Several pharmacodynamic parameters are being studied and applied to the design of dosage regimens. The thigh infection model in neutropenic mice has been used in this study to investigate the in vivo postantibiotic effect (PAE) of meropenem against S. aureus, E. coli and P. aeruginosa. The sub-minimum inhibitory concentration (sub-MIC) postantibiotic effect (PA SME) of 1/2, 1/4 and 1/8 x MIC was also determined in vitro on S. aureus and E. coli after pre-exposure of these microorganisms to 10 x MIC of meropenem. The in vitro PAE was also determined. In vivo killing curves using 2 different short dosage regimens were also studied to relate the lethal effect to the time that serum levels were above the MIC. No significant in vivo and in vitro PAEs were observed. The PA SMEs were higher for S. aureus than for E. coli. The 2 short dosage regimens, in vivo, were equally effective in killing S. aureus, but not E. coli. These results suggest that the pharmacodynamics of meropenem on Gram-negative strains may need further study to elucidate the mechanisms and characteristics of these parameters. On the other hand, we need to standardize a reliable in vitro method to monitor regrowth with a good correlation with the in vivo conditions.

Investigations of pharmacodynamic parameters (postantibiotic effect [PAE], sub-MIC effects [SMEs], etc.) have been progressively employed for the design of dosing schedules of antimicrobial agents. However, there are fewer in vivo than in vitro data, probably because of the simplicity of the in vitro procedures. In this study, we have investigated the in vitro PAE, SME, and previously treated (postantibiotic [PA]) SME (1/2 MIC, 1/4 MIC and 1/8 MIC) of azithromycin and isepamicin against standard strains ofStaphylococcus aureus and Escherichia coliby using centrifugation to remove the antibiotics. In addition, the in vivo PAE and SME have been studied with the thigh infection model in neutropenic mice. Finally, in vivo killing curves with two dosing schedules were determined to examine whether the PAE can cover the time that antimicrobial agents are below the MIC. The two antimicrobial agents induced moderate-to-high in vitro PAEs, SMEs, and PA SMEs against S. aureus (>8 h) andE. coli (3.38 to >7.64 h). The in vivo PAEs were also high (from 3.0 to 3.6 h), despite the fact that isepamicin had lower times above the MIC in serum. Only azithromycin showed a high in vivo SME against the two strains (1.22 and 1.75 h), which indicated that the in vivo PAEs were possibly overestimated. In the killing kinetics, no great differences (<0.5 log10) were observed between the schedule that took the PAE into account and the continuous administration of doses. These results are comparable with those of other authors and suggest that these antimicrobial agents could be administered at longer intervals without losing effectiveness.

The object of this work is to study in neutropenic mice the in vivo postantibiotic effect (PAE) of isepamicin, a new aminoglycoside, gentamicin and netilmicin on Staphylococcus aureus and Escherichia coli and in vivo killing kinetics using two different schedules (A and B) of isepamicin and gentamicin administration against S. aureus: (A) at time zero and every hour up to the 7th or 9th hour and (B) two doses only, at time zero and at the end of the PAE. The PAE of the three aminoglycosides was long (3-5 h), showing that of isepamicin to be the largest, especially on S. aureus. Both A and B treatment models show the same effectiveness for the two tested drugs. These results support the idea that the major significance of the PAE is in its application to dosing regimens.

The present study investigates the postantibiotic effect (PAE) in vivo, and the postantibiotic subinhibitory concentration effects (PA-SE) in vitro and SE in vivo of three 4-fluoroquinolones (ciprofloxacin, fleroxacin and lomefioxacin) against standard strains of Staphylococcus aureus and Escherichia coli. In vivo killing kinetics have also been performed using two different short administrations to study if the PAE duration could cover the time that the antibiotic was below the minimal inhibitory concentration (MIC) in serum. The results show that the three antimicrobial agents induced long PAEs (1.9–3.1 h) against the two microorganisms. Moderate but significant in vitro PA-SEs were also produced (1– > 9 h). The in vivo SEs were not significant except when the effect of lomefioxacin on E. coli was assayed (0.54 h). Finally, the in vivo killing kinetics showed that the administrations that included the PAE duration were as effective as the schedule that maintained the antibiotic levels in serum above the MIC. Only when fleroxacin and S. aureus were assayed, this last administration was more effective (+ 0.9 log₁₀ colony-forming units/thigh).

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