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Penicillin pharmacodynamics in four experimental pneumococcal infection models
H Erlendsdottir1, J D Knudsen, I Odenholt
1Departments of Microbiology, Landspitalinn (University Hospital), Reykjavík, Iceland.
Antimicrobial Agents and Chemotherapy
|March 21, 2001
Summary
Penicillin can effectively treat penicillin-nonsusceptible pneumococci (PNSP) infections with optimal dosing. Pharmacodynamic responses in animal models show that maximizing drug concentration and time above the minimum inhibitory concentration (MIC) is key for efficacy.
Area of Science:
- Pharmacology
- Infectious Diseases
- Microbiology
Background:
- Penicillin remains a crucial antibiotic, but resistance in Streptococcus pneumoniae is a growing concern.
- Penicillin-nonsusceptible pneumococci (PNSP) pose a therapeutic challenge, necessitating a deeper understanding of treatment efficacy.
- Previous studies suggest optimal dosing may overcome penicillin resistance.
Purpose of the Study:
- To compare the pharmacodynamic responses of penicillin-susceptible pneumococci (PSP) and PNSP to penicillin.
- To evaluate the impact of different penicillin dosing regimens on bacterial viability in various infection models.
- To identify key pharmacokinetic/pharmacodynamic (PK/PD) parameters predicting penicillin efficacy against PNSP.
Main Methods:
- Utilized four animal models: mouse peritonitis, pneumonia, thigh infection, and rabbit tissue cage infection.
- Employed two multidrug-resistant Streptococcus pneumoniae type 6B isolates with varying penicillin minimum inhibitory concentrations (MICs).
- Administered five distinct penicillin dosing regimens, varying maximum drug concentration (Cmax) and time above MIC (T>MIC).
Main Results:
- Bactericidal activity in mouse models was primarily dependent on T>MIC and, to a lesser extent, Cmax/MIC.
- Maximal bactericidal activities were comparable between PSP and PNSP across different infection sites.
- Optimal conditions for marked bactericidal activity were defined for both mouse and rabbit models, emphasizing T>MIC and Cmax/MIC ratios.
Conclusions:
- Penicillin efficacy against PNSP in nonmeningeal infections can be maximized through optimized Cmax/MIC and T>MIC.
- The penicillin MIC is a valuable guide for tailoring therapy to combat PNSP.
- Pharmacodynamic principles are essential for guiding effective penicillin dosing strategies against resistant pneumococcal strains.