Garenoxacin (BMS-284756) and moxifloxacin in experimental meningitis caused by vancomycin-tolerant pneumococci

Abstract

The emergence of multidrug-resistant strains of Streptococcus pneumoniae drives the development and evaluation of new antipneumococcal agents, especially for the treatment of bacterial meningitis. The aims of the present study were to assess the antibacterial effectiveness of two new quinolones, garenoxacin (BMS; BMS-284756) and moxifloxacin (MOX) in experimental meningitis caused by a vancomycin (VAN)-tolerant S. pneumoniae strain and to compare the results with those obtained by therapy with VAN and ceftriaxone (CRO) in combination. Meningitis was induced in young male New Zealand White rabbits by intracisternal inoculation of a VAN-tolerant pneumococcal strain (strain Tupelo) from a child with meningitis. Sixteen hours after inoculation, therapy was given by intravenous administration of BMS at 20 mg/kg of body weight, followed 5 h later by administration at a dosage of 10 mg/kg (n = 9 animals) or MOX as two doses of 20 mg/kg every 5 h (n = 8 animals). For comparison, we studied the following groups: (i) animals treated with VAN (20 mg/kg every 5 h, three doses) and CRO (125 mg/kg, one dose) (n = 9), (ii) animals infected with a VAN-tolerant strain but not treated (n = 8), (iii) animals infected with a VAN-tolerant pneumococcus isolated from the nasopharynx of a carrier and treated with BMS (n = 8), and (iv) animals infected with a cephalosporin-resistant type 6B S. pneumoniae strain and treated with BMS (n = 6). The MICs of penicillin, CRO, VAN, BMS, and MOX for the Tupelo strain were 2, 1, 0.5, 0.06, and 0.03 micro g/ml, respectively. The rates of killing of strain Tupelo (the change in the log(10) number of CFU per milliliter per hour) in cerebrospinal fluid at 5 h were -0.70 +/- 0.35, -0.61 +/- 0.44, and -0.49 +/- 0.36 for BMS, MOX, and VAN-CRO, respectively. Therapy with BMS and MOX was as effective as therapy with VAN-CRO against VAN-tolerant pneumococcal meningitis in rabbits.

FIG. 1.

Bacterial concentrations (means ± standard deviations) in CSF after the administration of different regimens in experimental meningitis caused by VAN-tolerant S. pneumoniae strain Tupelo. Animals were not treated (controls; solid diamonds) or were treated with BMS at 20 mg/kg, followed 5 h later by 10 mg/kg (solid circles), MOX at 20 mg/kg twice with the dosage administrations separated by 5 h (open triangles), or VAN at 20 mg/kg every 5 h for three doses in combination with CRO at 125 mg/kg as a single dose (open squares).

FIG. 2.

Bacterial concentrations in CSF after therapy with BMS (20 mg/kg, followed 5 h later by 10 mg/kg) in rabbits with meningitis caused by VAN-tolerant S. pneumoniae strain Tupelo (solid circles) and nasopharyngeal strains (open squares) and comparison of the results with those obtained with a VAN-susceptible type 6B strain (open triangles).