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Comparison of methicillin, nafcillin, and oxacillin in therapy of Staphylococcus aureus endocarditis in rabbits
Abstract:
Methicillin (M), nafcillin (N), and oxacillin (OX) (400 mg administered intramuscularly every 8 hours) were compared in the therapy of left-sided endocarditis in rabbits infected with two different strains of Staphylococcus aureus. The three antibiotics were equally effective in eliminating staphylococci from cardiac vegetations. N and OX were four to eight times as active against the staphylococci as M in broth but had equivalent activity in serum. The peak M and OX levels in serum were at least twice the peak N level, but the half-life of N in the serum (2.1 hours) was about three times that of M (0.6 hours) and twice that of OX (1.1 hours). Serum bactericidal activity tests demonstrated essentially equal activity with the three antibiotics 1 and 2 hours after injection; however, at 4 and 6 hours N had an advantage over M and OX. Therefore, despite clear differences in vitro activity, protein binding, and pharmacodynamics, M, N, and OX were equally effective in therapy of staphylcoccal endocarditis in rabbits.
Insights
Methicillin, nafcillin, and oxacillin showed equal effectiveness in treating Staphylococcus aureus endocarditis in rabbits. Differences in in vitro activity and pharmacokinetics did not translate to varied therapeutic outcomes.
Area of Science:
- Pharmacology
- Infectious Diseases
- Microbiology
Background:
- Left-sided endocarditis is a serious infection often caused by Staphylococcus aureus.
- Penicillinase-resistant penicillins, including methicillin, nafcillin, and oxacillin, are commonly used for S. aureus infections.
- Understanding the comparative efficacy of these agents is crucial for effective treatment strategies.
Purpose of the Study:
- To compare the therapeutic efficacy of methicillin, nafcillin, and oxacillin in a rabbit model of Staphylococcus aureus endocarditis.
- To evaluate the impact of pharmacokinetic and pharmacodynamic differences on treatment outcomes.
Main Methods:
- A rabbit model of left-sided endocarditis was infected with two strains of Staphylococcus aureus.
- Methicillin, nafcillin, and oxacillin were administered intramuscularly every 8 hours at a dose of 400 mg.
- Antibiotic activity in broth and serum, serum levels, half-life, and serum bactericidal activity were assessed.
- Efficacy was determined by the elimination of staphylococci from cardiac vegetations.
Main Results:
- All three antibiotics (methicillin, nafcillin, oxacillin) were equally effective in eradicating Staphylococcus aureus from cardiac vegetations.
- Nafcillin and oxacillin exhibited higher in vitro activity against S. aureus in broth compared to methicillin.
- Despite differing serum pharmacokinetics and peak levels, serum bactericidal activity was comparable early post-administration, with nafcillin showing an advantage later.
- No significant differences in therapeutic effectiveness were observed in vivo.
Conclusions:
- Methicillin, nafcillin, and oxacillin demonstrate equivalent clinical efficacy in treating experimental Staphylococcus aureus endocarditis in rabbits.
- In vitro and pharmacokinetic differences do not necessarily predict in vivo therapeutic outcomes for these penicillinase-resistant penicillins.
- The study highlights the importance of in vivo models for assessing antibiotic efficacy in complex infections like endocarditis.