The Investigation on Nosocomial Infection of Acinetobacter baumannii and the Clinical Analysis of Sequential Therapy of Cefoperazone/Sulbactam Sodium for Intracranial Infection.

Background: Intracranial infection is a serious complication after neurosurgery. According to a survey, the incidence of intracranial infection is about 2.2%-2.6%, and patients with severe symptoms may even pose a threat to their life safety. Objective: To explore the risk factors for intracranial infection caused by Acinetobacter baumannii after surgery and the clinical effect of sequential therapy of cefoperazone/sulbactam sodium.
Methods: In this study, a retrospective study was used. In this case-control study, 48 cases of intracranial Acinetobacter baumannii infection after neurosurgery in our hospital from January 2016 to December 2021 were selected as the infection group, and 96 patients without intracranial infection after surgery during the same period were selected as the control group to study all kinds of related factors and analyze the risk factors for intracranial Acinetobacter baumannii infection; in addition, in accordance with the therapeutic regimen for anti-infection, the infection group was divided into the tigecycline group (patients with tigecycline therapy in this group) and the combined group (patients with tigecycline combined with cefoperazone/sulbactam sequential therapy), with 24 cases in each group in order to compare the therapeutic effects of the two groups.
Results: Logistic regression factor model results show that increasing age of patients, surgical treatment for intracranial tumor or craniocerebral trauma, postoperative drainage time (≥3 days), and postoperative hospital stay (≥10 days) were the risk factors for postoperative intracranial infection of Acinetobacter baumannii in neurosurgical patients (P < 0.05), and postoperative prophylactic antibiotic treatment can reduce the incidence of intracranial infection (P < 0.05). The cerebrospinal fluid nucleated cell count, serum CRP, and serum PCT in the combined group 72 h after treatment were lower than those in the tigecycline group, and the difference was statistically significant (P < 0.05). Compared with the clinical efficacy after 72-hour treatment, the cure rate and effective rate in the combined treatment group were 83.33% and 16.67%, respectively, and those in the tigecycline group were 54.17% and 33.33%, respectively. The invalid interest rate was 12.50%, and the combined treatment group was superior to the tigecycline group (P < 0.05).
Conclusion: For patients with craniocerebral surgery, targeted preventive interventions should be carried out for the risk factors that may lead to intracranial Acinetobacter baumannii infection. The clinical effect of tigecycline combined with cefoperazone and sulbactam sodium sequentially in the treatment of intracranial Acinetobacter baumannii infection is better.

1. Introduction

As one of the common serious complications after neurosurgery, intracranial infection can make the patient's condition complicated. The incidence of intracranial infection is about 2.2%-2.6%, which directly affects the disease outcome and prognosis of patients and even leads to death. With strong clonal transmission ability and susceptibility to drug resistance, Acinetobacter baumannii becomes a common pathogen causing intracranial infection. And the risk factors causing intracranial infection with Acinetobacter baumannii have been discussed clinically [1]. Active anti-infective therapy is the first choice for intracranial infection; however, the anti-infective treatment of intracranial infection requires not only strong killing effect on pathogens but also the ability to penetrate the blood-brain barrier and achieve high drug concentration locally [2].

Tigecycline, the glycylcycline antibiotic, is a commonly used therapeutic drug for intracranial infection caused by Acinetobacter baumannii. However, due to the current situation of bacterial resistance, a considerable number of patients are still cured ineffectively after tigecycline treatment [3]. Cefoperazone/sulbactam sodium is a compound preparation composed of cephalosporin antibiotics and sulbactam sodium, and sulbactam can protect the antibacterial effect of cefoperazone by inhibiting the activity of β-lactamase [4]. In order to better solve the problem of postoperative infection in neurosurgery, this study analyzed the risk factors for postoperative intracranial infection of Acinetobacter baumannii to help clinically avoid risks and observed the clinical effect of sequential treatment of cefoperazone sulbactam sodium to provide a reference for clinical medication. The relevant reports are as follows.

1.1. Core Tips

Due to the great harmfulness of intracranial infection caused by Acinetobacter baumannii after surgery, the effect of tigecycline therapy remains unsatisfactory. This study found that the risk factors for intracranial infection caused by Acinetobacter baumannii after surgery included increasing age of patients, surgical treatment for intracranial tumor or craniocerebral trauma, postoperative drainage time (≥3 days) and postoperative hospital stay (≥10 days), and postoperative prophylactic antibiotic treatment could reduce the incidence of intracranial infection, so more attention should be paid to avoiding risks in future clinical work. And the clinical effect of sequential therapy of tigecycline combined with cefoperazone/sulbactam sodium was better than that with tigecycline alone.

2. Materials and Methods

2.1. General Information

In this case-control study, 48 patients with intracranial Acinetobacter baumannii infection after neurosurgery in our hospital from January 2016 to December 2021 were selected as the infection group, and 96 patients without intracranial infection after surgery during the same period were selected as the control group.

Inclusion criteria include (1) having a history of craniocerebral surgery, (2) being 18–75 years old, and (3) the main clinical manifestations of the patients being at least 2 of the following 5 points: headache, fever, nausea, vomiting, and meningeal irritation. The request of the expert group was signed by all the participants. Exclusion criteria include (1) other types of infection, (2) previous history of viral meningitis, (3) persons with mental illness, and (4) a history of craniotomy or craniocerebral trauma.

2.2. Treatment Methods

The patients in the tigecycline group were treated with tigecycline (Pfizer Pharmaceutical Co., Ltd., manufacturer name: WyEthan Lederle S.r.L., specification: 50 mg, approved by Chinese medicine HJ20160471), while the patients in the combined group were treated with sequential therapy of tigecycline combined with cefoperazone/sulbactam sodium (the trade name is “Supushin,” Pfizer Pharmaceutical Co., Ltd., specification: 3.0 g, approved by Chinese medicine H10960113), and the dosage of tigecycline in this group was the same as that in the control group. Intravenous infusion of cefoperazone/sulbactam sodium was injected 2 times a day, 3.0 g each time. Both groups were treated for 4 consecutive weeks to evaluate the curative effect.

2.3. Observation Indexes and Detection Methods

The white blood cells (WBC) in cerebrospinal fluid, the count of nucleated cells in cerebrospinal fluid, procalcitonin (PCT) in cerebrospinal fluid, and serum C-reactive protein (CRP) in the two groups of patients before and after treatment were detected and compared. By analyzing the clinical application of antibiotics for inpatients in neurosurgery [5], the treatment effect was divided into three outcomes: cured (after treatment, the patients' clinical symptoms and signs completely disappeared, the laboratory indexes became normal, and bacteriological examination were confirmed negative), effective (the clinical symptoms, signs, and laboratory indexes of patients were better, one of which was not up to the standard, and bacteriological examination was confirmed negative), and ineffective (72 hours after treatment, patients did not get better).

Before treatment and 72 hours after treatment, 3 mL of cerebrospinal fluid was extracted from the patient to be detected by a microscope for WBC, the rest of which was centrifuged at 2500 r/min for 10 minutes. The supernatant was collected to detect the sugar content and the nucleated cell count in the cerebrospinal fluid. The reagent kit used in this study was made by the Beijing North Institute of Biotechnology, and the detection instrument used in the study was a microplate reader (Shenzhen Mindray Medical Electronics Co., Ltd., RT-96A). Before treatment and 72 hours after treatment, 2 mL of peripheral venous blood was drawn from patients as samples to be centrifuged at 3000 r/min for 10 minutes in a centrifuge. After that, the serum was collected to detect CRP and PCT. The reagent kit used in this study was made by the Beijing North Institute of Biotechnology, and the detection instrument used in the study was a microplate reader (Shenzhen Mindray Medical Electronics Co., Ltd., RT-96A).

2.4. Statistical Processing

In this study, the patients' WBC, CSF counts of nucleated cells, serum CRP, serum PCT, and other measurement indexes were examined by normal distribution, all of which were in line with approximately normal distribution or normal distribution and were expressed as . In the study, the T-test was used to compare the two groups; the χ2 test was used for the comparison of count data between groups; the logistic regression model was adopted for the multivariate model, and the enter method was used for variable selection; the data was processed by professional SPSS21.0 software with the test standard of α = 0.05.

3. Results

3.1. Univariate Analysis

The univariate method was used to analyze the differences in age, BMI, operation time, gender, and other indexes between the infection group and the control group. The results showed that the age, prevalence rate of chronic obstructive pulmonary disease, the number of intracranial tumor, the number of craniocerebral trauma, postoperative drainage time (≥3 days), and postoperative hospital stay (≥10 days) in the infection group were significantly more than those in the control group. The proportion of patients with prophylactic use of antibiotics in the infection group was lower than that in the control group, and the difference was statistically significant (P < 0.05). See Table 1 for more details.

Table 1

Univariate analysis results.

Normal information	Infection group (n = 48)	Control group (n = 96)	t/χ2	P
Age (years)	66.4 ± 7.1	63.1 ± 6.8	2.705	0.008
BMI (kg/m2)	23.41 ± 1.55	23.28 ± 1.67	0.451	0.653
Operation time (min)	174.2 ± 22.5	170.7 ± 23.2	0.862	0.390
Gender (%)			0.508	0.476
Male	29 (60.42)	52 (54.17)
Female	19 (39.58)	44 (45.83)
Concomitant disease (%)
Hypertension	23 (47.92)	35 (36.46)	1.747	0.186
Diabetes	16 (33.33)	23 (23.96)	1.424	0.233
Coronary heart disease	6 (12.5)	8 (8.33)	0.633	0.426
Chronic obstructive pulmonary disease	15 (31.25)	14 (14.58)	5.527	0.019
Type of neurological disease (%)
Hypertensive intracerebral hemorrhage	11 (22.92)	34 (35.42)	2.327	0.127
Cerebral infarction	14 (29.17)	40 (41.67)	2.133	0.144
Intracranial tumor	12 (25)	7 (7.29)	8.761	0.003
Traumatic brain injury	8 (16.67)	5 (5.21)	5.116	0.024
Other	3 (6.25)	8 (8.33)	0.699	0.403
Prophylactic use of antibiotics (%)			5.116	0.024
Yes	40 (83.33)	91 (94.79)
No	8 (16.67)	5 (5.21)
Postoperative blood transfusion (%)			0.924	0.336
Yes	22 (45.83)	36 (37.5)
No	26 (54.17)	60 (62.5)
Postoperative drainage time (%)			12.382	0.000
≥3 d	25 (52.08)	22 (22.92)
<3 d	23 (47.92)	74 (77.08)
Postoperative hospital stay (%)			8.533	0.003
≥10 d	38 (79.17)	52 (54.17)
<10 d	10 (20.83)	44 (45.83)

3.2. Multivariate Analysis

This study took the occurrence of intracranial Acinetobacter baumannii infection as the dependent variable and took the statistically significant indexes including age, prevalence rate of chronic obstructive pulmonary disease, the number of intracranial tumor, the number of traumatic brain injury, postoperative drainage time, postoperative hospital stay, and prophylactic use of antibiotics as independent variables through the univariate analysis to establish a logistic regression factor model. And the results showed that increasing age of patients, surgical treatment for intracranial tumor or craniocerebral trauma, postoperative drainage time (≥3 days), and postoperative hospital stay (≥10 days) were the risk factors for postoperative intracranial infection of Acinetobacter baumannii in neurosurgical patients (P < 0.05), and postoperative prophylactic antibiotic treatment can reduce the incidence of intracranial infection (P < 0.05). See Table 2 for more details.

Table 2

Logistic multivariate analysis results.

Index	β	SE	Walds	P	OR	95% CI
Age	0.604	0.301	4.027	0.049	1.829	1.014	3.300
Chronic obstructive pulmonary disease	0.587	0.314	3.495	0.091	1.799	0.972	3.328
Type of neurological disease	0.718	0.327	4.821	0.041	2.050	1.080	3.892
Prophylactic use of antibiotics	0.594	0.264	5.063	0.038	1.811	1.080	3.039
Postoperative drainage time	0.773	0.328	5.554	0.031	2.166	1.139	4.120
Postoperative hospital stay	0.695	0.314	4.899	0.047	2.004	1.083	3.708
Constant term	1.103	0.627	3.095	0.058	3.013	0.882	10.298

3.3. Comparison of Laboratory Indexes before and after Treatment in Patients with Intracranial Infection

By detecting the laboratory indexes of the tigecycline group and the combination group before treatment and 72 hours after treatment, the number of nuclear cells in cerebrospinal fluid and serum CRP and PCT levels in the combination group after 72 hours of treatment were lower than those in the tigecycline group; the differences were statistically significant (P < 0.05). See Table 3.

Table 3

Comparison of laboratory indexes before and after treatment in patients with intracranial infection ().

Group	n	CSF WBC (10 × 106/L)		Serum CRP (mg/L)		Serum PCT (μg/L)
		Before therapy	Treatment 72 h	Treatment 72 h	Before therapy	Before therapy	Treatment 72 h
Tigecycline group	24	11.83 ± 1.95	8.11 ± 1.40	19.50 ± 4.41	7.52 ± 2.04	2.74 ± 0.77	0.41 ± 0.12
Joint group	24	11.55 ± 2.01	6.83 ± 1.63	21.07 ± 5.28	5.26 ± 1.83	2.68 ± 0.78	0.30 ± 0.10
t		0.49	2.918	-1.118	4.04	0.268	3.45
P		0.627	0.005	0.269	0	0.79	0.001

3.4. Comparison of Clinical Efficacy

72 hours after treatment, clinical curative effect comparison found in the combined treatment group of patients with cure rate was 83.33%, the effective rate was 16.67%, the treatment of patients with the tigecycline group was 54.17%, their effective rate was 33.33%, and the invalid rate was 12.50%. On this basis, the combination group was better than the tigecycline group (P < 0.05). See Table 4.

Table 4

Comparison of clinical efficacy (n (%)).

Group	n	Cure	In force	Invalid
Tigecycline group	24	13 (54.17)	8 (33.33)	3 (12.50)
Combined group	24	20 (83.33)	4 (16.67)	0 (0.00)
Z		-2.285
P		0.022

4. Discussion

The scope of intracranial infection involves brain tissue, spinal cord, and adjacent tissues. Certain studies showed that the intracranial infection rate after neurosurgery was 3.26%-9.40%, which was related to the destruction of the blood-brain barrier [6]. Postoperative opening central nervous system and cerebrospinal fluid circulation system, catheter drainage, tracheotomy, tracheal intubation, nasal feeding, and other factors will increase the risk of intracranial infection, and postoperative bloody cerebrospinal fluid is a good medium for bacterial reproduction [7]. Acinetobacter baumannii, a gram-negative bacillus, is not only a human conditional pathogenic bacteria but also a common pathogen that causes intracranial infections [8]. Most antibiotics cannot pass the blood-brain barrier, which results in difficulty and poor clinical efficacy in the treatment of intracranial infections [9]. The logistic regression factor model results in this study showed that increasing age of patients, surgical treatment for intracranial tumor or craniocerebral trauma, postoperative drainage time (≥3 days), and postoperative hospital stay (≥10 days) were the risk factors for postoperative intracranial infection of Acinetobacter baumannii in neurosurgical patients, and postoperative prophylactic antibiotic treatment can reduce the incidence of intracranial infection. In future clinical work, elderly patients, patients undergoing surgery due to intracranial tumor or traumatic brain injury, and patients with long postoperative drainage time and postoperative hospital stay should be regarded as high-risk groups of intracranial infection, and antibiotics should be used preventively before surgery to reduce the risk of infection.

Tigecycline, the glycylcycline antibiotics, has bacteriostatic effect on multidrug-resistant bacteria such as carbapenem-resistant Acinetobacter and Klebsiella pneumoniae, and its binding ability to bacterial ribosomes is stronger than that of other tetracycline antibiotics, so it is often used clinically in the treatment of complex skin and soft tissue infections, intra-abdominal infections, acquired pneumonia, and other diseases in adults [10]. Many studies showed that tigecycline had positive in vitro antibacterial activity against resistant Acinetobacter baumannii, but sole use of it may lead to resistant bacteria [11, 12]. Cefoperazone sulbactam sodium, the broad-spectrum antibiotic, has a certain therapeutic effect on respiratory tract infections, urogenital infections, intra-abdominal infections, bone and joint infections, intracranial infections, and skin and soft tissue infections caused by sensitive bacteria [13, 14].

In this study, it was found that the efficacy of sequential therapy of tigecycline combined with cefoperazone/sulbactam sodium was better than that of therapy of tigecycline alone. Immune response after intracranial infection will lead to higher WBC levels in blood and infected parts to remove pathogens, and the levels of WBC in cerebrospinal fluid after the destruction of the blood-brain barrier will also be higher [15]. After intracranial infection, the body's immune response leads to an increase in the level of WBC in the blood and local infection to eliminate pathogens, and the level of WBC in the cerebrospinal fluid and the count of nucleated cells in the cerebrospinal fluid increase after the breakdown of the blood-brain barrier [16]. Immune response after intracranial infection leads to elevated levels of blood and infected local nucleated cells (white blood cells, lymphocytes, and monocytes) to remove pathogens and increased cerebrospinal fluid nucleated cell count after blood-brain barrier damage. Cerebrospinal fluid lactate is a by-product of bacterial metabolism, whose level will not be influenced by blood lactate levels but will increase sharply after intracranial bacterial infection [17]. CRP and PCT are important diagnostic indexes and disease evaluation indexes in the early stage of bacterial infection, which can be higher in the early stage of infection. This study showed that the number of nuclear cells in cerebrospinal fluid, serum CRP, and serum PCT levels in patients treated with tigecycline combined with cefoperazone sulbactam sodium after 72 hours were lower than those in patients treated with tigecycline alone [18]. This study showed that 72 hours after tigecycline combined with cefoperazone and sulbactam sodium treatment, cerebrospinal fluid WBC, cerebrospinal fluid nucleated cell count, serum CRP, and serum PCT levels were lower than those in the tigecycline alone group. The above results suggest that the sequential therapy of tigecycline combined with cefoperazone/sulbactam sodium can better control intracranial infection in patients with intracranial Acinetobacter baumannii infection. This is because tigecycline can play an antibacterial role by binding to the 30S subunit of bacterial ribosome and inhibiting bacterial protein synthesis [19], and cefoperazone can exert its antibacterial effect by inhibiting bacterial cell wall synthesis. Although sulbactam sodium itself has no antibacterial effect, it has an irreversible inhibitory effect on the production of β-lactamase by gram-negative bacilli, reducing its effect on the efficacy of cephalosporin antibiotics [20]. In general, the three-drug components can exert synergistic effects through different pathways to better control intracranial infection.

To sum up, patients undergoing craniotomy are in need of targeted preventive intervention for risk factors that may lead to intracranial Acinetobacter baumannii infection; sequential therapy of tigecycline combined with cefoperazone/sulbactam sodium in patients with intracranial Acinetobacter baumannii infection has better clinical efficacy. Compared with previous studies, this study objectively and quantitatively reflected the efficacy of tigecycline combined with cefoperazone sulbactam sodium in the sequential treatment of intracranial Acinetobacter baumannii infection by detecting the number of nucleated cells in cerebrospinal fluid, serum CRP, serum PCT, and other indicators at 72 h after treatment, providing a reference for clinical medication. However, since only 48 patients with infection after craniotomy were selected in this study, the sample size after grouping was only 24 cases, which may have a certain bias on the results; more sample size should be accumulated to further explore the effect of tigecycline combined with cefoperazone sulbactam sodium in the sequential treatment of intracranial Acinetobacter baumannii infection.