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Once-daily gentamicin administration for community-associated methicillin resistant Staphylococcus aureus in an in vitro pharmacodynamic model: preliminary reports for the advantages for optimizing pharmacodynamic index.

Kim SW, Lee DG, Choi SM, Park C, Kwon JC, Kim SH, Park SH, Choi JH, Yoo JH, Shin WS - Yonsei Med. J. (2010)

Bottom Line: A > or = 3-log(10) reduction in CFU/mL was demonstrated prior to 4 hours in TD and OD, and continued until 8 hours for both strains.However, reductions in the colony counts at 24 and 48 hours were significantly larger for OD compared to TD in both strains (p < 0.001).After the 24 hours of experiments, OD of GEN would be advantageous not only in having more reductions in colony counts, but also suppressing the development of resistance or SCVs for 48 hours.

View Article: PubMed Central - PubMed

Affiliation: Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea.

ABSTRACT

Purpose: Community-associated methicillin resistant Staphylococcus aureus (CAMRSA) infections are increasing. Although gentamicin (GEN) is usually susceptible against CA-MRSA, GEN is rarely considered for treatment as monotherapy. We employed an in vitro pharmacodynamic model (IVPDM) to compare efficacies of GEN against CA-MRSA with two dosing regimens [thrice-daily (TD), once-daily (OD)].

Materials and methods: Using two strains of CA-MRSA, we adopted IVPDM comprised of two-compartments with a surface-to-volume ratio of 5.34 cm(-1). GEN regimens were simulated with human pharmacokinetic data of TD and OD. Experiments were performed over 48 hours in triplicate for each strain and dosing regimen.

Results: MICs of GEN for YSSA1 and YSSA15 were 1 and 2 mg/L, respectively. In OD, indices of peak/MIC were > 8.6 at least, in contrast to < 6.4 in TD. A > or = 3-log(10) reduction in CFU/mL was demonstrated prior to 4 hours in TD and OD, and continued until 8 hours for both strains. However, reductions in the colony counts at 24 and 48 hours were significantly larger for OD compared to TD in both strains (p < 0.001). During TD, resistance developed in YSSA1 and small colony variants (SCVs) were documented in YSSA15. No resistance or SCVs were observed during OD in both strains.

Conclusion: TD and OD showed the same killing slopes until 8 hours. After the 24 hours of experiments, OD of GEN would be advantageous not only in having more reductions in colony counts, but also suppressing the development of resistance or SCVs for 48 hours.

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Related in: MedlinePlus

Time-kill curves of gentamicin against YSSA1 (A) and YSSA15 (B). The results are presented as means ± standard deviations (error bar) of colony counts (log10 CFU/mL) for measurements done in triplicate. GEN, gentamicin; q8h, every 8 hours; q24, every 24 hours; SCVs, small colony variants.
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Figure 2: Time-kill curves of gentamicin against YSSA1 (A) and YSSA15 (B). The results are presented as means ± standard deviations (error bar) of colony counts (log10 CFU/mL) for measurements done in triplicate. GEN, gentamicin; q8h, every 8 hours; q24, every 24 hours; SCVs, small colony variants.

Mentions: Colony counts at 0 hour were in the range of 6.42-6.90 log10 CFU/mL. Results of the experiments with YSSA1 and YSSA15 are presented in Fig. 2. A ≥ 3-log10 reduction in CFU/mL was demonstrated prior to 4 hours in TD and OD regimen for both strains and continued until 8 hours. The slopes of bacterial killing were not different between OD and TD regimens in both regimens during 8 hours. Reductions in the colony counts at 24 and 48 hours were significantly larger for OD compared to TD in both strains (p < 0.001). For YSSA1, resistance developed with re-growth after 24 hours during TD. The post-exposure MIC at 24 hours was 16 mg/L, and persisted for 48 hours. For OD, the bacteria were eradicated by 8 hours, and still undetectable at the end of the experiment. For YSSA15, re-growth of the colonies were shown beyond the 8 hours time point and SCVs were documented starting at 30 hours of the TD therapy with the similar number of normal colonies, but none could be documented in the OD regimen for the entire experiment. No colony was observed after eradication 4 hours during OD dosing. The SCV had a GEN MIC greater than 512 mg/L.


Once-daily gentamicin administration for community-associated methicillin resistant Staphylococcus aureus in an in vitro pharmacodynamic model: preliminary reports for the advantages for optimizing pharmacodynamic index.

Kim SW, Lee DG, Choi SM, Park C, Kwon JC, Kim SH, Park SH, Choi JH, Yoo JH, Shin WS - Yonsei Med. J. (2010)

Time-kill curves of gentamicin against YSSA1 (A) and YSSA15 (B). The results are presented as means ± standard deviations (error bar) of colony counts (log10 CFU/mL) for measurements done in triplicate. GEN, gentamicin; q8h, every 8 hours; q24, every 24 hours; SCVs, small colony variants.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2908872&req=5

Figure 2: Time-kill curves of gentamicin against YSSA1 (A) and YSSA15 (B). The results are presented as means ± standard deviations (error bar) of colony counts (log10 CFU/mL) for measurements done in triplicate. GEN, gentamicin; q8h, every 8 hours; q24, every 24 hours; SCVs, small colony variants.
Mentions: Colony counts at 0 hour were in the range of 6.42-6.90 log10 CFU/mL. Results of the experiments with YSSA1 and YSSA15 are presented in Fig. 2. A ≥ 3-log10 reduction in CFU/mL was demonstrated prior to 4 hours in TD and OD regimen for both strains and continued until 8 hours. The slopes of bacterial killing were not different between OD and TD regimens in both regimens during 8 hours. Reductions in the colony counts at 24 and 48 hours were significantly larger for OD compared to TD in both strains (p < 0.001). For YSSA1, resistance developed with re-growth after 24 hours during TD. The post-exposure MIC at 24 hours was 16 mg/L, and persisted for 48 hours. For OD, the bacteria were eradicated by 8 hours, and still undetectable at the end of the experiment. For YSSA15, re-growth of the colonies were shown beyond the 8 hours time point and SCVs were documented starting at 30 hours of the TD therapy with the similar number of normal colonies, but none could be documented in the OD regimen for the entire experiment. No colony was observed after eradication 4 hours during OD dosing. The SCV had a GEN MIC greater than 512 mg/L.

Bottom Line: A > or = 3-log(10) reduction in CFU/mL was demonstrated prior to 4 hours in TD and OD, and continued until 8 hours for both strains.However, reductions in the colony counts at 24 and 48 hours were significantly larger for OD compared to TD in both strains (p < 0.001).After the 24 hours of experiments, OD of GEN would be advantageous not only in having more reductions in colony counts, but also suppressing the development of resistance or SCVs for 48 hours.

View Article: PubMed Central - PubMed

Affiliation: Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea.

ABSTRACT

Purpose: Community-associated methicillin resistant Staphylococcus aureus (CAMRSA) infections are increasing. Although gentamicin (GEN) is usually susceptible against CA-MRSA, GEN is rarely considered for treatment as monotherapy. We employed an in vitro pharmacodynamic model (IVPDM) to compare efficacies of GEN against CA-MRSA with two dosing regimens [thrice-daily (TD), once-daily (OD)].

Materials and methods: Using two strains of CA-MRSA, we adopted IVPDM comprised of two-compartments with a surface-to-volume ratio of 5.34 cm(-1). GEN regimens were simulated with human pharmacokinetic data of TD and OD. Experiments were performed over 48 hours in triplicate for each strain and dosing regimen.

Results: MICs of GEN for YSSA1 and YSSA15 were 1 and 2 mg/L, respectively. In OD, indices of peak/MIC were > 8.6 at least, in contrast to < 6.4 in TD. A > or = 3-log(10) reduction in CFU/mL was demonstrated prior to 4 hours in TD and OD, and continued until 8 hours for both strains. However, reductions in the colony counts at 24 and 48 hours were significantly larger for OD compared to TD in both strains (p < 0.001). During TD, resistance developed in YSSA1 and small colony variants (SCVs) were documented in YSSA15. No resistance or SCVs were observed during OD in both strains.

Conclusion: TD and OD showed the same killing slopes until 8 hours. After the 24 hours of experiments, OD of GEN would be advantageous not only in having more reductions in colony counts, but also suppressing the development of resistance or SCVs for 48 hours.

Show MeSH
Related in: MedlinePlus