In Vitro and In Vivo Activity of Miltefosine Against Penicillin-Sensitive and -Resistant Streptococcus pneumoniae Strains

Abstract The in vitro and in vivo activity of miltefosine against penicillin-sensitive and penicillin-resistant pneumococcal strains was studied. The minimum inhibitory concentrations (MICs) of miltefosine were determined in cation-adjusted Mueller Hinton plus 2% lysed horse blood (CAMHB) and in Todd-Hewitt (TH) broth. The respective MICs were higher using CAMHB (128 and 64 mg/L) than using TH broth (4 and 8 mg/L). The In Vivo activity was studied in a murine peritonitis-sepsis model. Miltefosine was orally administered at doses of 15 and 30 mg/kg/day after, at the time of, and before bacterial challenge for 3-5 days. All control and 16 out of the 17 (94.1%) miltefosine-treated animals that were inoculated with the penicillin-sensitive strain died. No survival was observed among control and miltefosine-treated animals inoculated with the penicillin-resistant pneumococcal strain. The In Vivo unresponsiveness of miltefosine in this sepsis model could be attributed to some inhibitory effect of blood, inadequate pharmacokinetics and/or the extracellular localization of the pneumococcus.

[1]  L. Rivas,et al.  In Vitro Bactericidal Activity of the Antiprotozoal Drug Miltefosine against Streptococcus pneumoniae and Other Pathogenic Streptococci , 2007, Antimicrobial Agents and Chemotherapy.

[2]  F. Soriano,et al.  Correlation between in vitro and in vivo activity of levofloxacin and moxifloxacin against pneumococcal strains with different susceptibilities to fluoroquinolones. , 2006, International journal of antimicrobial agents.

[3]  T. Sorrell,et al.  Hexadecylphosphocholine (Miltefosine) Has Broad-Spectrum Fungicidal Activity and Is Efficacious in a Mouse Model of Cryptococcosis , 2006, Antimicrobial Agents and Chemotherapy.

[4]  C. Unger,et al.  Distribution and metabolism of hexadecylphosphocholine in mice , 1987, Lipids.

[5]  A. Rojas de Arias,et al.  Efficacy of Orally Administered 2-Substituted Quinolines in Experimental Murine Cutaneous and Visceral Leishmaniases , 2005, Antimicrobial Agents and Chemotherapy.

[6]  A. Henriques-Pons,et al.  Effect of the lysophospholipid analogues edelfosine, ilmofosine and miltefosine against Leishmania amazonensis. , 2004, The Journal of antimicrobial chemotherapy.

[7]  C. Unger,et al.  Distribution of hexadecylphosphocholine and octadecyl-methyl-glycero-3-phosphocholine in rat tissues during steady-state treatment , 2004, Cancer Chemotherapy and Pharmacology.

[8]  S. Zerp,et al.  Alkyl-lysophospholipids as anticancer agents and enhancers of radiation-induced apoptosis. , 2001, International journal of radiation oncology, biology, physics.

[9]  Mary Jane Ferraro,et al.  Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically : approved standard , 2000 .

[10]  S. Sundar,et al.  Miltefosine, an oral agent, for the treatment of Indian visceral leishmaniasis. , 1999, The New England journal of medicine.

[11]  C. Rosenow,et al.  Contribution of novel choline‐binding proteins to adherence, colonization and immunogenicity of Streptococcus pneumoniae , 1997, Molecular microbiology.

[12]  V. Yardley,et al.  The activities of four anticancer alkyllysophospholipids against Leishmania donovani, Trypanosoma cruzi and Trypanosoma brucei. , 1996, The Journal of antimicrobial chemotherapy.

[13]  C. Unger,et al.  Hexadecylphosphocholine: determination of serum concentrations in rats. , 1991, Journal of lipid mediators.