Daptomycin in experimental murine pneumococcal meningitis

Abstract

Background: Daptomycin, a lipopeptide antibiotic, could be an alternative to vancomycin for treatment of pneumococcal meningitis. We determined the activity of daptomycin versus vancomycin, with dexamethasone as an adjuvant, in a murine model of pneumococcal meningitis.

Methods: Ninety-six 25-30 gram mice were inoculated intracisternally with serotype 3 Streptococcus pneumoniae modified by the integration of a luminescent lux operon. All mice were treated with either dexamethasone 1 mg/kg intraperitoneally every 6 hours alone or in combination with either vancomycin or daptomycin, also administered intraperitoneally. Serum antimicrobial concentrations were selected to approximate those achieved in humans. Following treatment, bioluminescence and cerebrospinal fluid (CSF) bacterial concentrations were determined. Caspase-3 staining was used to assess apoptosis on brain histopathology.

Results: Sixteen hours post intracisternal inoculation, bacterial titers in CSF were 6.8 log10 cfu/ml. Amongst the animals given no antibiotic, vancomycin 50 mg/kg at 16 and 20 hours or daptomycin 25 mg/kg at 16 hours, CSF titers were 7.6, 3.4, and 3.9 log10 cfu/ml, respectively, at 24 hours post infection (p-value, < 0.001 for both vancomycin or daptomycin versus no antibiotic); there was no significant difference in bactericidal activity between the vancomycin and daptomycin groups (p-value, 0.18). CSF bioluminescence correlated with bacterial titer (Pearson regression coefficient, 0.75). The amount of apoptosis of brain parenchymal cells was equivalent among treatment groups.

Conclusion: Daptomycin or vancomycin, when given in combination with dexamethasone, is active in the treatment of experimental pneumococcal meningitis.

Figure 1

Time kill assay. Bactericidal activities of daptomycin (1 μg/ml) or vancomycin (2 μg/ml) are not affected by dexamethasone (100 μg/ml). DP, daptomycin; VN, vancomycin; DX, dexamethasone.

Figure 2

Serum antibiotic concentration after a single intraperitoneal dose of vancomycin (50 mg/kg) or daptomycin (25 mg/kg).

Figure 3

Concentrations of Streptococcus pneumoniae in cerebrospinal fluid. Concentration of S. pneumoniae in cerebrospinal fluid after 0, 4 and 8 hours of intraperitoneal injection of dexamethasone (administered at 0 and 6 hours) alone (DX), daptomycin (administered at 0 hours) and dexamethasone (administered at 0 and 6 hours) (DX/DP), or vancomycin (administered at 0 and 4 hours) and dexamethasone (administered at 0 and 6 hours) (DX/VN).

Figure 4

Representative bioluminescence images. Representative bioluminescence images taken using the Lumazone Imaging System after 0, 4 and 8 hours of treatment with dexamethasone (administered at 0 and 6 hours) alone (DX), daptomycin (administered at 0 hours) and dexamethasone (administered at 0 and 6 hours) (DX/DP), or vancomycin (administered at 0 and 4 hours) and dexamethasone (administered at 0 and 6 hours) (DX/VN). Photons/second are displayed on a calibrated color overlay (blue = low, through red = high).

Figure 5

Correlation between bacterial cerebrospinal fluid concentration and chemiluminescence (Pearson's R, 0.75; P < 0.0001).

Figure 6

Photomicrographs of brain from pre-treatment (16 hours) mice. Upper panels; H&E 400× left, caspase-3 400× right, and lower panels; H&E 400× left; cresyl echt violet 500× right. Meninges of the cerebellum showed a mild infiltrate of neutrophils (upper left panel), exhibiting multifocal positivity with the apoptosis marker (upper right panel). Foci of necrosis with hemorrhage in the brain stem (lower left panel), focally infiltrated by neutrophils and associated with bacterial cocci (lower right panel), were noted.