In vivo Postantibiotic Effect of Isepamicin and Other Aminoglycosides in a Thigh Infection Model in Neutropenic Mice

Scandinavian Journal of Infectious Diseases

Martín

Izquierdo

et al. 1995

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.

Section: Introductionsupporting

confidence: 67%

In Vivo and in Vitro Study of Several Pharmacodynamic Effects of Meropenem

Scandinavian Journal of Infectious Diseases

Martín

Izquierdo

et al. 1995

“…With aminoglycosides, the PAEs against most of the standard strains have been considerably long. Against S. aureus, PAEs of 3.4 to 6.7 h have been obtained with gentamicin by this model (4,11,18), while a PAE of 2.3 h has been reported with amikacin and other techniques (27). With E. coli, a wide range of PAEs have been reported: 1.4 to 4.5 h with gentamicin (4, 11, 18), 1.7 to 2.9 h with netilmicin, and 1.8 to 2.1 h with tobramicin (10).…”

Section: Discussionmentioning

confidence: 92%

“…The model of infection in the neutropenic mouse thigh (12) is one of the most employed models because it is faster and less laborious than others. We have previously observed long PAEs with quinolones (9) and aminoglycosides (18) by using this model, although meropenem did not induce significant values (8,15). Other authors have also reported significant in vivo PAEs with macrolides (4) and aminoglycosides (4,27) by using this model and others.…”

mentioning

confidence: 75%

“…The study of the PA SME or SME in vivo has never been carried out according to the in vitro specifications or similar methods. However, complementary experiments to ensure that the suppression of the microorganism growth was a true PAE have generally been reported when the thigh infection model in mice had been performed (9,18,30). We have previously carried out these experiments and applied the formula of the in vitro SME to determine the analogous in vivo effect (9), but no significant values were obtained.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Postantibiotic and Sub-MIC Effects of Azithromycin and Isepamicin against Staphylococcus aureus and Escherichia coli

Antimicrob Agents Chemother

Izquierdo

Martín

et al. 1998

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.

“…In vivo models have not been investigated with fleroxacin and lomefloxacin. In general, these PAEs are mod erate compared with the delays induced by other groups of antibiotics, such as aminogly cosides or macrolides [24,26], However, they are significantly higher than those produced by penicillins, cephalosporins or carbapenems [24,27], There is a variety of factors that can affect the duration of the in vivo PAE, one of them being the specific bactericidal action against the microorganism assayed. According to that, ciprofloxacin exhibits greater bactericid al activity against E. coli than the other two drugs [28], and consequently its longer PAE is induced by a lower time above MIC and AUC/MIC ratio.…”

Section: Discussionmentioning

confidence: 99%

Pharmacodynamic Effects of Ciprofloxacin, Fleroxacin and Lomefloxacin in vivo and in vitro

Martín²,

Izquierdo³

et al. 1996

Chemotherapy

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).