Comparative efficacy of novobiocin and amoxicillin in experimental sepsis caused by β-lactam-susceptible and highly resistant pneumococci

Violeta Rodríguez-Cerrato (1) , Gema del Prado (2) , Lorena Huelves (2) , Plínio Naves (2) , Vicente Ruiz (2) , Ernesto García (1) , Carmen Ponte (2) , Francisco Soriano (2)

1 Department of Molecular Microbiology and Infection Biology
2 Department of Medical Microbiology and Antimicrobial Chemotherapy

Therapeutic alternatives are needed against infections caused by highly multidrug-resistant . Novobiocin, an old antibiotic, was tested in vitro and in a murine sepsis model against one amoxicillin-susceptible and three amoxicillin-resistant strains [minimum inhibitory concentrations (MICs) 8-64mg/L]. Novobiocin MICs for all strains were 0.25-0.5mg/L. In sepsis, novobiocin and amoxicillin were evaluated at 25, 50, 100 and 200mg/kg given at 1, 5, 24 and 48h post bacterial challenge. The most effective regimens in animals infected with the amoxicillin-susceptible strain were 200mg/kg novobiocin and 25mg/kg amoxicillin, achieving 100% survival and undetectable organisms in the peritoneum. Among mice infected with amoxicillin-resistant , 200mg/kg novobiocin gave the highest protection (90-100% survivors), followed by 200mg/kg amoxicillin (60-100%), 100mg/kg novobiocin (50-87.5%) and 50mg/kg amoxicillin (14.3-25%). The killing effect of antibiotics in the peritoneum (mean Δlog colony-forming units/mL between treated and control mice) was as follows: 200mg/kg novobiocin (−6.6)>200mg/kg amoxicillin (−5.6)>100mg/kg novobiocin (−3.7)>50mg/kg amoxicillin (−0.7). Total plasma and ultrafiltrate pharmacokinetics of novobiocin (200mg/kg, single dose) in non-infected mice showed, respectively, half-lives of 151min and 215min, area under the concentration-time curves (AUCs) of 945.0mg h/L and 136.6mg h/L and maximal concentrations of 147mg/L and 18mg/L. Novobiocin may be a promising agent for therapy of highly β-lactam-resistant pneumococcal infections.

Mots clés: Streptococcus pneumoniae; Antibiotic resistance; Sepsis; Novobiocin

Violeta Rodríguez-Cerrato, Gema del Prado, Lorena Huelves, Plínio Naves, Vicente Ruiz, et al.. Comparative efficacy of novobiocin and amoxicillin in experimental sepsis caused by β-lactam-susceptible and highly resistant pneumococci. International Journal of Antimicrobial Agents, 2010, 35 (6), pp.544. ⟨10.1016/j.ijantimicag.2010.02.007⟩. ⟨hal-00585822⟩