Cerebrospinal fluid concentrations of fluoroquinolones and carbapenems in tuberculosis meningitis

Abstract

Background: Tuberculosis meningitis (TBM) is the most lethal form of TB. It is difficult to treat in part due to poor or uncertain drug penetration into the central nervous system (CNS). To help fill this knowledge gap, we evaluated the cerebrospinal fluid (CSF) concentrations of fluoroquinolones and carbapenems in patients being treated for TBM.Methods: Serial serum and CSF samples were collected from hospitalized patients being treated for TBM. CSF was collected from routine lumbar punctures between alternating timepoints of 2 and 6 h after drug administration to capture early and late CSF penetration. Rich serum sampling was collected after drug administration on day 28 for non-compartmental analysis.Results: Among 22 patients treated for TBM (8 with confirmed disease), there was high use of fluoroquinolones (levofloxacin, 21; moxifloxacin, 10; ofloxacin, 6) and carbapenems (imipenem, 11; meropenem, 6). Median CSF total concentrations of levofloxacin at 2 and 6 h were 1.34 mg/L and 3.36 mg/L with adjusted CSF/serum ratios of 0.41 and 0.63, respectively. For moxifloxacin, the median CSF total concentrations at 2 and 6 h were 0.78 mg/L and 1.02 mg/L with adjusted CSF/serum ratios of 0.44 and 0.62. Serum and CSF concentrations of moxifloxacin were not affected by rifampin use. Among the 76 CSF samples measured for carbapenem concentrations, 79% were undetectable or below the limit of detection.Conclusion: Fluoroquinolones demonstrated high CSF penetration indicating their potential usefulness for the treatment of TBM. Carbapenems had lower than expected CSF concentrations.

A Difficult Case of Ventriculitis in a 40-Year-Old Woman with Acute Myeloid Leukemia

“…Vaborbactam was shown to permeate the CSF fluid effectively in all the measurements, while meropenem was undetectable. However, the low CNS penetration of meropenem and substantial interindividual variability have already been observed in the literature [28][29][30][31]. Unfortunately, for our patient, it was not possible to conduct therapeutic drug monitoring (TDM) due to laboratory limitations throughout the hospital stay.…”

Dynamic PET Reveals Compartmentalized Brain and Lung Tissue Antibiotic Exposures

“…Although brain tissue exposures for pyrazinamide are unknown in humans, PET imaging in non-human primates with a chemically identical radioanalog of pyrazinamide demonstrated excellent brain tissue exposures 35 , which were consistent with our data (mass spectrometry) from the mouse studies. Similarly, while moxi oxacin (Mx), active against several MDR strains of M. tuberculosis, has excellent CSF penetration 36,37 , brain tissue exposures are not known and our data from mouse studies demonstrated limited brain (tissue/plasma ratio 0.23) but excellent lung tissue penetration (tissue/plasma ratio 3.34). Overall, these data suggested that pretomanid and pyrazinamide based multidrug regimens could be highly effective in TB meningitis.…”

First case of meningoencephalitis and bacteraemia with Flavobacterium lindanitolerans

“…In our case Flavobacterium was resistant to sulfamethoxazole/trimethoprim, in contrast to other reported Flavobacteria , which were susceptible to this therapeutic agent. Based on the antimicrobial susceptibility testing with a low MIC and given the excellent central nervous system penetration of levofloxacin [ 12 ] , we chose this agent to treat the patient. Regarding duration of therapy, we treated the patient based on the guidelines for community acquired Gram-negative meningitis, according to which an antibiotic therapy of at least 21 days is recommended [ 1 ] .…”