Two Cases Report of Intrathecal Tigecycline Therapy for Intracranial Infection with Acinetobacter baumannii and Review of Literatures.

OBJECTIVE: To explore the treatment scheme for intracranial infection with Acinetobacter baumannii.
METHODS: We retrospective analyzed two cases of patients of intracranial infection with Acinetobacter baumannii.
RESULTS: The intracranial infection was controlled effectively by the scheme to intravenous"tigecycline + cefperazone-sulbactam"combined with intrathecal tigecycline injection, the two patients recover well with 21 months' follow-up.
CONCLUSIONS: Tigecycline-based drug scheme combined with intrathecal tigecycline injection can achieve the effect of controlling intracranial infection. Lumbar cisterna drainage tube plays a major role in controlling intracranial infection.

Introduction

Acinetobacter baumannii intracranial infection has been a cause of hospital-acquired infections and resulted in high morbidity and mortality rates.1,2 Because of the presence of multiresistance and drugs poor penetration through the blood brain barrier, it’s still challengeable to treat it. Recent years, many studies revealed that it is a reliable choice to treat multiresistant Acinetobacter meningitis with the scheme of intraventricular/intrathecal and intraventricular/intrathecal colistin,3 however, considered the neurotoxicity, its application still limited. Tigecycline has a effective effect against multiresistant BA, however, tigecycline can only be used as an intravenous drug.4 And its poor penetration through blood brain barrier, it still resulting in bad effect to the intracranial infection with BA. It would be a breakthrough if tigecycline can be used in intraventricular/intrathecal. Intraventricular/intrathecal tigecycline has few been reported. Here, we described two cases infected with post-neurosurgical extensive drug resistant (XDR A) baumannii, and it was successfully cured by intrathecal tigecycline therapy.

Case Report

Case 1 A female patient, 16 years old, undergoing retrosigmoid craniotomy for resection of Vestibular Schwannomas. However, she got a high fever 39.5°C, it showed a high level of white blood cell and a low level of both glucose in the laboratory tests for cerebrospinal fluid (CSF) (Table 1) of her. Then she was diagnosed as meningitis and treated with vancomycin and meropenem. The MRI imaging was shown in Figure 1. Later, we changed the scheme to tigecycline and cefoperazone-sulbactam, because the CSF sputum culture showed she was infected with XDRA baumannii which was only sensitive to tigecycline (Table 2). The dose was 100mg/day (50mg twice a day) and cefoperazone-sulbactam (3g twice a day). Consideration the poor blood brain barrier permeability of tigecycline, intrathecal tigecycline therapy was an effective way to cure this patient. After permission from the hospital ethics committee and his family members, we carried out the therapeutic schedule of intrathecal tigecycline therapy. We injected 5mg tigecycline into Lumbar cisterna drainage tube every day, and then closed the Lumbar cisterna drainage tube about 2 hours. This patient tolerated the treatment well. After 6 days, her fever improved, but the CSF culture was still positive. We continued the schedule of intrathecal tigecycline and the CSF culture became negative after 4 weeks, with normal levels of white blood cell, glucose, the temperature decreased to 36.8°C and all symptoms disappeared. We stopped the intrathecal tigecycline therapy. In the next 3 days, the CSF cultures were all negative, in that case, the intracranial infection was effectively cured. (The appearances of CSF before and after treatment are shown in Figure 2, and the laboratory tests for CSF in the period of treatment are shown in Table 1). Intravenous antibiotics were stopped 2 weeks later, and the patient was recover well.

Table 1

Laboratory Tests for CSF in the Period of Treatment of case 1

Date	March	March	March	April	April	April	April	April
	26th	27th	30th	2nd	5th	8th	10th	27th
WBC, 10^6/L	5482	3200	1653	986	440	259	19	5
Glucose, mmol/L	0.04	0.01	0.03	1.5	1.07	1.99	2.02	2.53
Chlorine, mmol/L	108	103	107	105	97	110	113	115.96

Abbreviations: CSF, cerebrospinal fluid; WBC, white blood cell.

Figure 1

MRI imaging of case 1.

Table 2

Antibiotics Susceptibility Tests for Acinetobacter baumannii in CSF of case 1

Antimicrobial Agent	MIC (μg/mL)	Susceptibility
Tigecycline	2	Susceptible
Piperacillin-tazobactam	>64	Resistant
Ciprofloxacin	>2	Resistant
Amikacin	>32	Resistant
Imipenem	>8	Resistant
Meropenem	>8	Resistant
Ceftazidime	>16	Resistant
Levofloxacin	>8	Resistant
Trimethoprim–sulfamethoxazole	>2/38	Resistant
Cefoperazone-sulbactam	18	Intermediate
Cefepime	>16	Resistant
Ampicillin	>16/8	Resistant

Figure 2

The appearances of CSF before and after treatment of case 1.

Case 2 A male patient, 80 years old, accepted the operation of craniotomy removal of the frontal meningiomas. The MRI imaging was shown in Figure 3. At the first day after surgery, the patient got high fever 39°C, it showed a high level of white blood cell and a low level of both glucose in the laboratory tests for cerebrospinal fluid (CSF) (Table 3) of him. At the same time, Stagoscopy of the cerebrospinal fluid reminded gram negative bacilli, and then the CSF sputum culture showed he was infected with XDRA baumannii (Table 4), we chose the scheme of tigecycline+cefoperazone-sulbactam. We carried out the therapeutic schedule of intrathecal tigecycline therapy after permission from the hospital ethics committee and his family members. We injected 5mg tigecycline into Lumbar cisterna drainage tube and then closed the Lumbar cisterna drainage tube about 2 hours. This patient tolerated the treatment well. After 3 days, his fever improved, and his CSF culture became negative 1 weeks later, with normal levels of white blood cell, glucose. His temperature decreased to normal and all symptoms disappeared at the same time. We stopped the intrathecal tigecycline therapy. In the next 3 days, the CSF cultures were all negative, in that case, the intracranial infection was effectively cured.(The appearances of CSF before and after treatment are shown in Figure 4, and the laboratory tests for CSF in the period of treatment are shown in Table 3). Intravenous antibiotics were stopped 2 weeks later, and the patient was recover well.

Figure 3

MRI imaging of case 2.

Table 3

Laboratory Tests for CSF in the Period of Treatment of case 2

Date	March	March	March	April	April	April	April	April
	24th	27th	30th	2nd	5th	8th	10th	27th
WBC, 10^6/L	8058	4200	2012	986	440	220	96	3
Glucose, mmol/L	0.15	0.42	0.98	0.97	1.07	2.13	2.32	3.6
Chlorine, mmol/L	116.1	113.66	117.7	116.7	118.6	119.6	123	122.3

Abbreviations: CSF, cerebrospinal fluid; WBC, white blood cell.

Table 4

Antibiotics Susceptibility Tests for Acinetobacter baumannii in CSF of case 2

Antimicrobial Agent	MIC (μg/mL)	Susceptibility
Ampicillin	>16/8	Resistant
Piperacillin-tazobactam	>64	Resistant
Ciprofloxacin	>2	Resistant
Amikacin	>32	Resistant
Imipenem	>8	Resistant
Meropenem	>8	Resistant
Ceftazidime	>16	Resistant
Levofloxacin	>8	Resistant
Trimethoprim–sulfamethoxazole	>2/38	Resistant
Cefepime	>16	Resistant
Cefoperazone-sulbactam	18	Intermediate
Tigecycline	2	Susceptible

Figure 4

The appearances of CSF before and after treatment of case 2.

Follow-Up

The two patients were recover well at 21 months of follow-up, they returned to normal life.

Discussion

BA is an opportunistic microorganism that exists widely in healthcare institutes.2 Patients with a history of ICU-stay are prone to BA infection,5 and even multiple drug-resistant BA infection,2,6 and central nervous system infections are mostly associated with craniocerebral trauma or craniocerebral surgery.7 Central system infection caused by BA accounts for 3.6%~11.2%,5 extremely poor prognosis of infection caused by BA or multi-resistant BA, with a high mortality rate. In case 1, the patient was teenagers with a history of ICU-stay. According to the Stagoscopy of the cerebrospinal fluid, we take therapeutic schedule of cefoperone sodium+tigecycline. Because of the poor blood brain barrier permeability of tigecycline, we carried out the therapeutic schedule of intrathecal tigecycline therapy. Liang et al7 summarized various combinations of antibiotics through a large number of intracranial cases of BA, they assigned patients to different groups according to whether they had intraventricular/intrathecal injection of antibiotic agents or cerebrospinal fluid (CSF) drainage therapy. They took different scheme according to the results of cerebrospinal fluid culture. Lauretti et al8 reported the scheme of intraventricular tigecycline 2 mg. It was reported that infection did not control until they changed to scheme of tigecycline 4 mg, the same to others.3,8–10 Considering the pure suppuricity of the patient’s cerebrospinal fluid, poor drainage and severe infection, we finally took intrathecal 5mg tigecycline. During the period, the patient’s Lumbar cisterna drainage was not fluent, but it can be pumped through the syringe, the drainage tube was unobstructed, it may be caused by low intracranial pressure. In case 2, the patient was an old male also with a history of ICU-stay. According to the results of cerebrospinal fluid culture, we take the same scheme, finally we controlled infection with Lumbar cisterna drainage tube. In the two cases, consolidated treatment of tiagecycline + cefoperidone continued after infection control, and with no recurrence after consolidation.

In the two cases, the laboratory tests for cerebrospinal fluid (CSF) showed a high level of white blood cell and a low level of glucose, if it happens to patients, we should be aware of the possibility of BA intracranial infection. The CSF is turbidity, Lumbar cisterna drainage was not fluent, especially in case 1, it is important to keep the drainage tube fluent. Liang et al7 reported large numbers of BA intracranial infection, they reached the conclusion that both intraventricular/intrathecal injection of antibiotic agents and CSF drainage are helpful for CSF sterilization, CSF drainage is the key to the treatment of BA intracranial infection.

To date, the most sensitive antibiotics for the treatment of BA intracranial infection are mainly polymucand and tigecycline.4,11–15 Polymytin family mainly contain polymytin B and polymytin E, but polymytin is less used in China and expensive. In the two patients, the polymytin was not accessible and was expensive, and there were no other more reasonable treatment. In that case, the teticycline was selected. Tecycline is a broad-spectrum glycine-negative bacterium and gram-positive coccus,4 which is better active for multiple drug-resistant pathogens. In the treatment of intraventricular/intrathecal tigecycline, the most common adverse reactions are digestive system symptoms, such as abdominal pain, nausea, vomiting, and there are also reports of other adverse drug reactions of intravenous teticycline. No drug effects have been reported.7–9 In case 1, when intrathecal tigecycline, the patient had obvious abdominal pain, it alleviated about 20 minutes. During the intraventricular/intrathecal tigecycline, the intraventricular/intrathecal tigecycline speed shall be as slow as possible and diluted with 10mL physiological saline, even using the micropump. The current clinical guidelines and tigecycline manual4,16 do not mention the way of intraventricular/intrathecal tigecycline. Intraventricular/intrathecal tigecycline is a hyperdrug manual, and the manual should be modified.

Conclusion

Tigecycline intravenous combined with intraventricular/intrathecal tigecycline is an effective way to cure BA infection. CSF drainage is the key to treat BA intracranial infection.