R. Nau et al., ACTIVITY OF FOSFOMYCIN IN A RABBIT MODEL OF EXPERIMENTAL PNEUMOCOCCALMENINGITIS, Journal of antimicrobial chemotherapy, 36(6), 1995, pp. 997-1004
Fosfomycin is an antibacterial substance of low molecular weight and n
egligible binding to plasma proteins exhibiting in-vitro activity agai
nst most pathogens involved in bacterial meningitis including pneumoco
cci. Due to these properties the drug has been recommended for therapy
of central nervous system (CNS) infections. For this reason, fosfomyc
in at doses of 10, 40, 80 and 160 mg/kg/h iv, was investigated in the
rabbit model of pneumococcal meningitis. Bacterial counts in cerebrosp
inal fluid (CSF) before, and 2, 5 and 8 h after initiation of therapy
were quantitated by plating on blood agar. Fosfomycin concentrations i
n serum and CSF were determined by the agar well diffusion method. The
MIC and MBC of fosfomycin for the Streptococcus pneumoniae type 3 str
ain used was 4 and 32 mg/L, respectively. The MIC of ceftriaxone was 0
.016 mg/L. In vitro, both drugs showed an additive effect (fractional
inhibitory concentration index = 0.75). In vivo at each dose tested, f
osfomycin was less active than ceftriaxone (means +/- S.D.): delta log
cfu/mL/h at 10 mg/kg/h + 0.130 +/- 0.062 (n = 2), at 40 mg/kg/h - 0.2
17 +/- 0.185 (n = 3), at 80 mg/kg/h - 0.270 +/- 0.121 (n = 3), at 160
mg/kg/h - 0.331 +/- 0.118 (n = 3) vs -0.647 +/- 0.193 at 10 mg/kg/h ce
ftriaxone (n = 3). CSF penetration of fosfomycin as estimated by the C
SF-to-serum concentration ratio at 8 h was 0.55 +/- 0.22 (n = II). For
bactericidal activity CSF concentrations of at least ten times the MI
C were necessary. Coadministration of both drugs (I mg/kg/h ceftriaxon
e + 40 mg/kg/h fosfomycin) tended to be more active than either drug a
lone (in-vivo drug interaction = 1.3). In conclusion, fosfomycin at ve
ry high doses reduced bacterial counts in CSF. However, fosfomycin CSF
concentrations usually observed in patients with meningitis receiving
fosfomycin were not bactericidal in this model. At all doses tested t
he bactericidal rate was lower than that of ceftriaxone. Fosfomycin is
therefore unsuitable as a single agent, but may be used as a reserve
antibiotic in combination with a newer cephalosporin for pneumococcal
meningitis unresponsive to conventional therapy.