Meropenem and Amikacin for Management of Post-Neurosurgical Infections from Acinetobacter baumannii

Abstract

Background:

Intra-cranial infection with Acinetobacter baumannii is a tough problem because of the presence of multi-resistance and poor drug penetration through the blood–brain barrier. Such intra-cranial infections can lead to serious complications and death. We retrospectively analyzed the culture results and clinical characteristics of patients with intra-cranial infections in our hospital and suggested intravenous (IV) meropenem and intra-thecal (IT) amikacin therapy may be effective in the management of A. baumannii infection.

Case presentation:

We reported four cases of post-neuro-surgical A. baumannii intra-cranial infection whose clinical futures were high fever and consciousness disturbance. Our patients were treated successfully with IV meropenem and IT amikacin.

Conclusion:

We presented our cases of pandrug-resistant A. baumannii intra-cranial infection that was managed successfully with a systemic provision of IV meropenem and IT amikacin. Therefore, these cases exemplify that systemic administration of IV meropenem and IT amikacin can be a good therapeutic option against A. baumannii intra-cranial infection when colistin is not available.

Post-operative nervous system infection is a common complication of neuro-surgical operation, and the incidence rate accounts for 0.8%–7% of intra-cranial infections [1]. The most common pathogens are gram-negative bacilli and Staphylococcus aureus, but in recent years Acinetobacter baumannii has emerged as a main infectious agent in hospitals worldwide [2]. Post-neuro-surgical A. baumannii infection is usually multi-drug resistant (MDR); there is even pandrug resistance to carbapenems, compound sulfamethoxazole, and sulbactam because of its ability to tolerate desiccation and to accumulate diverse mechanisms of resistance [3]. The management of such infections is challenging, with a high associated mortality rate ranging from 20% to 40% [4].

Although multi-drug resistant/extensively drug resistant-A. baumannii (MDR/XDR-Ab) is resistant to multiple antibiotic agents, previous studies indicate that currently it is still susceptible to polymyxins. In view of the high molecular weight of polymyxins and the existence of the blood–brain barrier, the treatment of intravenous (IV) combined with intra-thecal (IT)/intra-cerebral ventricle injection is applied to achieve an effective therapeutic concentration [5].

Tigecycline showed marvelous activity against MDR A. baumannii in vitro, but it has poor penetration through the blood–brain barrier, resulting in poor effectiveness for intra-cranial infection. In addition, at present this drug can be administered only IV. Recent case reports and case series, however, provided information that treatment with continuous ventricular irrigation and intra-ventricular (IVT) tigecycline may be effective [6]. Although polymyxins and tigecycline have a certain effect in A. baumannii infection treatment, nerve toxicity and other side effects have limited their application. The colistin-associated neurotoxicity incidence is reported up to 21.7% [7].

Besides considering the high prices and unavailability of these drugs for a lot of hospitals in China, an alternative treatment option is needed urgently. In this report, we demonstrate the clinical characteristics of A. baumannii in our hospital and describe the use of IV meropenem in conjunction with IT amikacin for management of intra-cranial infection from A. baumannii.

Patients and Methods

Patients and procedures

A retrospective study was performed at Suizhou Hospital Affiliated to Hubei Medical College in Hubei, China. Records of all patients with nosocomial meningitis who received the diagnosis more than 48 hours after their admission to hospital during 2013 to 2017 were reviewed. There were 45 (60%) males and 30 (40%) females, with age ranging from 26 to 79 years (mean age 53.6 years). The patients were identified by reviewing cerebrospinal fluid (CSF) cultures analyzed in the hospital's microbiology laboratory. The isolates of pathogenic bacteria were identified with the Bio-Merieux API^® System. A disk diffusion method was used to determine antibiotic susceptibility.

Other diagnostic criteria applied in establishing the diagnosis were fever, elevated white blood cell (WBC) counts in the blood and CSF, altered consciousness, meningeal signs, raised intra-cranial pressure, and elevated CSF protein and glucose levels [8]. Ethical committee approval for this study was obtained from the Suizhou Hospital Affiliated to Hubei Medical College

Statistical analysis

All statistical analyses were performed using SPSS 19.0 for Windows. The Fisher exact test was used to evaluate the difference in proportions. A p value <0.05 was considered statistically significant.

Results

Pathogen distribution

All kinds of bacteria were highly concentrated and widely distributed. The Staphylococcus detection rate is highest—a total of 57 (70.3%) strains, including 16 (19.7%) strains of S. epidermidis, 10 (12.3%) strains of S. haemolyticus, and five (6.17%) strains of S. aureus. Ten (12.3%) strains of A. baumannii were isolated, ranking second (Table 1).

Table 1.

Pathogen Distribution in Intra-Cranial Infection (%)

Pathogens	No.	Percentage
Gram-positive bacterium	64	79.0
Staphylococcus aureus	5	6.17
Staphylococcus hominis	2	2.5
Staphylococcus capitis	10	12.3
Staphylococcus epidermidis	16	19.7
Staphylococcus sciuri	6	7.4
Staphylococcus warneri	2	2.5
Staphylococcus lentus	4	4.9
Staphylococcus haemolyticus	10	12.3
Staphylococcus cocci	2	2.5
Enterococcus faecalis	1	1.2
Enterococcus faecium	6	7.4
Gram-negative bacterium	17	21.0
Escherichia coli	1	1.2
Klebsiella pneumoniae	2	2.5
Pseudomonas aeruginosa	1	1.2
Acinetobacter baumannii	10	12.3
Flavoroid	1	1.2
Hermann Escherichia coli	1	1.2
Sphingomonas paucimobilis	1	1.2
Total	81	100

Antibiotic susceptibility

There were 27 (90.0%) strains of MDR bacteria among the three kinds of common intra-cranial infection isolates. A. baumannii is highly resistant to most antimicrobial agents. The drug tolerance rates to amikacin, imipenem, compound sulfamethoxazole, and levofloxacin are relatively lower, but the rates for polymyxin and tigecycline are unknown. S. aureus has high resistance to tetracycline, levofloxacin, oxacillin, erythromycin, but is sensitive to tigecycline, vancomycin, linezolid, rifampicin, and moxifloxacin. Staphylococcus epidermis strains are resistant to oxacillin, erythromycin, ciprofloxacin, and penicillin, but susceptible to gentamicin, tigecycline, vancomycin, linezolid, rifampicin, and moxifloxacin (Table 2).

Table 2.

Susceptibility of Common Intra-Cranial Infection Isolates (%)

Antibiotic	A. baumannii (n = 10)			S. aureus (n = 5)			S. epidermidis (n = 15)
Antibiotic	No.	R	S	No.	R	S	No.	R	S
Gentamicin	10	100	0	5	40	60	15	6.7	93.3
Tetracycline				5	80	20	15	33.3	66.7
Tigecycline				5	0	100	15	0	100
Vancomycin				5	0	100	15	0	100
Levofloxacin	8	60	40	5	80	20	15	13.3	86.7
Linezolid				5	0	100	15	0	100
Oxacillin				5	100	0	15	100	0
Compound
Sulfamethoxazole	8	87	13	5	20	80	15	80	20
Rifampicin				5	0	100	14	0	100
Erythrocin				5	100	0	15	93.3	6.7
Clindamycin				5	100	0	15	86.7	13.3
Penicillin				5	100	0	15	100	0
Ciprofloxacin	10	100	0	5	80	20	15	60	40
Moxifloxacin				5	20	80	15	0	100
Piperacillin/Tazobactam	2	100	0
Aztreonam	2	100	0
Ceftriaxone	10	100	0
Macrodantin	10	100	0	5	0	100
Ampicillin/Sulbactam	9	100	0
Tobramycin	10	100	0
Amikacin	8	50	50
Ceftazidime	10	100	0
Cefepime	10	100	0
Imipenem	8	87	13

R = resistant; S = sensitive.

Clinical characteristics

We chose 10 cases randomly of other pathogens to be compared with 10 cases of A. baumannii samples. The risk factors of the comparison are gender, diagnosis, surgical history, tracheotomy, ventricular drainage, and lumbar cistern drainage, CSF leakage, pulmonary infection (A. baumannii), duration of hospitalization, MDR bacteria, and prognosis. Because of fewer samples (n < 40), we used the Fisher exact test to analyze the differences. We found that patients with A. baumannii intra-cranial infections tended more to have had tracheotomy, lumbar cistern drainage, and pulmonary infection (A. baumannii) than other bacteria (Table 3).

Table 3.

Clinical Characteristics of Acinetobacter baumannii

Risk factors	A. baumannii (n = 10)		Other pathogens (n = 10)		Fisher
Risk factors	No.	Percentage (%)	No.	Percentage (%)	Fisher
Gender
Male	6	60	5	50	1.0
Female	4	40	5	50
Diagnosis
Intra-cranial hemorrhage	5	50	5	50	1.0
Brain injury	5	50	5	50
Surgical history
Craniotomy	6	60	6	60	1.0
Trepanation	4	40	4	40
Tracheotomy
Yes	10	100	4	40	0.011^*
No	0	0	6	60
Brain drainage
Yes	5	50	4	40	1.0
No	5	50	6	60
Lumbar cistern drainage
Yes	5	50	0	0	0.033^*
No	5	50	10	100
Leakage of cerebrospinal fluid
Yes	1	10	1	10	1.0
No	9	90	9	90
Pulmonary infection (A. baumannii)
Yes	8	70	2	20	0.023^*
No	2	30	8	80
Prognosis
cured	4	40	6	60	0.656
died	6	60	4	40
MDR
Yes	10	100	6	60	0.087
No	0	0	4	40
Duration of hospitalization
≤40 d	5	50	4	40	1.0
>40 d	5	50	6	60

MDR = multi-drug resistant.

p < 0.05; pulmonary infection (Acinetobacter baumannii); pulmonary infection by A. baumannii.

Case Reports

Case 1

July 5, 2018. A 28-year-old female was admitted to the hospital because of a brain injury. The diagnosis was fronto-temporal top subdural hematoma, right frontal pillow parietal lobe contusion concurrent with hematoma; decompressive craniotomy was performed as an emergency. On the second day, she underwent tracheotomy. Cefoperazone/tazobactam was administered empirically to prevent infection.

On July 9, the brain drainage tube was pulled out. On July 10 and July 12, lumbar puncture was performed, and the color of the CSF was blood red. On July 14, lumbar cistern drainage was placed, and the CSF was light red. Pseudomonas aeruginosa was isolated from sputum culture on July 14, and then aztreonam was administered. On July 28, the patient had persistent high fever, stiff neck, and turbid yellow CSF. The CSF culture result indicated XDR A. baumannii, sensitive to amikacin. Antibiotic agents were immediately upgraded to IV meropenem (2 g q8h); meanwhile, amikacin (20 mg) and dexamethasone (2.5 mg) were injected through the lumbar cistern drainage tube. The drainage tube was closed for about one hour, then opened.

On July 31, the drainage tube was removed. Therapy with IT amikacin and dexamethasone was started through intermittent lumbar puncture. 08.10, 08.15, 08.19 The CSF culture results on August 10, 15, and 19 were negative, and results of CSF biochemical analysis returned to normal. The patient's consciousness improved gradually.

Case 2

September 23, 2015. A 62-year-old male was admitted to the hospital because of a small cerebral hemorrhage. Decompressive craniotomy and lateral ventricle drainage were performed on an emergency basis under general anesthesia. Tracheotomy was performed on the second day. Latamoxef was administered for infection prevention. On September 29 and October 5, lumbar puncture was performed, and CSF was blood red. On October 10, results of sputum culture indicated MDR A. baumannii. The antibiotic agent was replaced by cefoperazone/sulbactam.

By October 13, the patient's level of consciousness had deteriorated; he also had persistent high fever and a stiff neck. The CSF culture results showed XDR A. baumannii. At that point, IV meropenem (2 g q8h) and etimicin therapy was started. In the meantime, IT amikacin (20 mg) and dexamethasone (2.5 mg) were employed. The peak temperature of the patient dropped below 38.0C after 24 hours. On October 19 and 21, results of CSF culture were negative. The patient's body temperature dropped to normal gradually, and his level of consciousness improved.

Case 3

June 23, 2017. A 46-year-old male was admitted to the hospital because of thalamic hemorrhage, and external ventricular drainage was performed under general anesthesia. Ceftriaxone/tazobactam were administered post-operatively. On June 29, lumbar cistern drainage was performed, and on July 4, he underwent tracheotomy under local anesthesia. On July 15, Klebsiella pneumoniae was isolated from sputum culture, at which point sensitive aztreonam was added to the antibiotic regimen.

On July 16, the patient had persistent high fever and his level of consciousness deteriorated; CSF obtained by lumbar drainage was yellow and turbid. At that time, IV meropenem (2 g q8h) and aztreonam therapy was initiated. On July 17, the lumbar cistern drainage was removed. On July 18, IT amikacin (20 mg) and dexamethasone (2.5 mg) were administered through intermittent lumbar puncture. By July 23 and 25, results of CSF cultures were negative, and body temperature dropped. The patient was discharged from the hospital after two weeks.

Case 4

December 14, 2017. A 32-year-old male was admitted to the hospital because of a brain injury, and emergency decompressive craniotomy was performed under general anesthesia. Pipercillin/sulbactam was administered to prevent infection. On December 16, tracheotomy was performed, and four days later the head hematoma cavity drainage tube was removed. On December 21, lumbar puncture was performed, and CSF was pink and turbid.

By December 22, the patient had high fever that diminished after levofloxacin was added. On January 6, lumbar cistern drainage was performed. On January 8, the patient was shown to have persistent high fever. On January 12, S. sciuri was isolated from CSF cultures. Vancomycin (2.5 mg) and dexamethasone (2.5 mg) were injected through the lumbar cistern drainage tube. The drainage tube was closed for about one hour and then opened.

On January 13, A. baumannii was isolated from sputum culture. Then IV meropenem (1 g q8h) and etimicin therapy was started. By January 19, the patient's high fever had returned. Cultures from the purulent secretion and CSF yielded XDR A. baumannii. The lumbar cistern drainage tube was removed, and meropenem was increased to 2g q8h. On January 20, IT amikacin (20 mg) and dexamethasone (2.5 mg) was administered through intermittent lumbar puncture. Results of CSF culture on February 1, 5, and 8 were negative, and body temperature dropped to normal gradually.

Four patients died in hospital after intra-cranial infection. For two patients, family members gave up treatment, and the patients died after hospital discharge.

Discussion

The study collected 75 cases of CSF specimens and related clinical data from our hospital. We isolated 81 strains of bacteria, including five cases of mixed infection. In a previous report, Wu et al. [9] had also demonstrated mixed bacteria in intra-cranial infection. This shows that mixed infection exists in meningitis. Our culture results showed gram-positive bacteria have the highest detection rate (79.0%), including S. epidermidis (19.7%) ranking first and then A. baumannii (12.3%). The results are consistent with the China Antimicrobial Surveillance Network (2017) reports [10]. In addition, cephalic staphylococci (12.3%) and S. haemolyticus (12.3%) as follows, which may reflect the differences of the region and hospital infection.

By analyzing the drug susceptibility results of various strains, we found that the drug resistance of both gram-positive and gram-negative bacteria is very serious—for example, that of gram-positive bacteria, S. aureus and S. epidermidis. The proportion of methicillin-resistant S. aureus is as high as 100%. For erythromycin and clindamycin, the resistance rate is also 100%, and the rate of tetracycline, levofloxacin, and ciprofloxacin is very high. These antibiotic agents should not be used for empiric treatment.

As for tigecycline, vancomycin, linezolid, rifampicin, moxifloxacin, and gentamicin, these medicines are more sensitive. Vancomycin is an empiric choice for management of MDR S. aureus. The proportion of methicillin-resistant S. epidermidis is also as high as 100%, while it is more sensitive to tigecycline, vancomycin, linezolid, rifampicin, moxifloxacin, gentamicin, and levofloxacin.

The situation of resistant gram-negative bacteria is more serious, especially that of A. baumannii, which is resistant to almost all antibiotics. The China Antimicrobial Surveillance Network (2017) indicated its rates of drug resistance to imipenem and meropenem are 66.7% and 69.3%, respectively; to cefoperazone/sulbactam and minocycline are 43.5% and 44.4%, respectively; to polymyxin B and tigecycline are 0.1% and 6.0%, respectively; and to others are above 40% [10].

Our hospital's A. baumannii susceptibility results show no data for cefoperazone/sulbactam, minocycline, polymyxin B, and tigecycline, but its resistant rates to gentamicin, ciprofloxacin, piperacillin/tazobactam, aztreonam, and ceftriaxone are all 100%; A. baumannii is only partly sensitive to amikacin, compound sulfamethoxazole, and imipenem.

The proportion of intra-cranial infection caused by A. baumannii is increasing steadily. The risk factors are blood–brain barrier damage for injury or neuro-surgical procedure, ventricular drainage tube placement, the application of high-dose corticosteroids, post-operative CSF leakage, the use of antibacterial drugs, etc. [11]. This article reports 10 cases of A. baumannii infection, which all involve patients undergoing neuro-surgical operations. Five patients had IVT external drainage, five underwent lumbar cistern drainage, and one had CSF leakage. These patients are all high-risk groups for intra-cranial infection. We selected randomly 10 cases of other intra-cranial bacterial infection to be compared with A. baumannii in gender, diagnosis, surgical history, tracheotomy, ventricular drainage and lumbar cistern drainage, CSF leakage, pulmonary infection (A. baumannii), duration of hospitalization, MDR bacteria, and prognosis.

We found that there are significant statistical differences in tracheotomy, lumbar cistern drainage, and lung infection (A. baumannii). Lumbar cistern drainage can be used in the management of ventricular hemorrhage, intra-cranial infec tion, subarachnoid hemorrhage, CSF leakage, etc. [12], but post-operative intra-cranial infection could occur from mismanagement. Tracheotomy is an invasive operation, and patients with neuro-surgical procedures have damaged blood-brain barrier and reduced immune function. These procedures increase the risk of MDR bacterial infection.

Interestingly, we found that 80% of patients with A. baumannii intra-cranial infection had sputum cultures with A. baumannii. We speculate that the pathogenic bacterium of intra-cranial infection is very likely from lung infection. Therefore, lung infection from A. baumannii should be cured simultaneously in the management of A. baumannii intra-cranial infection. Our case reports, however, are limited by few samples. More samples should be accumulated for further study.

In the management of A. baumannii intra-cranial infection, sensitive antimicrobial agents that can traverse the blood–brain barrier effectively should be considered primarily. For MDR-Ab, XDR-Ab, and PDR-Ab infection, it is recommended that combination therapy often take four to six weeks. Meropenem (6 g IV) was recommended for A. baumannii infection. When there is resistance to carbapenems, cefoperazone/sulbactam can be used. For XDR-Ab or PDR-Ab, combination medication or polymyxin B should be considered [13].

Sacar et al. [14] reported IV application of high-dose meropenem can be used for the management of intra-cranial infection caused by A. baumannii. Under normal circumstances, the transmittance of meropenem into the CSF is very low (1–10%). Lodise et al. [15] reported that the median (inter-quartile range) penetration of meropenem into the CSF, as measured by the area under the curve (AUC)CSF/AUC serum ratio, was 4% (2%–8%), but the severe meninges inflammation reaction could increase this ratio to as high as 39%.

Studies have shown that patients with intra-cranial infection received meropenem, 2 g IV over 30 minutes. The concentration maxima of meropenem in the ventricular CSF observed are high enough to kill fully susceptible pathogens [16]. Because of the large amounts of meropenem use in clinical practice, however, the drug resistance of A. baumannii has increased gradually to 69.3% [10]. According to the pharmacokinetic/pharmacodynamic drug adjustment method, extending the dosing time and increasing the dose can improve the drug concentrations and enhance antibacterial effect [14,17]. Therefore, in this article, four cases of A. baumannii intra-cranial infection were managed successfully with high-dose IV meropenem (2 g q8h).

To strengthen the antibacterial effect and reduce the risk of drug resistance, we use aminoglycosides in combination. Some research indicated that IVT aminoglycosides have been used in the therapy of Acinetobacter meningitis [18]. Most of these reports involve use of IVT aminoglycosides in combination with systemically administered antibiotic agents (such as carbapenems and polymyxins). Amikacin is a kind of half synthetic aminoglycoside antibiotic agent kills bacteria by inhibiting protein synthesis. Amikacin seems to have greater in vitro activity against Acinetobacter than gentamicin [19], but the poor penetration of aminoglycosides through the blood–brain barrier means that IV administration can only result in low CSF concentrations. Therefore, in our study, the IT route of amikacin was used in management of meningitis combined with IV meropenem.

In a recent study by Longo et al. [20], A. baumannii shunt-related meningitis and other catheter-related infections were related to biofilm-forming strains. Therefore, ventricular shunts should be removed entirely or replaced with external drainage in the situation of catheter-related meningitis. In our study, there are three cases of post-neuro-surgical Acinetobacter meningitis after placement of lumbar cistern drainage. We suspected the infection was catheter related and removed the lumbar drainage tube, performed intermittent lumbar puncture for IT drug administration and reduction of intra-cranial pressure.

Conclusion

Acinetobacter meningitis has emerged as a major relevant world nosocomial pathogen. Post-neuro-surgical intra-cranial infection is a serious complication when MDR A. baumannii are isolated. In this article, we reported four cases of patients with A. baumannii intra-cranial infection who were treated with IV meropenem and IT amikacin. The drug strategy could be a treatment option against A. baumannii when colistin is not available. In our practice, we treated four patients successfully with pandrug-resistant A. baumannii intra-cranial infection. Therefore, even though A. baumannii is resistant to most other potent antimicrobial agents, systemic provision of IV meropenem and IT amikacin should not be undermined.

Footnotes

Author Disclosure Statement

No competing financial interests exist.

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