Abstract
The pharmacokinetic (PK) and pharmacodynamic (PD) parameters which correlated with the in vivo efficacy of cefiderocol were evaluated using neutropenic murine thigh and lung infection models in which the infections were caused by a variety of Gram-negative bacilli. The dose fractionation study using the thigh infection model in which the infection was caused by Pseudomonas aeruginosa showed that the cumulative percentage of a 24-h period that the free drug concentration in plasma exceeds the MIC (%fT >MIC) rather than the free peak level divided by the MIC (fC max/MIC) and the area under the free concentration-time curve over 24 h divided by the MIC (fAUC/MIC) was the PK/PD parameter that best correlated with efficacy. The study with multiple carbapenem-resistant strains revealed that the %fT >MIC determined in iron-depleted cation-adjusted Mueller-Hinton broth (ID-CAMHB) better reflected the in vivo efficacy of cefiderocol than the %fT >MIC determined in cation-adjusted Mueller-Hinton broth (CAMHB). The mean %fT >MIC of cefiderocol required for a 1-log10 reduction against 10 strains of Enterobacteriaceae and 3 strains of Pseudomonas aeruginosa in the thigh infection models were 73.3% and 77.2%, respectively. The mean %fT >MIC for Enterobacteriaceae, P. aeruginosa, Acinetobacter baumannii, and Stenotrophomonas maltophilia in the lung infection model were 64.4%, 70.3%, 88.1%, and 53.9%, respectively. These results indicate that cefiderocol has potent efficacy against Gram-negative bacilli, including carbapenem-resistant strains, irrespective of the bacterial species, in neutropenic thigh and lung infection models and that the in vivo efficacy correlated with the in vitro MIC under iron-deficient conditions.
Highlights
The pharmacokinetic (PK) and pharmacodynamic (PD) parameters which correlated with the in vivo efficacy of cefiderocol were evaluated using neutropenic murine thigh and lung infection models in which the infections were caused by a variety of Gram-negative bacilli
Based on our results using the conventional dose fractionation methodology in the murine thigh infection model with P. aeruginosa, the %fTϾMIC was shown to be the PK/PD parameter which best correlated with in vivo efficacy for cefiderocol, as well as cefepime (Fig. 1). This could be identical to the previous observation that the efficacy of cefiderocol was enhanced in a rat respiratory tract infection model under the conditions used to cause the prolonged %fTϾMIC [13]
The iron concentrations in ID-cation-adjusted Mueller-Hinton broth (CAMHB) and CAMHB are reported to be approximately 0.02 and 0.15 mg/ liter, respectively [14], and it has been reported that the upregulation of iron transporters caused the decrease in the MIC of cefiderocol in ID-CAMHB [5, 15]
Summary
The pharmacokinetic (PK) and pharmacodynamic (PD) parameters which correlated with the in vivo efficacy of cefiderocol were evaluated using neutropenic murine thigh and lung infection models in which the infections were caused by a variety of Gram-negative bacilli. The mean %fTϾMIC for Enterobacteriaceae, P. aeruginosa, Acinetobacter baumannii, and Stenotrophomonas maltophilia in the lung infection model were 64.4%, 70.3%, 88.1%, and 53.9%, respectively These results indicate that cefiderocol has potent efficacy against Gram-negative bacilli, including carbapenem-resistant strains, irrespective of the bacterial species, in neutropenic thigh and lung infection models and that the in vivo efficacy correlated with the in vitro MIC under iron-deficient conditions. Carbapenem antibiotics, such as meropenem, have been used for the treatment of serious health care-associated infections, including complicated urinary tract infection, sepsis, and pneumonia, due to Gram-negative pathogens. The goals of our studies were (i) to clarify the pharmacokinetic (PK) and pharmacodynamic (PD) parameter which best correlates with in vivo efficacy, (ii) to determine appropriate MIC culture conditions for cefiderocol to predict in vivo efficacy, and (iii) to determine the magnitude of the PK/PD parameter for bactericidal activity
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