Efficacy and Safety Factors Related to Plasma Concentration-Optimized Polymyxin B Therapy in Treating Carbapenem-Resistant Gram-Negative Bacterial Infections in China

Figures & data

Table 1 Patients Demographics and Clinical Outcomes

Parameters	Variable
Demographics
Age, years, median (IQR)	67 (51.3, 78.0)
<18, n (%)	24 (18.5)
18~64, n (%)	32 (24.6)
65~80, n (%)	48 (36.9)
>80, n (%)	26 (20.0)
Male, n (%)	88 (67.7)
Weight, kg, median (IQR)	60.0 (50.0, 67.5)
SOFA score, median (IQR)	6.0 (3.0, 10.0)
Postoperative patients, n (%)	70 (53.8)
CRRT, n (%)	16 (12.3)
ICU, n (%)	114 (87.7)
Length of ICU stay, days, median (IQR)	28 (16, 45)
Total length of hospital stays, days, median (IQR)	43 (28, 70)
Infection types, n (%)
Lung infection	84 (64.6)
Bloodstream infection	52 (40.0)
Abdominal infection	20 (15.4)
Other infections^a	6 (4.6)
Comorbidities, n (%)
Diabetes	31 (23.8)
Cardiovascular diseases	77 (59.2)
Neoplastic disease	22 (16.9)
Chronic digestive diseases	40 (30.8)
Kidney disease	19 (14.6)
COVID-19	15 (11.5)
Pathogenic bacteria species, n (%)
CR Klebsiella Pneumoniae	67 (51.5)
CR Acinetobacter baumannii	61 (46.9)
CR Pseudomonas aeruginosa	17 (13.1)
Stenotrophomonas maltophilia	5 (3.8)
Escherichia coli	5 (3.8)
Klebsiella oxytoca	3 (2.3)
Others^b	5 (3.8)
PMB MIC, μg/mL
≤0.5, n (%)	57(43.9)
1, n (%)	54(41.5)
≥2, n (%)	19(14.6)
PMB administration duration, days, median (IQR)	13 (7, 17)
3~7, n (%)	35 (26.9)
8–14, n (%)	54 (41.5)
15~21, n (%)	22 (16.9)
22–30, n (%)	9 (6.9)
≥31, n (%)	9 (6.9)
Concomitant antibiotics, n (%)
Carbapenems	86 (66.2)
Cefoperazone-sulbactam	21 (16.2)
Piperacillin-tazobactam	7 (5.4)
Cefepime	6 (4.6)
Tigecycline	17 (13.1)
Fosfomycin	30 (23.1)
Amikacin	3 (2.3)
Vancomycin	18 (13.8)
Amikacin	3 (2.3)
Others^c	33 (25.4)
Outcomes
Total clinical effective rate, n (%)	85 (65.4)
Clinical effective rate in 7 days, n (%)	31 (23.8)
Total bacterial clearance, n (%)	70 (53.9)
Bacterial clearance in 7 days, n (%)	35 (26.9)
Time of bacterial clearance, days, median (IQR)	9 (6, 12)
30-day mortality, n (%)	39 (30.0)

Notes: Bacterial names are in italics. ^aIntracranial infection; Biliary tract infection; Wound infection. ^bEnterobacter cloacae; Klebsiella aerogenes. ^CCeftazidime avibactam; Ceftazidime; Levofloxacin; Teicolanin; Linezolid; Voriconazole; Fluconazole.

Abbreviations: IQR, interquartile range; SOFA, Sequential Organ Failure Assessment; CRRT, continuous renal replacement therapy; ICU, intensive care unit; MIC, Minimal Inhibitory Concentration; COVID-19, Coronavirus Disease 2019; CR, Carbapenem-resistant.

Table 2 Univariate and Multivariate Analysis of Clinical Efficacy of Polymyxin B

Parameters	Efficacious n=85	Non-Efficacious n=45	OR (95% CI)	P value
Univariate analysis
Age, years, median (IQR)	65 (40,76)	72 (63,83)		0.169
<18 vs >80, n (%)	18 (21.2)/ 13 (15.3)	6 (13.3)/13 (28.9)	3.00 (0.902–9.980)	0.073
18~64 vs >80, n (%)	24 (28.2)	8 (17.8)	3.00 (0.989–9.100)	0.052
65~80 vs >80, n (%)	30 (35.3)	18 (40.0)	1.67 (0.635–4.377)	0.300
Comorbidities, n (%)
Cardiovascular diseases	44 (51.8)	33 (73.3)	0.39 (0.178–0.856)	0.019
COVID-19	6 (7.1)	9 (20.0)	0.30 (0.101–0.918)	0.035
Test index before PMB treatment
WBC, X10^9/L, median (IQR)	12.1 (7.9,16.4)	12.1 (7.4,17.2)	0.99 (0.941–1.040)	0.680
CRP, mg /L, median (IQR)	82.0 (40.0.131.0)	130.5 (62.8.160.0)
<160 vs ≥160, n (%)	15 (17.6)	19 (42.2)	0.32 (0.140–0.725)	0.006
PCT, ng /mL, median (IQR)	1.1 (0.3,6.8)	1.1 (0.4,5.0)	1.00 (0.984–1.018)	0.908
eGFR, mL /min, median (IQR)	87.1 (49.4.134.1)	61.7 (27.5,93.3)	1.01 (0.999–1.010)	0.101
SOFA, median (IQR)	6.0 (3.0,9.0)	6.0 (3.0,12.0)	0.97 (0.902–1.048)	0.460
Mechanical ventilation, n (%)	45 (52.9)	24 (53.3)	0.95 (0.477–2.031)	0.966
CRRT, n (%)	6 (7.1)	10 (22.2)	0.27 (0.090–0.789)	0.017
Surgery, n (%)	51 (60.0)	19 (42.2)	2.05 (0.986–4.275)	0.055
Vasopressors, n (%)	25 (29.4)	20 (44.4)	0.52 (0.246–1.103)	0.089
Infection type, n (%)
Bloodstream infection	43 (50.6)	9 (20.0)	4.10 (1.759–9.535)	0.001
Lung infection	46 (54.1)	38 (84.4)	0.22 (0.087–0.541)	0.001
Abdominal infection	16 (18.8)	4 (8.9)	2.38 (0.744–7.596)	0.144
PMB Therapeutic regimen
Loading dose, n (%)	69 (81.2)	36 (80.0)	1.08 (0.434–2.680)	0.871
Loading dose, mg /kg, median (IQR)	1.7 (1.4,2.0)	1.8 (1.7,2.0)	1.14 (0.718–1.819)	0.573
Maintenance dose, mg/kg, median (IQR)	1.0 (0.8,1.1)	0.9 (0.8,1.0)	1.85 (0.433–7.872)	0.407
Daily dose, mg /kg, median (IQR)	1.9 (1.6,2.3)	1.9 (1.5,2.0)	1.51 (0.702–3.256)	0.291
Concomitant antibiotics, n (%)
Carbapenems	53 (62.4)	32 (71.1)	0.67 (0.309–1.467)	0.319
Cefoperazone Sodium Sulbactam	16 (18.8)	5 (11.1)	1.86 (0.632–5.447)	0.261
Tigecycline	11 (12.9)	6 (13.3)	0.97 (0.332–2.810)	0.950
Fosfomycin	20 (23.5)	10 (22.2)	1.08 (0.454–2.553)	0.866
TDM, median (IQR)
Cmin /MIC	2.1 (1.3,3.9)	2.7 (2.1,4.7)	0.95 (0.853–1.064)	0.392
Cmax /MIC	6.2 (3.8,9.3)	7.4 (4.6,10.2)	0.99 (0.935–1.055)	0.828
AUC /MIC	96.2 (57.7.160.9)	109.7 (76.3.182.1)	1.00 (0.996–1.002)	0.573
Pathogenic bacteria species, n (%)
CR Klebsiella Pneumoniae	46 (54.1)	20 (44.4)	1.47 (0.713–3.049)	0.295
CR Acinetobacter baumannii	40 (47.1)	22 (48.9)	0.93 (0.451–1.915)	0.842
CR Pseudomonas aeruginosa	13 (15.3)	8 (17.8)	0.84 (0.318–2.194)	0.715
Multivariate analysis
Lung infection			0.23 (0.083–0.653)	0.006
CRRT			0.16 (0.037–0.663)	0.012
CRP, mg/L
<160 vs ≥160			0.31 (0.123–0.780)	0.013

Note: P values<0.05 are in bold; Bacterial names are in italics.

Abbreviations: WBC, White Blood Cells; CRP, C-reactive protein; PCT, Procalcitonin; SOFA, Sequential Organ Failure Assessment; CRRT, continuous renal replacement therapy; eGFR, estimated glomerular filtration rate; MIC, Minimal Inhibitory Concentration; CR, Carbapenem-resistant.

Table 3 Univariate and Multivariate Analysis of 30-Day All-Cause Mortality

Parameters	Univariate Analysis
	HR	95% CI	P value
Univariate analysis
Age, years			0.042
<18 vs >80	0.17	0.038–0.784	0.023
18~64 vs >80	0.46	0.177–1.177	0.104
65~80 vs >80	0.98	0.468–2.069	0.966
Comorbidities
Diabetes	2.23	1.168–4.257	0.015
Cardiovascular diseases	2.24	1.090–4.569	0.028
COVID-19	3.21	1.518–6.782	0.002
Test index before PMB treatment
WBC, X10^9/L	0.10	0.951–1.048	0.948
CRP, mg/L
<160 vs ≥160	3.92	2.058–7.450	0.000
PCT, ng/mL	1.00	0.987–1.015	0.904
SOFA score, 1-point increments	1.06	0.998–1.128	0.060
Surgery operation	0.56	0.298–1.067	0.055
CRRT	2.27	1.040–4.942	0.039
Mechanical ventilation	1.36	0.718–2.574	0.345
Vasopressors	2.15	1.144–4.022	0.017
Infection type
Bloodstream infection	0.29	0.129–0.661	0.003
Lung infection	3.40	1.422–8.113	0.006
Abdominal infection	0.43	0.132–1.391	0.158
TDM
Cmin /MIC	1.05	0.982–1.126	0.150
Cmax /MIC	1.02	0.976–1.061	0.413
AUC /MIC	1.00	0.999–1.004	0.229
Multivariate analysis
Bloodstream infection	0.30	0.122–0.713	0.007
Vasopressors	2.12	1.086–4.138	0.028
CRP, mg/L
<160 vs ≥160	3.45	1.752–6.803	0.000
COVID-19	2.48	1.151–5.354	0.020

Note: P values<0.05 are in bold.

Abbreviations: WBC, White Blood Cells; CRP, C-reactive protein; PCT, Procalcitonin; SOFA, Sequential Organ Failure Assessment; CRRT, continuous renal replacement therapy; MIC, Minimal Inhibitory Concentration; COVID-19, Coronavirus Disease 2019.

Figure 1 Kaplan–Meier survival estimates for 30-day all-cause mortality.

Notes: (A) Bloodstream infection and Non- Bloodstream infection (P < 0.01). (B) Use of Vasopressors and No Vasopressors (P < 0.01). (C) CRP<160 mg/L and ≥160 mg/L (P < 0.01). (D) With COVID-19 and Without COVID-19 (P < 0.01).

Abbreviations: CRP, C-reactive protein; COVID-19, Coronavirus Disease 2019.

Table 4 Analysis of Factors Influencing Acute Kidney Injury During Polymyxin B Treatment

Parameters	AKI n=19	Non- AKI n=111	OR (95% CI)	P value
Univariate analysis
Age, years, median (IQR)	80 (70.5, 86.0)	65 (44.0, 75.0)	1.06 (1.016–1.097)	0.005
>73, n (%)	11(73.7)	32 (28.8)	6.91 (2.300–20.779)	0.001
Test index before PMB treatment
Creatinine, μmol/L, median (IQR) (IQR)median(IQR) (IQR)	51.5 (35.1, 79.6)	56.0 (37.1, 116.4)	9.99 (0.985–1.003)	0.213
SOFA, median (IQR)	6.0 (3.0, 9.0)	6.0 (3.0, 10.0)	0.97 (0.873–1.077)	0.563
PMB therapeutic regimen, median (IQR)
Loading dose, mg/kg	1.8 (1.5, 2.0)	1.7 (1.5, 2.0)	1.32 (0.663–2.638)	0.427
Maintenance dose, mg/kg	0.8 (0.8, 1.0)	1.0 (0.8, 1.1)	0.12 (0.012–1.219)	0.073
Daily dose, mg/kg	1.7 (1.5, 2.0)	2.0 (1.6, 2.3)	0.39 (0.123–1.225)	0.106
Accumulated dose, mg/kg	15.0 (10.4, 24.4)	20.5 (14.0,29.7)	0.98 (0.954–1.016)	0.326
Treatment duration, days	11.0 (7.0, 18.0)	13.0 (7.5, 16.0)	0.99 (0.958–1.029)	0.696
TDM
Cmin, μg/mL, median (IQR)	2.9 (2.4,4.0)	1.9 (1.2,3.0)	1.43 (1.060–1.931)	0.019
>2.3, n (%)	14 (73.3)	38 (34.2)	5.38 (1.802–16.059)	0.003
Cmax, μg/mL, median (IQR)	5.7 (4.7, 7.8)	5.1 (3.7, 6.7)	1.11 (0.944–1.315)	0.202
AUC, mg·h/L, median (IQR)	104.3(85.5, 136.0)	78.7 (56.5, 111.0)	1.01 (1.000–1.020)	0.049
>82, n (%)	16 (84.2)	53 (47.7)	5.84 (1.610–21.163)	0.007
Concomitant antibiotics, n (%)
Carbapenem	7 (36.8)	79 (71.2)	0.25 (0.089–0.682)	0.007
Cefepime	1 (5.3)	5 (4.5)	1.18 (1.130–10.676)	0.884
Amikacin	1 (5.3)	2 (1.8)	3.03 (0.261–35.147)	0.376
Vancomycin	5 (26.3)	13 (11.7)	2.69 (0.833–8.706)	0.098
Piperacillin-tazobactam	5 (26.3)	2 (1.8)	19.65 (3.445–109.974)	0.001
Multivariate analysis
Age, year, >73 vs ≤ 73			3.63 (1.04–12.73)	0.044
Cmin, μg/mL, >2.3 vs ≤ 2.3			7.37 (1.57–34.58)	0.011
Vancomycin			9.47 (1.73–51.73)	0.009
Piperacillin-tazobactam			21.87 (3.14–152.3)	0.002

Note: P values<0.05 are in bold.

Abbreviations: SOFA, Sequential Organ Failure Assessment; TDM, Therapeutic drug concentration monitoring; C_min, Trough concentration; C_max, Peak concentration; AUC, Area Under the concentration-time Curve.

Figure 2 Receiver operating characteristic curve of the C_min and AUC₂₄ of PMB for AKI.

Abbreviations: C_min, Trough concentration; AUC₂₄, Area Under the concentration-time Curve across 24 h.