Pharmacodynamic profile of tigecycline against methicillin-resistant Staphylococcus aureus in an experimental
Pornpan Koomanachai1, Jared L Crandon, Mary Anne Banevicius
1Center for Anti-Infective Research and Development, Hartford Hospital, Hartford, CT 06102, USA.
Abstract:
Tigecycline (TGC) is an extended-spectrum antibiotic with activity against Staphylococcus aureus, including methicillin (meticillin)-resistant S. aureus strains, which are well-recognized pathogens in nosocomial pneumonia. The objective of this study was to characterize the exposure-response relationship for TGC against S. aureus in an immunocompromised BALB/c murine pneumonia model. Six S. aureus isolates were studied, and the TGC MICs for those isolates ranged from 0.125 to 0.5 mg/liter. The pharmacokinetics (PK) of TGC in serum and bronchoalveolar lavage (BAL) fluid were evaluated, as was the level of protein binding of the compound in this murine species. Administration of TGC at 1.56 to 150 mg/kg of body weight/day in single or two to three divided doses was used in the efficacy studies. TGC displayed linear PK and had a mean half-life of 10.9 +/- 2.5 h. Efficacy was highly correlated with the area under the free concentration-time curve (fAUC)/MIC (r(2) = 0.93). The 80% and 50% effective exposure indexes and the stasis exposure index were similar between the isolates (means +/- standard deviations, 3.04 +/- 1.12, 1.84 +/- 1.3, and 1.9 +/- 1.5, respectively). Maximal efficacy was predicted at a 2.85-log(10)-CFU reduction. TGC appeared to accumulate in the interstitial space, as the ratios of the fAUC from 0 to 8 h of epithelial lining fluid to plasma were 7.02, 15.11, and 23.95 for doses of 12.5, 25, and 50 mg/kg, respectively. TGC was highly effective in this murine pneumonia model. In light of current MIC distributions, the fAUC/MIC targets that we defined against S. aureus are readily achievable in humans given conventional doses of TGC.
Insights
Tigecycline (TGC) effectively treats Staphylococcus aureus pneumonia in mice, demonstrating a strong link between drug exposure and treatment success. The study suggests TGC doses are achievable in humans for treating infections caused by this pathogen.
Area of Science:
- Pharmacology
- Infectious Diseases
- Microbiology
Background:
- Tigecycline (TGC) is a broad-spectrum antibiotic effective against Staphylococcus aureus, a common cause of hospital-acquired pneumonia.
- Methicillin-resistant S. aureus (MRSA) strains pose a significant threat in nosocomial infections.
Purpose of the Study:
- To determine the exposure-response relationship of TGC against S. aureus in a murine pneumonia model.
- To evaluate TGC pharmacokinetics (PK) and protein binding in mice.
- To establish PK/pharmacodynamic (PK/PD) targets for TGC efficacy.
Main Methods:
- An immunocompromised BALB/c murine pneumonia model infected with six S. aureus isolates (MICs 0.125–0.5 mg/L).
- TGC administered at doses ranging from 1.56 to 150 mg/kg/day.
- PK analysis in serum and bronchoalveolar lavage (BAL) fluid.
- Correlation of efficacy with the ratio of the area under the free concentration-time curve (fAUC) to the MIC (fAUC/MIC).
Main Results:
- TGC exhibited linear PK with a mean half-life of 10.9 ± 2.5 hours.
- Efficacy strongly correlated with fAUC/MIC (r² = 0.93).
- Effective exposure indices were consistent across isolates, with maximal efficacy predicted at a 2.85-log(10)-CFU reduction.
- TGC accumulated in lung interstitial space, with fAUC ratios increasing with dose.
Conclusions:
- TGC demonstrated high efficacy in a murine model of S. aureus pneumonia.
- The established fAUC/MIC targets are achievable with conventional human TGC doses.
- TGC is a promising therapeutic option for S. aureus pneumonia, including MRSA infections.
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