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Activity of sub-minimal inhibitory concentrations of aspoxicillin in prolonging the postantibiotic effect against
T Oshida1, T Onta, N Nakanishi
1Biological Research Laboratory, Tanabe Seiyaku Co., Ltd., Saitama, Japan.
Abstract:
Aspoxicillin, a newly developed acylureido-penicillin with a long half-life in mouse serum of 55 min, induced postantibiotic effects (PAEs) against Staphylococcus aureus Smith of 1.7 h in vitro and 5.2 h in vivo in a thigh infection model in neutropenic mice. The long serum half-life meant that in order to evaluate the in-vivo PAE, it was necessary to examine the contribution of the drug at a sub-minimal inhibitory concentration (sub-MIC). Growth suppression by sub-MICs of aspoxicillin was examined in vitro using either previously unexposed bacterial cells or cells which had been pre-exposed to twice the MIC of aspoxicillin for 2 h. At each sub-MIC tested, the duration of growth suppression for pre-exposed cells was longer than that for unexposed cells. In an attempt to eliminate the sub-MIC effect in vivo, penicillinase was injected into mice at the time after administration when the aspoxicillin serum concentration approached the MIC. The in-vivo PAE decreased to 2.7 h when penicillinase was injected. It was concluded that aspoxicillin induced a PAE in vivo which was additional to the effect of sub-inhibitory residual drug, but that sub-MIC levels of the drug were simultaneously involved in suppressing bacterial regrowth after the drug concentration decreased below the MIC. Similar postantibiotic sub-MIC effects may also occur with other long half-life antibiotics.
Insights
Aspoxicillin, a new antibiotic, demonstrated significant postantibiotic effects (PAEs) against Staphylococcus aureus. Sub-minimal inhibitory concentrations (sub-MICs) prolonged bacterial growth suppression, indicating a dual mechanism of action for this long-half-life penicillin.
Area of Science:
- Pharmacology
- Microbiology
- Infectious Diseases
Background:
- Aspoxicillin is a novel acylureido-penicillin characterized by a prolonged serum half-life.
- Understanding postantibiotic effects (PAEs) is crucial for optimizing antibiotic dosing strategies.
- The influence of sub-minimal inhibitory concentrations (sub-MICs) on PAEs requires further investigation.
Purpose of the Study:
- To evaluate the in vitro and in vivo postantibiotic effects (PAEs) of aspoxicillin against Staphylococcus aureus.
- To investigate the contribution of sub-minimal inhibitory concentrations (sub-MICs) to the overall PAE of aspoxicillin.
- To elucidate the mechanisms underlying aspoxicillin's prolonged activity.
Main Methods:
- Determination of in vitro and in vivo PAEs of aspoxicillin against Staphylococcus aureus Smith in neutropenic mice.
- Assessment of bacterial growth suppression by various sub-MICs of aspoxicillin on both unexposed and pre-exposed bacterial cells.
- In vivo evaluation of PAE by administering penicillinase to neutralize residual aspoxicillin.
Main Results:
- Aspoxicillin exhibited a notable PAE of 1.7 hours in vitro and 5.2 hours in vivo.
- Pre-exposure to sub-MICs of aspoxicillin significantly prolonged bacterial growth suppression compared to unexposed cells.
- Neutralization of aspoxicillin with penicillinase reduced the in vivo PAE to 2.7 hours, confirming the contribution of residual drug.
Conclusions:
- Aspoxicillin induces a significant in vivo PAE that is distinct from the effects of sub-inhibitory drug concentrations.
- Sub-MIC levels of aspoxicillin play a concurrent role in suppressing bacterial regrowth after the drug concentration falls below the MIC.
- The findings suggest that similar sub-MIC effects may contribute to the efficacy of other long half-life antibiotics.