Low Tigecycline Concentrations in the Cerebrospinal Fluid of a Neutropenic Patient with Inflamed Meninges

Abstract

Nosocomial infections with multidrug-resistant (MDR) pathogens are a life-threatening complication, especially in patients with prolonged neutropenia after intensive chemotherapeutic regimens. Tigecycline belongs to the novel glycylcycline extended-spectrum antibiotics exhibiting activity against a broad range of MDR pathogens, including methicillin-resistant staphylococci, vancomycin-resistant enterococci, penicillin-resistant streptococci, extended-spectrum β-lactamase (ESBL)-producing Escherichia coli and Klebsiella pneumonia, and carbapenem-resistant Acinetobacter baumannii strains (1, 4, 5, 11). Despite its high efficacy against MDR pathogens, tigecycline is currently not recommended in cases of meningeal infections, based on data showing modest penetration to the cerebrospinal fluid (CSF) in healthy volunteers (7, 9). However, inflamed meninges may facilitate penetration to the CSF (3). No pharmacodynamic studies are available, but recently successful treatment has been reported in patients with MDR pathogen-induced meningitis receiving parenteral tigecycline (2, 8, 10). To test this hypothesis, we assessed tigecycline concentrations in the CSF of a 33-year-old male patient with acute lymphoblastic leukemia who was developing Enterococcus faecium-induced meningitis. The patient was initially subjected to chemotherapy and external ventricular drain for hydrocephalus due to spontaneous intracerebral and subarachnoidal bleedings. Three weeks later, altered consciousness was observed, and CSF collected through the ventricular drain showed a high number of Enterococcus faecium CFU. In vitro testing revealed bacterial strains resistant to ampicillin, erythromycin, and ciprofloxacin and susceptible to vancomycin, linezolid, and tetracycline. After 4 weeks of frustrane therapy with parenteral vancomycin and a change of the ventricular drain device, parenteral tigecycline (50 mg twice a day [BID]) was added to the treatment. Tigecycline concentrations were measured in plasma and CSF samples after 11 days of treatment, ensuring that the patient was at steady state, by liquid chromatography/tandem mass spectrometry (LC/MS-MS; performed according to FDA and EMEA standards). This technique combines high-pressure liquid chromatography with mass spectrometry and represents at present the most advanced bioanalytical technique for drug measurement in plasma or tissues. CSF samples were collected through the ventricular drain. We then assessed comparable steady-state levels in samples collected within 5 to 9 h after exposure to 50 mg tigecycline (plasma, 0.0366 ± 0.0014 μg/ml [mean ± standard deviation]; CSF, 0.031 ± 0.0045 μg/ml; t test, P = 0.2) and identical trough levels of tigecycline (plasma, 0.0254; CSF, 0.0250 μg/ml). Calculations of the AUC (area under the concentration-time curve) and the ratio between CSF and plasma yielded identical values (0.85). Peak levels assessed in plasma 30 min after infusion (0.232 μg/ml) could not be reproduced in CSF analyzed at a corresponding point in time (0.0386 μg/ml), although some bias may have been introduced by the collection of CSF through the ventricular drain system. Tigecycline treatment was sustained for 12 days and administered in combination with ceftazidime. The patient was neutropenic >90% of the time during the course of treatment. Levels in CSF were constantly lower than the Enterococcus faecium MIC measured in our patient (0.08 ± 0.02 μg/ml) and inferior to reported tigecycline MICs for other pathogens (6). Enterococcus faecium was not eradicated from CSF, probably due to insufficient local concentrations of tigecycline, especially in the presence of a foreign body (ventricular drain) in the CSF. Our data suggest a higher penetration of tigecycline to the CSF in cases of inflamed meninges than in reported patients with noninflamed meninges where CSF peak levels maximally reached 41% of the corresponding plasma levels (10). However, drug levels may still remain too low for efficient treatment of meningitis at the studied dose level of 50 mg BID.