylogroups