Treatment of Carbapenem-Resistant Multidrug-Resistant Gram-Negative Bacilli with Intracerebroventricular Injection of Polymyxin B: A Retrospective Study

Figures & data

Table 1 Drug Susceptibility Results of 41 MDR/XDR Gram-Negative Bacilli

Antibiotic		KP (N=22)		AB(N=15)		PA(N=3)		ES(N=1)
		n	n%	n	n%	n	n%	n	n%
Polymyxin B	R	0	0.0%	0	0.0%	0	0.0%	0	0.0%
	I	0	0.0%	0	0.0%	0	0.0%	0	0.0%
	≤0.5/S	22	100.0%	15	100.0%	3	100.0%	1	100.0%
Meropenem	≥16‎/R	22	100.0%	15	100.0%	3	100.0%	1	100.0%
	I	0	0.0%	0	0.0%	0	0.0%	0	0.0%
	≤1‎/S	0	0.0%	0	0.0%	0	0.0%	0	0.0%
Imipenem	≥16‎/R	22	100.0%	15	100.0%	3	100.0%	1	100.0%
	I	0	0.0%	0	0.0%	0	0.0%	0	0.0%
	≤1‎/S	0	0.0%	0	0.0%	0	0.0%	0	0.0%
Tigecycline	≥8/R	4	18.2%	4	26.7%	1	33.3%	0	0.0%
	=4/I	2	9.1%	2	13.3%	1	33.3%	0	0.0%
	≤2/S	16	72.7%	9	60.0%	1	33.3%	1	100.0%
Tobramycin	≥16‎/R	19	86.4%	12	80.0%	1	33.3%	0	0.0%
	=8‎/I	1	4.5%	0	0.0%	1	33.3%	0	0.0%
	≤1‎/S	2	9.1%	3	20.0%	1	33.3%	1	100.0%
cotrimoxazole	≥320/R	15	68.2%	8	53.3%	3	100.0%	1	100.0%
	I	0	0.0%	0	0.0%	0	0.0%	0	0.0%
	≤20‎/S	7	31.8%	7	46.7%	0	0.0%	0	0.0%
Minocycline	≥16‎/R	15	68.2%	9	60.0%	2	66.7%	0	0.0%
	=8‎/I	0	0.0%	2	13.3%	0	0.0%	0	0.0%
	≤4‎/S	7	31.8%	4	26.7%	1	33.3%	1	100.0%
Piperacillin	≥128/R	22	100.0%	15	100.0%	2	66.7%	1	100.0%
	I	0	0.0%	0	0.0%	0	0.0%	0	0.0%
	≤4‎/S	0	0.0%	0	0.0%	1	33.3%	0	0.0%
Piperacillin-tazobactam	≥32‎/R	21	95.5%	15	100.0%	2	66.7%	1	100.0%
	I	0	0.0%	0	0.0%	0	0.0%	0	0.0%
	≤8‎/S	1	4.5%	0	0.0%	1	33.3%	0	0.0%
Cefepime	≥64/R	22	100.0%	15	100.0%	2	66.7%	1	100.0%
	I	0	0.0%	0	0.0%	0	0.0%	0	0.0%
	≤1‎/S	0	0.0%	0	0.0%	1	33.3%	0	0.0%
Ciprofloxacin	≥4/R	21	95.5%	13	86.7%	2	66.7%	1	100.0%
	=2‎/I	0	0.0%	0	0.0%	1	33.3%	0	0.0%
	≤0.5‎/S	1	4.5%	2	13.3%	0	0.0%	0	0.0%
Levofloxacin	≥8‎/R	21	95.5%	10	66.7%	2	66.7%	1	100.0%
	=4‎/I	0	0.0%	3	20.0%	1	33.3%	0	0.0%
	≤1‎/S	1	4.5%	2	13.3%	0	0.0%	0	0.0%
Gentamicin	≥16/R	16	72.7%	11	73.3%	1	33.3%	0	0.0%
	=8‎/I	0	0.0%	1	6.7%	0	0.0%	0	0.0%
	≤21/S	6	27.3%	3	20.0%	2	66.7%	1	100.0%

Abbreviations: AB, Acinetobacter baumannii; KP, Klebsiella pneumoniae; PA, Pseudomonas aeruginosa; ES, Enterobacter sulcus; S, susceptible; I, intermediate; R, resistant.

Table 2 Clinical Characteristics of Patients Enrolled in the Study

Case	Age	Gender	Primary Disease	Surgeries	Foreign Body
1	59	M	TBI	EICH+DC+VP+EVD	EVD
2	52	M	TBI	EICH+DC+EVD	EVD
3	61	F	TBI	EBA+EICH	NA
4	15	M	Brain aneurysm	EICT+EVD+LCD+OTP	EVD+LCD+OTP
5	64	F	Brain aneurysm	EICH+DC+EVD	LCD
6	51	M	ICH	EICH+EVD	EVD
7	18	M	Brain tumors	EICT+EVD+LCD+OTP	EVD+LCD+OTP
8	56	F	ICH	EICH+DC+LCD	LCD
9	57	M	ICH	EICH+DC+EVD	EVD
10	46	M	TBI+CFL	EICH+DC+LCD	LCD
11	65	M	Chronic subdural hematoma	EVD	EVD
12	58	M	TBI	EICH+DC+LCD+LCD	EVD+LCD
13	62	M	Brain aneurysm	EICH+DC+EVD	EVD+LCD
14	33	M	ICH	EICH+DC+EVD	EVD
15	17	F	TBI+CFL	EICH+DC+LCD	LCD
16	16	F	Hydrocephalus	EVD+LCD	EVD+LCD
17	33	M	Brain aneurysm	EICH+DC+ICAC+VP+EVD+LCD	EVD+LCD
18	53	M	ICH	EICH+ICAC+EVD+DC	EVD
19	42	F	ICH	EICH+EVD+LCD	EVD+LCD
20	15	M	TBI+CFL	EICH+DC+LCD	LCD
21	71	M	TBI+CFL	EICH+DC+EVD	EVD
22	25	M	ICH	EVD	EVD
23	33	M	TBI+CFL	EICH+DC+LCD	LCD
24	2	F	Brain tumors	EICT+EVD	EVD
25	59	F	ICH	EVD	EVD
26	20	M	TBI	EICH+VP+EVD	EVD
27	39	M	Brain aneurysm	ICAC+EICH+DC+LCD	EVD
28	55	M	ICH	EICH+DC+LCD+EVD	EVD
29	31	M	TBI+CFL	EICH+DC+EVD	EVD
30	33	M	TBI	EICH+DC+EVD+LCD	LCD
31	26	F	Brain tumors	EICT+EVD+LCD	LCD
32	57	F	Brain aneurysm	EICH+DC+LCD	LCD
33	25	M	TBI	EICH+DC+LCD	EVD+LCD+OTP
34	27	M	TBI	EVD+LCD	EVD
35	24	F	TBI+CFL	EICH+DC+VP+EVD+LCD	LCD
36	16	M	ICH	EICH+DC+VP+EVD+LCD	EVD+LCD
37	56	M	ICH	EICH+DC+VP+EVD+LCD	EVD
38	18	M	TBI+CFL	EICH+DC+EVD+LCD	EVD+LCD
39	30	M	TBI+CFL	EICH+DC+EVD+LCD	LCD
40	2	M	Brain tumors	EICT+EVD	EVD
41	24	F	ICH	LCD+VP+EVD	EVD

Abbreviations: DC, decompressive craniectomy; ICH, intracerebral hemorrhage; EVD, external ventricular drain; LCD, umbar cisterna drainage; TBI, traumatic brain injury; EICH, evacuation intracranial hematoma; EBA, excision of brain abscess; EICT, excision of intracranial tum; ICAC, intracranial aneurysm clipping; OTP, Ommaya tube placement; CFL, cerebrospinal fluid leakage; F, female; M, male.

Table 3 Cerebrospinal Fluid (CSF) Culture and Treatment Strategies for Each Patient

Case	CSF Isolate	Drug Susceptibility	Concomitant Infection	Antibiotics Before CSF Culture	IV Sensitive Antibiotics	Duration of IV (Days)	IVT Polymyxin B Delay Period	IVT Polymyxin B (mg, qd)	Duration of IVT Polymyxin B (Days)	CSF Bacterial Clearance Days	Multiloculated/Normal Ventricle	Ventricular Segment Counts	Isolated Ventricular	CSF Purification Time	Outcome	Survival Follow-Up Period (Months)
1	KP	CR	NO	CRO	AK	35	3	5	14	6	N	1	NO	254	Cure	Alive/62
2	KP	CR	NO	CAZ	PB	31	3	5	13	6	M	2	TA	93	Cure	Alive/32
3	KP	CR	NO	AK	TGC	16	3	5	19	12	N	1	NO	95	Cure	Alive/16
4	KP	CR	AB	AK	TGC	32	3	5	27	6	N	1	NO	56	Cure	Alive/22
5	AB	CR	NO	MEM	TGC	23	3	5	10	5	N	1	NO	46	Cure	Alive/57
6	AB	CR	NO	LEV	TGC	14	3	5	12	5	N	1	NO	37	Cure	Alive/64
7	KP	CR	NO	MEM+VA	TGC	83	3	5	25	14	M	2	TA	178	Cure	Alive/44
8	AB	CR	NO	MEM+VA	FOS	5	3	5	12	5	M	3	TA+FV	100	Cure	Alive/11
9	AB	CR	Se	CAZ	TGC	66	5	5	19	7	N	1	NO	48	Cure	Alive/36
10	KP	CR	NO	LEV	TGC	24	5	5	18	8	N	1	NO	102	Cure	Alive/35
11	KP	CR	NO	LEV	CIP	32	5	5	21	14	N	1	NO	40	Cure	Alive/10
12	KP	CR	NO	LEV	TGC	12	5	5	20	8	N	1	NO	96	Cure	Alive/52
13	AB	CR	NO	MEM+VA	TOB	13	6	5	10	3	M	2	TA	70	Cure	Alive/66
14	KP	CR	NO	CRO	TGC	58	7	5	21	8	M	1	TA	124	Cure	Alive/17
15	KP	CR	NO	CAZ	TGC	48	7	5	27	14	N	1	NO	97	Cure	Alive/57
16	AB	CR	EC	CFPs	TGC	40	7	5	18	7	M	1	FV	106	Cure	Alive/51
17	KP	CR	NO	LEV	TGC	32	7	5	10	3	M	1	TA+FV	236	Cure	Alive/30
18	KP	CR	NO	MEM	TGC	19	7	5	13	5	M	4	TA+LRLV	170	Cure	Alive/38
19	KP	CR	NO	Biapenem	TGC	20	8	5	20	NA	M	2	LLV+RLV	NA	Death	Death
20	KP	CR	NO	CRO	FOS	46	9	5	26	12	N	1	NO	50	Cure	Alive/9
21	AB	CR	NO	LEV	TGC	38	10	5	9	3	M	2	FV	50	Cure	Alive/43
22	AB	CR	NO	CFPs	TGC	57	11	5	12	5	N	1	NO	70	Cure	Alive/45
23	AB	CR	NO	TGC	TGC	78	13	5	30	10	M	2	TA	51	Cure	Alive/57
24	AB	CR	NO	TGC	PB	73	13	5	13	4	M	2	TA	119	Cure	Alive/32
25	EC	CR	Se	TGC	AK	15	13	5	27	9	M	1	LLV+RLV	12	Cure	Alive/51
26	KP	CR	NO	TGC	TGC	39	20	5	33	NA	M	1	LLV+RLV	NA	Death	Death
27	KP	CR	AB	TGC+PB	TGC	86	20	5	35	NA	M	3	TA+LRLV	NA	Death	Death
28	AB	CR	NO	TGC	TGC	19	20	5	18	6	M	1	FV	12	Cure	Alive/64
29	AB	CR	NO	TGC	CFPs	7	25	5	15	NA	M	3	TA+FV	NA	Death	Death
30	PA	CR	Se	TGC	AK	10	25	5	13	5	N	1	NO	203	Cure	Alive/62
31	AB	CR	E.faecium	LEV	LEV	63	26	5	35	NA	M	2	LLV+RLV	NA	Death	Death
32	KP	CR	E.faecalis	TGC	TGC	6	26	5	22	10	N	1	NO	14	Cure	Alive/37
33	KP	CR	NO	TGC	TGC	88	30	5	18	6	N	1	NO	30	Cure	Alive/60
34	AB	CR	NO	TGC	TGC	3	30	5	23	NA	M	2	LLV+RLV	NA	Death	Death
35	AB	CR	BC	AK	AK	23	30	5	26	NA	N	1	NO	NA	Death	Death
36	KP	CR	Se	TGC	TGC	26	30	5	14	5	M	2	TA	17	Cure	Alive/64
37	KP	CR	NO	TGC	TGC	5	37	5	35	NA	M	2	LLV+RLV	NA	Death	Death
38	KP	CR	SM	TGC	TGC	48	40	5	38	NA	M	2	TA	NA	Death	Death
39	PA	CR	NO	CAZ	CAZ	159	45	5	19	6	N	1	NO	147	Cure	Alive/54
40	PA	CR	SC	CAZ	CAZ	34	97	5	30	14	M	2	TA	47	Cure	Alive/56
41	KP	CR	Se	TGC	AK	44	192	5	28	15	N	1	NO	83	Cure	Alive/38

Abbreviations: AB, Acinetobacter baumannii; KP, Klebsiella pneumoniae; PA, Pseudomonas aeruginosa; ES, Enterobacter sulcus; EC, Escherichia coli; Se, Staphylococcus epidermidis; E. faecium, Enterococcus faecium; BC, Burkholderia cepacia; SM, Serratia marcescens; SC, Staphylococcus caprae; CR, carbapenem resistance; IVT, intraventricular; IV, intravenous; CRO, Ceftriaxone; CAZ, ceftazidime; CAZ, Ceftazidime-avibactam; MEM, Meropenem; VA, Vancomycin; LEV, Levofloxacin; TGC, Tigecycline; TOB, Tobramycin; AK, Amikacin; CAZ, Ceftazidime; CFPs, Cefoperazone/sulbactam; PB, Polymyxin B; CFPs, Cefoperazone sulbactam sodium; CIP, Ciprofloxacin; FOS, Fosfomycin; CST, Compound sulfamethoxazole tablets; GN, Gentamicin; TA, Temporal angle; FV, Fourth ventricle; N, Normal; M, Multiloculated; LLV, Left lateral ventricle; RLV, Right lateral ventricle.

Table 4 Clinical Symptoms and Laboratory Data in Patients

Variable	Before IVT Polymyxin B	After IVT Polymyxin B	p
Temperature (◦C)	38.2±0.45	37.0±0.65	0
GCS score	7.54±3.36	8.49±3.78	0.03
Serum Creatinine (μmoI/L)	65.10±16.12	63.45±14.78	0.08
CSF
Leukocytes (cells/μL)	1848 (280, 4244)	4 (2, 9)	0
Glucose (mmol/L)	0.58 (0.45, 1.90)	3.61 (3.20, 3.97)	0
Protein (g/L)	0.44 (0.20, 0.97)	3.00 (1.00, 4.50)	0

Abbreviations: CNS, central nervous system; GCS, Glasgow Coma Scale; CSF, cerebrospinal fluid.

Table 5 Clinical Outcomes and Complications

Outcome/Complication	No. Cases(%)
Bacterial clearance rate	32 (78.0%)
Cured rate	32 (78.0%)
Mortality	9 (22.0%)
30-day mortality	1 (2.4%)
90-day mortality	8 (19.5%)
Adverse events
Epilepsy	0 (0%)
Acute kidney injury	0 (0%)
Skin hyperpigmentation	1 (2.4%)
Sequelae of infection
Hydrocephalus and VP	31 (75.6%)
Remove the drainage tube	1 (2.4%)
Multiloculated ventricle	18 (43.9%)

Figure 1 Multiloculated hydrocephalus and skin pigmentation in carbapenem-resistant MDR/XDR gram-negative central nervous system infections. (A) CT indicated multiloculated hydrocephalus in 23 carbapenem-resistant MDR/XDR gram-negative central nervous system infections. (B) One patient developed hyperpigmentation after receiving 50 mg q12h intravenous Polymyxin B for 31 days.

Table 6 Clinical Factors and Mortality

Variable	Cure	Death	p
DP of IVT Polymyxin B			0.002
Early IVT group	18 (100%)	0 (0%)
Late IVT group	14 (60.9%)	9 (39.1%)
Pupil light reflex			0.021
Presence	22(91.7%)	2(8.3%)
Disappeared	10 (58.8%)	7(41.2%)
Multiloculated hydrocephalus			0.005
Multiloculated	15 (65.2%)	8(34.8%)
Normal	17 (94.4%)	1(5.6%)

Note: DP, delay period; DP ≤7 days for the early IVT injection group; DP >7 days for the late IVT injection group.