In vivo evaluation of cefazolin inoculum effect in the treatment of experimental Staphylococcus aureus pneumonia with cefazolin.

Abstract

Objectives: This study compared the efficacy of cefazolin in a mouse pneumonia model caused by a methicillin-susceptible Staphylococcus aureus (MSSA) strain with cefazolin inoculum effect (CIE) and its blaZ-eliminated derivative.

Methods: An isogenic blaZ gene-eliminated strain was derived from type A blaZ-positive MSSA blood isolates exhibiting CIE: PNIDSA230 (parental strain, CIE+) and PNIDSA230c (blaZ-eliminated strain, CIE-). Mice were inoculated with 2 × 10⁶ to 2 × 10⁷ cfu of MSSA via endotracheal tubes and treated with intraperitoneal cefazolin or oxacillin 5 h post-inoculation. Bacterial loads in the lungs (primary sites), liver, and kidneys (metastatic foci) were measured 24 h later.

Results: Cefazolin reduced bacterial densities in the lungs of CIE-positive MSSA-infected mice (n = 11) compared with untreated controls (n = 11) (mean log10 cfu/g ± SD, 6.0 ± 1.6 versus 9.4 ± 2.7; P = 0.006). However, the efficacy of cefazolin was significantly lower in CIE+ infections than in CIE- infections (mean log10 cfu/g ± SD, 6.0 ± 1.6 versus 4.4 ± 0.8, P = 0.0258). Cefazolin-treated CIE- MSSA-infected mice showed no metastatic infections, while 7 of the 11 CIE+ MSSA-infected mice developed liver or kidney infections despite cefazolin treatment. Oxacillin treatment significantly reduced bacterial densities of the lungs, liver, and kidney in CIE-positive (n = 4) and CIE-negative (n = 4) MSSA-infected mice, with no significant differences between CIE-positive and CIE-negative MSSA infections.

Conclusions: CIE may diminish cefazolin's efficacy in severe MSSA infections and contribute to the development of metastatic infection foci. Oxacillin remains effective regardless of CIE status.