Clinical and Molecular Characteristics of Patients with Bloodstream Infections Caused by KPC and NDM Co-Producing Carbapenem-Resistant Klebsiella pneumoniae

Figures & data

Table 1 Clinical Characteristics and Infection Data of Patients with BSIs Caused by KPC-NDM-CRKP and KPC-CRKP

Characteristics	KPC-NDM-CRKP BSI (n=25)	KPC-CRKP BSI (n=206)	P value
Age, years, mean ± SD	54.2 ± 12.3	52.1 ± 15.7	0.546
Male sex	21 (84%)	156 (75.7%)	0.356
Acquisition
Community-acquired	0	6 (2.9%)	1.000
ICU-acquired	21 (84%)	119 (57.8%)	0.011*
Underlying conditions
Solid cancer	3 (12%)	27 (13.1%)	1.000
Hypertension	12 (48%)	64 (31.1%)	0.089
Cardiovascular disease	4 (16%)	30 (14.6%)	1.000
Neurologic disorder	1 (4%)	38 (18.4%)	0.124
Diabetes mellitus	3 (12%)	48 (23.3%)	0.198
Gastrointestinal fistula	12 (48%)	79 (38.3%)	0.351
Chronic renal failure	1 (4%)	14 (6.8%)	0.916
Fatty liver	2 (8%)	24 (11.7%)	0.833
Chronic liver disease	3 (12%)	19 (9.2%)	0.932
Biliary tract disease	8 (32%)	71 (34.5%)	0.806
Malnutrition	2 (8%)	27 (13.1%)	0.683
Trauma	6 (24%)	28 (13.6%)	0.277
Surgery within 30 days	14 (56%)	78 (37.9%)	0.080
Source of BSI
Respiratory tract	1 (4%)	39 (18.9%)	0.113
Abdomen	22 (88%)	155 (75.2%)	0.155
Urinary tract	1 (4%)	9 (4.4%)	1.000
Skin and soft tissue	1 (4%)	3 (1.5%)	0.370
Infection data
WBC count, ×10^9/L, median (IQR)	9.2 (4.8–18.5)	10.1 (6.5–15.1)	0.796
Albumin, g/L, mean ± SD	31.1 ± 4.7	31.4 ± 5.0	0.794
PCT, μg/L, median (IQR)	11.8 (1.8–28.5)	3.6 (1–13.5)	0.117
CRP, mg/L, median (IQR)	147.6 (74.9–204.6)	143.2 (90.2–204)	0.872
Platelet count, ×10^9/L, median (IQR)	133 (47–238.5)	171 (90.2–251.2)	0.619
NEUT%, median (IQR)	90.4 (77.6–93.6)	88.8 (83.5–93)	0.877
Hospital stay prior to CRKP isolation, median (IQR)	20 (8–32.5)	15 (5–25)	0.099
ICU stay, median (IQR)	32 (18.5–67.5)	29 (11–51)	0.162
Full hospital stay, median (IQR)	42 (19.5–89)	40.5 (25–66)	0.761
APACHE II score at infection onset, median (IQR)	17 (8.5–21)	11 (7–18)	0.192
Pitt bacteremia score at infection onset, median (IQR)	4 (2–5)	2 (0–4)	0.023*
Sepsis/septic shock at infection onset	16 (64%)	105 (51%)	0.218
Empirical therapy
Monotherapy	5 (20%)	69 (33.5%)	0.172
Combination therapy	20 (80%)	137 (66.5%)	0.172
Fluoroquinolone-containing regimens	4 (16%)	27 (13.1%)	0.928
Aminoglycoside-containing regimens	3 (12%)	12 (5.8%)	0.451
Cephalosporin-containing regimens	0	11 (5.3%)	0.492
Carbapenem-containing regimens	16 (64%)	161 (78.2%)	0.114
Tigecycline-containing regimens	9 (36%)	66 (32%)	0.690
Colistin-containing regimens	6 (24%)	50 (24.3%)	0.976
Ceftazidime-avibactam-containing regimens	6 (24%)	20 (9.7%)	0.072
Inappropriate empirical treatment	14 (56%)	120 (58.3%)	0.829
30-day mortality	14 (56%)	67 (32.5%)	0.020*

Notes: Data are presented as No. (%) of patients unless otherwise specified. *P < 0.05, the comparison between KPC-NDM-CRKP BSI and KPC-CRKP BSI.

Abbreviations: KPC, Klebsiella pneumoniae carbapenemase; NDM, New Delhi metallo-β-lactamase; CRKP, carbapenem-resistant Klebsiella pneumoniae; KPC-NDM-CRKP, KPC and NDM co-producing carbapenem-resistant Klebsiella pneumoniae; KPC-CRKP, KPC-producing carbapenem-resistant Klebsiella pneumoniae; BSI, bloodstream infection; ICU, intensive care unit; WBC, white blood cell; PCT, procalcitonin; CRP, C-reactive protein; NEUT%, neutrophilic granulocyte percentage; APACHE, acute physiologic and chronic health evaluation; SD, standard deviation; IQR, interquartile range.

Table 2 Multivariable Logistic Regression of Risk Factors Independently Associated with KPC-NDM-CRKP BSIs

Variables	Univariate Analysis		Multivariate Analysis
	OR (95% CI)	P value	OR (95% CI)	P value
Age	1.009 (0.982–1.037)	0.501
Male	1.683 (0.551–5.135)	0.361
ICU-acquired	3.838 (1.272–11.582)	0.017*	3.761 (1.216–11.631)	0.021*
Hypertension	2.048 (0.886–4.736)	0.094
Surgery within 30 days	2.089 (0.903–4.830)	0.085	2.558 (1.055–6.203)	0.038*
Hospital stay prior to CRKP isolation	1.023 (1.003–1.043)	0.023*	1.025 (1.003–1.047)	0.023*

Notes: *P < 0.05.

Abbreviations: KPC, Klebsiella pneumoniae carbapenemase; NDM, New Delhi metallo-β-lactamase; CRKP, carbapenem-resistant Klebsiella pneumoniae; KPC-NDM-CRKP, KPC and NDM co-producing carbapenem-resistant Klebsiella pneumoniae; BSI, bloodstream infection; ICU, intensive care unit; OR, odds ratio; CI, confidence interval.

Table 3 Percentage of Antimicrobial Resistance of CRKP Strains

Antimicrobial agents	KPC-NDM-CRKP (n=25)	KPC-CRKP (n=206)	P value
Piperacillin-tazobactam	25 (100%)	206 (100%)	NA
Cefoperazone-sulbactam	25 (100%)	204 (99%)	1.000
Ceftazidime	25 (100%)	205 (99.5%)	1.000
Cefepime	25 (100%)	204 (99%)	1.000
Aztreonam	25 (100%)	206 (100%)	NA
Ertapenem	25 (100%)	206 (100%)	NA
Imipenem	25 (100%)	206 (100%)	NA
Meropenem	25 (100%)	206 (100%)	NA
Amikacin	24 (96%)	140 (68%)	0.004*
Tobramycin	24 (96%)	167 (81.1%)	0.113
Ciprofloxacin	25 (100%)	205 (99.5%)	1.000
Levofloxacin	25 (100%)	204 (99%)	1.000
Doxycycline	11 (44%)	168 (81.6%)	< 0.001*
Minocycline	16 (64%)	165 (80.1%)	0.065
Tigecycline	8 (32%)	73 (35.4%)	0.734
Colistin	3 (12%)	20 (9.7%)	0.994
Trimethoprim-sulfamethoxazole	25 (100%)	110 (53.4%)	< 0.001*

Notes: Data are presented as No. (%) of patients. *P < 0.05, the comparison between KPC-NDM-CRKPs and KPC-CRKPs.

Abbreviations: KPC, Klebsiella pneumoniae carbapenemase; NDM, New Delhi metallo-β-lactamase; CRKP, carbapenem-resistant Klebsiella pneumoniae; KPC-NDM-CRKP, KPC and NDM co-producing carbapenem-resistant Klebsiella pneumoniae; KPC-CRKP, KPC-producing carbapenem-resistant Klebsiella pneumoniae; NA, not available.

Table 4 Clinical and Microbiological Characteristics Associated with 30-Day Mortality of CRKP BSIs

Characteristics	All CRKP BSIs			KPC-NDM-CRKP BSIs			KPC-CRKP BSIs
	Death (n=81)	Survivors (n=150)	P value	Death (n=14)	Survivors (n=11)	P value	Death (n=67)	Survivors (n=139)	P value
Age, years, mean ± SD	56.8 ± 13.4	49.9 ± 15.8	0.001*	56.6 ± 10.7	51.2 ± 14.1	0.280	56.8 ± 14	49.8 ± 15.9	0.002*
Male sex	65 (80.2%)	112 (74.7%)	0.339	11 (78.6%)	10 (90.9%)	0.775	54 (80.6%)	102 (73.4%)	0.258
Acquisition
Community-acquired	1 (1.2%)	5 (3.3%)	0.601	0	0	NA	1 (1.5%)	5 (3.6%)	0.690
ICU-acquired	65 (80.2%)	75 (50.0%)	< 0.001*	13 (92.9%)	8 (72.7%)	0.416	52 (77.6%)	67 (48.2%)	< 0.001*
Underlying conditions
Solid cancer	10 (12.3%)	20 (13.3%)	0.831	1 (7.1%)	2 (18.2%)	0.823	9 (13.4%)	18 (12.9%)	0.923
Hypertension	39 (48.1%)	37 (24.7%)	< 0.001*	9 (64.3%)	3 (27.3%)	0.066	30 (44.8%)	34 (24.5%)	0.003*
Cardiovascular disease	16 (19.8%)	18 (12.0%)	0.112	2 (14.3%)	2 (18.2%)	1.000	14 (20.9%)	16 (11.5%)	0.074
Neurologic disorder	16 (19.8%)	23 (15.3%)	0.392	0	1 (9.1%)	0.440	16 (23.9%)	22 (15.8%)	0.163
Diabetes mellitus	15 (18.5%)	36 (24.0%)	0.338	2 (14.3%)	1 (9.1%)	1.000	13 (19.4%)	35 (25.2%)	0.358
Gastrointestinal fistula	34 (42.0%)	57 (38.0%)	0.555	6 (42.9%)	6 (54.5%)	0.561	28 (41.8%)	51 (36.7%)	0.481
Chronic renal failure	8 (9.9%)	7 (4.7%)	0.125	1 (7.1%)	0	1.000	7 (10.4%)	7 (5.0%)	0.250
Fatty liver	5 (6.2%)	21 (14.0%)	0.072	1 (7.1%)	1 (9.1%)	1.000	4 (6%)	20 (14.4%)	0.078
Chronic liver disease	8 (9.9%)	14 (9.3%)	0.893	2 (14.3%)	1 (9.1%)	1.000	6 (9%)	13 (9.4%)	0.926
Biliary tract disease	35 (43.2%)	44 (29.3%)	0.034*	6 (42.9%)	2 (18.2%)	0.378	29 (43.3%)	42 (30.2%)	0.064
Malnutrition	12 (14.8%)	17 (11.3%)	0.446	0	2 (18.2%)	0.183	12 (17.9%)	15 (10.8%)	0.156
Trauma	11 (13.6%)	23 (15.3%)	0.720	2 (14.3%)	4 (36.4%)	0.417	9 (13.4%)	19 (13.7%)	0.963
Surgery within 30 days	33 (40.7%)	59 (39.3%)	0.835	7 (50%)	7 (63.6%)	0.783	26 (38.8%)	52 (37.4%)	0.847
Source of BSI
Respiratory tract	19 (23.5%)	21 (14.0%)	0.070	1 (7.1%)	0	1.000	18 (26.9%)	21 (15.1%)	0.044*
Abdomen	61 (75.3%)	116 (77.3%)	0.729	13 (92.9%)	9 (81.8%)	0.823	48 (71.6%)	107 (77.0%)	0.406
Urinary tract	1 (1.2%)	9 (6.0%)	0.174	0	1 (9.1%)	0.440	1 (1.5%)	8 (5.8%)	0.299
Skin and soft tissue	0	4 (2.7%)	0.340	0	1 (9.1%)	0.440	0	3 (2.2%)	0.552
Infection and microbiological data
WBC count, ×10^9/L, median (IQR)	10.8 (7.4–17.2)	9.2 (6.3–14.4)	0.222	9.7 (4.5–19.9)	9.2 (5.1–17.5)	0.979	10.8 (7.5–16)	9.3 (6.3–14.3)	0.163
Albumin, g/L, mean ± SD	31.6 ± 5.5	31.2 ± 4.6	0.563	31.4 ± 5.5	30.7 ± 3.5	0.695	31.6 ± 5.6	31.2 ± 4.7	0.602
PCT, μg/L, median (IQR)	9.2 (2.7–25.1)	2.1 (0.7–13.5)	< 0.001*	13.4 (6.5–36.9)	5.7 (0.7–13.5)	0.120	7.7 (2.6–24.8)	1.9 (0.7–13.5)	< 0.001*
CRP, mg/L, median (IQR)	182.4 (128–250.7)	129.6 (66.9–182.4)	< 0.001*	184.6 (136.3–250.6)	67.7 (39.8–154.1)	0.014*	180 (127.4–252.6)	130.7 (70.7–184.2)	< 0.001*
Platelet count, ×10^9/L, median (IQR)	94 (44–169.5)	206 (108.5–277.8)	< 0.001*	81 (37.8–179.8)	231 (76–401)	0.051	94 (49–170)	205 (110–277)	< 0.001*
NEUT%, median (IQR)	91.2 (86.5–94.2)	87.1 (81.4–92.2)	< 0.001*	91.7 (85.6–94.5)	82.6 (74.5–93)	0.166	91.1 (86.6–93.9)	87.3 (82.2–92.1)	< 0.001*
Hospital stay prior to CRKP isolation, median (IQR)	16 (9–25.5)	15 (4–26.2)	0.416	18 (10.2–32)	25 (7–33)	0.767	15 (8–25)	15 (4–25)	0.483
Full hospital stay, median (IQR)	28 (18–37.5)	54.5 (34.8–82.2)	< 0.001*	24.5 (17.2–41.8)	83 (43–140)	0.004*	29 (18–38)	54 (34–76)	< 0.001*
ICU stay, median (IQR)	24 (13–35)	37 (13–63.5)	0.006*	24.5 (17.2–39)	50 (19–121)	0.120	24 (11–35)	33 (12–62)	0.011*
APACHE II score at infection onset, median (IQR)	19 (16.5–23)	9 (6–12)	< 0.001*	19 (16.8–23)	6 (4–13)	< 0.001*	18 (16–23)	9 (6–12)	< 0.001*
Pitt bacteremia score at infection onset, median (IQR)	5 (3–7)	1.5 (0–3)	< 0.001*	5 (4–8)	2 (0–3)	< 0.001*	4 (3–6)	1 (0–3)	< 0.001*
Sepsis/septic shock at infection onset	68 (84.0%)	53 (35.3%)	< 0.001*	12 (85.7%)	4 (36.4%)	0.033*	56 (83.6%)	49 (35.3%)	< 0.001*
KPC-NDM-CRKP	14 (17.3%)	11 (7.3%)	0.020*	—	—	—	—	—	—
Empirical therapy
Combination therapy	65 (80.2%)	92 (61.3%)	0.003*	13 (92.9%)	7 (63.6%)	0.190	52 (77.6%)	85 (61.2%)	0.019*
Carbapenem-containing regimens	66 (81.5%)	111 (74.0%)	0.200	9 (64.3%)	7 (63.6%)	1.000	57 (85.1%)	104 (74.8%)	0.095
Tigecycline-containing regimens	32 (39.5%)	43 (28.7%)	0.093	4 (28.6%)	5 (45.5%)	0.650	28 (41.8%)	38 (27.3%)	0.037*
Colistin-containing regimens	28 (34.6%)	28 (18.7%)	0.007*	6 (42.9%)	0	0.043*	22 (32.8%)	28 (20.1%)	0.047*
Ceftazidime-avibactam-containing regimens	13 (16.0%)	13 (8.7%)	0.090	4 (28.6%)	2 (18.2%)	0.895	9 (13.4%)	11 (7.9%)	0.210
Inappropriate empirical treatment	37 (45.7%)	97 (64.7%)	0.005*	6 (42.9%)	8 (72.7%)	0.277	31 (46.3%)	89 (64%)	0.015*

Notes: Data are presented as No. (%) of patients unless otherwise specified. *P < 0.05 compared with survivors.

Abbreviations: KPC, Klebsiella pneumoniae carbapenemase; NDM, New Delhi metallo-β-lactamase; CRKP, carbapenem-resistant Klebsiella pneumoniae; KPC-NDM-CRKP, KPC and NDM co-producing carbapenem-resistant Klebsiella pneumoniae; KPC-CRKP, KPC-producing carbapenem-resistant Klebsiella pneumoniae; BSI, bloodstream infection; ICU, intensive care unit; WBC, white blood cell; PCT, procalcitonin; CRP, C-reactive protein; NEUT%, neutrophilic granulocyte percentage; APACHE, acute physiologic and chronic health evaluation; SD, standard deviation; IQR, interquartile range; NA, not available.

Table 5 Multivariate Analysis for Predictors of 30-Day Mortality in Patients with CRKP BSIs

Variables	Univariate Analysis		Multivariate Analysis
	OR (95% CI)	P value	OR (95% CI)	P value
Age	1.031 (1.012–1.051)	0.001*
ICU-acquired	4.062 (2.156–7.656)	< 0.001*	10.216 (2.707–38.559)	0.001*
Hypertension	2.836 (1.600–5.027)	< 0.001*	2.705 (0.974–7.511)	0.056
Fatty liver	0.404 (0.146–1.116)	0.080
Biliary tract disease	1.833 (1.044–3.218)	0.035*
Respiratory tract	1.882 (0.944–3.755)	0.073
PCT	1.023 (1.009–1.037)	0.001*
CRP	1.008 (1.005–1.012)	< 0.001*
Platelet count	0.993 (0.990–0.996)	< 0.001*
NEUT%	1.090 (1.040–1.143)	< 0.001*
Full hospital stay	0.958 (0.944–0.972)	< 0.001*	0.967 (0.937–0.999)	0.043*
ICU stay	0.981 (0.971–0.992)	0.001*	0.958 (0.921–0.996)	0.030*
APACHE II score at infection onset	1.353 (1.256–1.458)	< 0.001*	1.435 (1.288–1.599)	< 0.001*
Pitt bacteremia score at infection onset	1.582 (1.383–1.810)	< 0.001*
Sepsis/septic shock at infection onset	9.573 (4.844–18.920)	< 0.001*
KPC-NDM-CRKP	2.640 (1.138–6.127)	0.024*	8.355 (1.103–63.270)	0.040*
Combination therapy	2.561 (1.353–4.848)	0.004*
Tigecycline-containing regimens	1.625 (0.920–2.870)	0.094
Colistin-containing regimens	2.302 (1.244–4.258)	0.008*
Ceftazidime-avibactam-containing regimens	2.015 (0.886–4.583)	0.095
Inappropriate empirical treatment	0.459 (0.265–0.797)	0.006*

Notes: *P < 0.05.

Abbreviations: KPC, Klebsiella pneumoniae carbapenemase; NDM, New Delhi metallo-β-lactamase; CRKP, carbapenem-resistant Klebsiella pneumoniae; KPC-NDM-CRKP, KPC and NDM co-producing carbapenem-resistant Klebsiella pneumoniae; BSI, bloodstream infection; ICU, intensive care unit; PCT, procalcitonin; CRP, C-reactive protein; NEUT%, neutrophilic granulocyte percentage; APACHE, acute physiologic and chronic health evaluation; OR, odds ratio; CI, confidence interval.