CP-CRE/non-CP-CRE Stratification And CRE Resistance Mechanism Determination Help In Better Managing CRE Bacteremia Using Ceftazidime–Avibactam And Aztreonam–Avibactam

Figures & data

Figure 1 Distribution of CRE bacteremia cases and bacteremic isolates. (A) Dynamic distribution of species-specific CRE bacteremic isolates. (B) Dynamic distribution of CP-CRE and non-CP-CRE bacteremia cases. (C) Species distribution of CP-CRE and non-CP-CRE bacteremic isolates. (D) Source of CRE bacteremia.

Table 1 Antimicrobial Susceptibility Profiles Of CP-CRE And Non-CP-CRE Bacteremic Isolates

Antimicrobial Agents	Total (N = 81)	Carbapenemase Positive (N = 55)			Carbapenemase Negative (N = 26)			P Value
		R (%)	R	I	S	R	I	S
Ertapenem	81 (100.00%)	55 (100.00%)	0 (0.00%)	0 (0.00%)	26 (100.00%)	0 (0.00%)	0 (0.00%)	NA
Imipenem	63 (77.78%)	51 (92.72%)	2 (3.63%)	2 (3.63%)	12 (46.15%)	1 (3.84%)	13 (50.00%)	<0.001
Meropenem	53 (65.43%)	48 (87.27%)	2 (3.63%)	5 (9.09%)	5 (19.23%)	12 (46.15%)	9 (34.62%)	<0.001
Ciprofloxacin	66 (81.48%)	44 (80.00%)	1 (1.81%)	10 (18.18%)	24 (92.30%)	0 (0.00%)	2 (7.69%)	0.16
Levofloxacin	65 (80.24%)	42 (76.36%)	2 (3.63%)	11 (20.00%)	23 (88.46%)	1 (3.84%)	2 (7.69%)	0.20
Gentamycin	65 (80.24%)	46 (83.63%)	0 (0.00%)	9 (16.36%)	19 (73.07%)	0 (0.00%)	7 (26.92%)	0.632
Tobramycin	58 (71.60%)	43 (78.18%)	3 (5.45%)	9 (16.36%)	15 (57.69%)	3 (11.53%)	8 (30.76%)	0.06
Colistin	3 (3.70%)	3 (5.45%)	0 (0.00%)	52 (92.85%)	0 (0.00%)	0 (0.00%)	26 (100.00%)	0.22
Tigecycline	2 (2.46%)	2 (3.63%)	0 (0.00%)	54 (96.42%)	0 (0.00%)	0 (0.00%)	26 (100.00%)	0.32

Table 2 Univariate Analysis Of Risk Factors And Outcomes For Patients With CP-CRE, Non-CP-CRE, And ESBL Bacteremia

Variable	CP-CRE(n = 55)	Non-CP-CRE(n = 25)	ESBLs	CP-CRE vs Non-CP-CRE		CP-CRE vs ESBLs		Non-CP-CRE vs ESBLs
			(n = 60)	OR (95% CI)	P Value	OR (95% CI)	P Value	OR (95% CI)	P Value
Demographic characteristics
Gender, male, n (%)	36 (65.45%)	15 (60%)	32 (53.33%)	0.82 (0.30–2.22)	0.70	1.477 (0.58–3.72)	0.41	0.95 (0.32–2.80)	0.93
Age	60.55 ± 14.53	53.04 ± 16.69	54.83 ± 12.26	NA	0.04	NA	0.02	NA	0.45
Pre-existing medical conditions
Surgery in the last 6 months	33 (60.00%)	11 (44.00%)	32 (53.33%)	1.03 (0.33–3.27)	0.95	1.35 (0.64–2.82)	0.42	0.51 (0.16–1.66)	0.26
Cancer	35 (63.63%)	10 (40.00%)	15 (25.00%)	2.84 (1.07–7.53)	0.03	5.22 (2.11–13.00)	0.001	2.24 (0.69–7.30)	0.18
Liver cancer	13 (23.63%)	1 (4.00%)	1 (1.67%)	8.79 (1.07–71.93)	0.04	8.73 (0.23–330.11)	0.22	1.16 (0.02–72.70)	0.94
Pancreatic cancer	8 (14.54%)	1 (4.00%)	1 (1.67%)	4.74 (0.55–41.11)	0.16	11.51 (1.17–112.29)	0.036	7.51 (0.3–89.86)	0.21
Leukemia	4 (7.27%)	4 (16.00%)	5 (8.33%)	0.63 (0.14–2.84)	0.55	0.16 (0.02–1.17)	0.07	0.26 (0.02–2.50)	0.24
Other cancers	10 (18.18%)	4 (16.00%)	7 (11.67%)	0.88 (0.26–2.94)	0.85	1.79 (0.48–6.72)	0.38	0.97 (0.19–4.78)	0.97
Diabetes	13 (23.63%)	5 (20.00%)	12 (20.00%)	0.88 (0.21–3.63)	0.86	1.01 (0.33–3.12)	0.98	1.02 (0.24–4.36)	0.97
Heart failure	12 (21.81%)	2 (8.00%)	4 (6.67%)	1.99 (0.29–13.45)	0.48	3.43 (0.79–14.56)	0.09	1.43 (0.17–12.34)	0.74
Chronic kidney disease	12 (21.81%)	3 (12.00%)	8 (13.33%)	1.18 (0.20–6.83)	0.84	1.46 (0.41–5.16)	0.56	1.94 (0.37–10.11)	0.43
Chronic obstructive pulmonary disease	5 (9.09%)	1 (4.00%)	4 (6.67%)	2.12 (0.21–21.43)	0.52	1.16 (0.24–5.65)	0.85	0.68 (0.05–8.35)	0.76
Liver disease	4 (7.27%)	1 (4.00%)	2 (3.33%)	1.51 (0.14–16.08)	0.74	1.18 (0.14–9.47)	0.87	1.77 (0.15–21.22)	0.65
Immunocompromising comorbidities
Chemotherapy	20 (36.36%)	7 (28.00%)	6 (10.00%)	1.76 (0.44–7.14)	0.42	3.68 (1.16–11.64)	0.026	2.25 (0.48–10.48)	0.30
Solid organ transplantation	5 (9.09%)	1 (4.00%)	1 (1.67%)	1.11 (0.074–16.64)	0.94	0.29 (0.01–11.86)	0.52	2.86 (0.11–74.65)	0.53
Hematopoietic stem cell transplantation	2 (3.63%)	4 (16.00%)	1 (1.67%)	0.21 (0.015–3.02)	0.25	1.55 (0.08–27.24)	0.77	1.95 (0.11–34.63)	0.65
Chronic corticosteroid therapy^a	9 (16.36%)	3 (12.00%)	1 (1.67%)	1.75 (0.27–11.01)	0.55	2.13 (0.51–8.88)	0.29	1.39 (0.24–8.05)	0.71
Absolute neutrophil count <200 cells/mL	14 (25.45%)	6 (24.00%)	4 (6.67%)	1.14 (0.26–4.98)	0.84	1.42 (0.40–5.01)	0.58	1.96 (0.34–11.38)	0.45
Likely source of bacteremia
Urinary tract	12 (21.81%)	5 (20.00%)	23 (38.33%)	0.57 (0.10–3.18)	0.52	1.06 (0.40–2.63)	0.96	0.85 (0.18–3.94)	0.84
Pneumonia	29 (52.72%)	8 (32.00%)	20 (33.33%)	2.43 (0.51–11.63)	0.26	2.05 (0.82–5.10)	0.12	0.27 (0.05–1.53)	0.14
Intra-abdominal	12 (21.81%)	2 (8.00%)	3 (5.00%)	3.13 (0.32–30.92)	0.32	2.38 (0.53–10.74)	0.26	3.88 (0.61–24.86)	0.15
Biliary tract	11 (20.00%)	4 (16.00%)	6 (10.00%)	0.23 (0.02–2.29)	0.21	1.20 (0.32–4.53)	0.78	1.07 (0.17–6.91)	0.94
Invasive operations
On dialysis	4 (7.27%)	1 (4.00%)	2 (3.33%)	2.37 (0.23–24.11)	0.46	4.42 (0.62–31.99)	0.14	4.60 (0.31–68.38)	0.26
Transfusion	34 (61.82%)	10 (40.00%)	7 (10.17%)	1.74 (0.57–5.36)	0.33	18.44 (4.61–73.79)	0.001	8.23 (1.51–44.79)	0.015
Gastric tube use	29 (52.72%)	9 (36.00%)	7 (11.67%)	0.69 (0.12–3.83)	0.68	2.02 (0.56–7.32)	0.28	2.48 (0.54–11.39)	0.24
Drainage tube use	36 (65.45%)	8 (32.00%)	22 (36.67%)	6.73 (1.05–43.03)	0.04	1.98 (0.77–5.12)	0.17	0.53 (0.15–1.83)	0.31
Urinary catheterization	46 (83.63%)	16 (64.00%)	37 (61.67%)	1.54 (0.29–8.17)	0.61	2.30 (0.75–7.04)	0.15	1.01 (0.27–3.82)	0.98
Tracheal cannula	28 (50.90%)	9 (36.00%)	7 (11.67%)	0.53 (0.07–3.94)	0.54	1.69 (0.40–7.10)	0.47	0.96 (0.18–5.08)	0.96
Venous catheterization	43 (78.18%)	19 (76.00%)	13 (21.67%)	0.80 (0.12–5.48)	0.82	9.29 (2.99–28.822)	0.001	12.69 (3.26–49.31)	0.001
Mechanical ventilation	22 (40.00%)	8 (32.00%)	10 (16.67%)	0.76 (0.17–3.31)	0.72	0.44 (0.12–1.62)	0.28	0.47 (0.10–2.67)	0.34
Antibiotic treatment before the positive bacteria isolation
Penicillin	15 (27.27%)	5 (20.00%)	13 (21.67%)	0.58 (0.10–3.33)	0.54	0.69 (0.17–2.75)	0.60	0.89 (0.23–3.43)	0.87
Cephalosporins	23 (41.82%)	7 (28.00%)	22 (36.60%)	0.63 (0.14–2.83)	0.55	1.36 (0.64–2.89)	0.44	0.44 (0.14–1.44)	0.17
Fluoroquinolone	10 (18.18%)	3 (12.00%)	15 (25.00%)	0.73 (0.10–5.21)	0.76	0.67 (0.27–1.64)	0.38	0.24 (0.05–1.21)	0.08
Aminoglycosides	10 (18.18%)	2 (8.00%)	4 (6.67%)	4.86 (0.55–42.55)	0.15	3.92 (0.89–17.28)	0.07	1.39 (0.21–9.12)	0.73
Carbapenem	29(52.72%)	5 (20.00%)	4 (6.67%)	12.63 (2.30–69.34)	0.004	28.32 (7.71–104.08)	0.001	3.83 (0.68–21.50)	0.12
Prognosis
Mortality	34 (61.82%)	6 (24.00%)	4 (6.67%)	NA	0.002	NA	0.001	NA	0.001
Length of hospitalization	66.64 ± 108.89	33.67 ± 32.76	25.95 ± 14.68	NA	0.04	NA	0.001	NA	0.001
Admission to ICU	34 (61.82%)	8 (32.00%)	13 (21.67%)	4.12 (1.22–13.94)	0.023	4.09 (1.64–10.25)	0.003	0.92 (0.22–3.88)	0.90
Length of ICU stay	20.91 ± 41.43	5.92 ± 20.72	2.67 ± 6.23	NA	0.03	NA	0.001	NA	0.018

Notes: Antibiotic treatment refers to empirical antibiotic treatment before bacterial culture results. ^aUse of corticosteroids (prednisone equivalent >20 mg/day) for at least 14 days, or other recognized immunosuppressive therapy.

Abbreviation: NA, Not applicable.

Table 3 Multivariate Analyses Of Risk Factors For The Isolation Of CP-CRE Group Versus Non-CP-CRE Group, CP-CRE Group Versus ESBL Group, And Non-CP-CRE Group Versus ESBL Group

Variable	95% CI	OR	P Value
CP-CRE vs non-CP-CRE
Age	NA	NA	0.04
Admission to ICU	0.59–7.55	2.12	0.25
Length of ICU stay	NA	NA	0.03
Cancer	1.22–15.46	4.35	0.023
Liver cancer	0.28–30.16	2.91	0.37
Use of drainage tube	0.62–10.34	2.23	0.19
Previous carbapenem exposure	1.91–30.77	7.67	0.004
CP-CRE vs ESBLs
Age	NA	NA	0.01
Admission to ICU	0.10–2.20	0.46	0.33
Length of ICU stay	NA	NA	0.02
Transfusion	3.15–93.72	17.19	0.001
Cancer	3.56–71.37	15.91	<0.001
Chemotherapy	0.17–5.16	0.94	0.94
Venous catheterization	1.82–35.90	8.10	0.006
Previous carbapenem exposure	5.03–154.19	27.86	0.001
Non-CP-CRE vs ESBLs
Length of ICU stay	NA	NA	0.018
Transfusion	0.32–4.78	1.24	0.75
Venous catheterization	3.03–34.87	10.29	0.001

Abbreviation: NA, Not applicable.

Table 4 Distribution And Corresponding Carbapenem MIC Ranges For Strains With Different Resistance Determinants

Carbapenem Resistance Mechanisms	No. Of Isolates	MIC Range (μg/mL)
		ETP	IMP	MEM
Carbapenemase positive	55
NDM-1, ESBLs, OMP loss or deficiency	10	8–256	4–64	4–128
NDM-5, ESBLs, OMP loss or deficiency	8	16–256	8–256	4–256
KPC-2, OMP loss or deficiency	34	4–128	1–128	1–128
IMP-4, ESBLs, OMP deficiency	1	64	8	8
IMP-8, ESBLs, OMP loss	1	8	8	8
KPC-2, IMP-4, ESBLs, OMP deficiency	1	256	256	128
Carbapenemase negative	26
AmpC, ESBLs	1	4	2	0.25
AmpC, OMP loss	1	2	2	1
AmpC, ESBLs, OMP loss	1	4	4	0.25
ESBLs, OMP loss or deficiency	23	2–32	0.25–16	0.25–8

Table 5 Antibacterial Activities Of CAZ/AVI And ATM/AVI Against 58 CRE Bacteremic Isolates

Resistance Mechanisms	MIC of CAZ/AVI (μg/mL)
	0.125/4	0.25/4	0.5/4	1/4	2/4	4/4	8/4	16/4	32/4	64/4	>64/4
Carbapenemase positive
NDM-1, ESBLs, OMP loss or deficiency	0	0	0	0	0	0	0	1	2	0	1
NDM-5, ESBLs, OMP loss or deficiency	0	0	0	0	0	0	0	1	3	0	1
KPC-2, ESBLs, OMP loss or deficiency	0	0	1	2	11	11	4	1	0	0	1
IMP-4, ESBLs, OMP deficiency	0	0	0	0	0	0	0	0	0	1	1
IMP-8, ESBLs, OMP loss	0	0	0	0	0	0	0	1	0	0	0
KPC-2, IMP-4, ESBLs, OMP deficiency	0	0	0	0	0	0	0	0	0	0	1
Carbapenemase negative
AmpC, ESBL	1	0	0	0	0	0	0	0	0	0	0
AmpC, OMP loss	0	0	0	0	0	0	1	0	0	0	0
AmpC, ESBLs, OMP loss	0	0	0	0	0	0	0	1	0	0	0
ESBLs, OMP loss or deficiency	0	0	1	1	4	3	1	1	0	0	0
Resistance mechanisms	MIC of ATM/AVI (μg/mL)
	0.125/4	0.25/4	0.5/4	1/4	2/4	4/4	8/4	16/4	32/4	64/4	>64/4
Carbapenemase positive
NDM-1, ESBLs, OMP loss or deficiency	0	2	1	0	0	1	0	0	0	0	0
NDM-5, ESBLs, OMP loss or deficiency	1	0	1	1	0	1	1	0	0	0	0
KPC-2, OMP loss or deficiency	3	9	7	8	2	1	1	0	0	0	0
IMP-4, ESBLs, OMP deficiency	0	1	0	1	0	0	0	0	0	0	0
IMP-8, ESBLs, OMP loss	0	1	0	0	0	0	0	0	0	0	0
KPC-2, IMP-4, ESBLs, OMPs deficiency	0	0	0	0	1	0	0	0	0	0
Carbapenemase negative
AmpC, ESBLs	1	0	0	0	0	0	0	0	0	0	0
AmpC, OMP loss	1	0	0	0	0	0	0	0	0	0	0
AmpC, ESBLs, OMP loss	1	0	0	0	0	0	0	0	0	0	0
ESBLs, OMP loss or deficiency	2	5	2	1	1	0	0	0	0	0	0