Pharmacokinetic–pharmacodynamic modelling of meropenem against VIM-producing Klebsiella pneumoniae isolates: clinical implications

Tsala, Marilena; Vourli, Sophia; Kotsakis, Stathis D.; Daikos, George L.; Tzouvelekis, L. S.; Zerva, Loukia; Miriagou, Vivì; Meletiadis, Joseph

doi:10.1099/jmm.0.000214

Cited by 12 publications

(4 citation statements)

References 26 publications

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“…10 This model has been recently validated using in vivo data from a thigh infection animal model. 11 In Vitro Pharmacokinetics Two dosing regimens of meropenem were simulated, the standard short (0.5-h) and the alternative prolonged (3-h) infusion regimen of 1 g every 8 h. In the in vitro model, the peak concentrations of mean ± SD 100 ± 30 and 30 ± 10 mg/L with a half-life <2 h were targeted 8 (Fig. 2) as previously found in patients.…”

Section: In Vitro Pharmacokineticepharmacodynamic Modelmentioning

confidence: 99%

Comparison of Short Versus Prolonged Infusion of Standard Dose of Meropenem Against Carbapenemase-Producing Klebsiella pneumoniae Isolates in Different Patient Groups: A Pharmacokinetic–Pharmacodynamic Approach

Vourli

Tsala

Kotsakis

et al. 2016

Journal of Pharmaceutical Sciences

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Dose optimization is required to increase carbapenem's efficacy against carbapenemase-producing isolates. Four clinical Klebsiella pneumoniae isolates were used: one susceptible to meropenem with minimum inhibitory concentration (MIC) 0.031 mg/L and 3 verona integron-borne metallo bete-lactamase-1-producing isolates with MICs 8, 16, and 128 mg/L. The human pharmacokinetics of short (0.5-h) and prolonged (3-h) infusion regimens of 1 g meropenem every 8 h were simulated in an in vitro pharmacokinetic-pharmacodynamic model. Time-kill curves were constructed for each isolate and dosing regimen, and the %T > MIC associated with maximal bactericidal activity was estimated. The percentage of pharmacodynamic target attainment for isolates with different MICs was calculated for 350 ICU, surgical, and internal medicine patients. The isolates with MIC ≤8 mg/L were killed with both dosing regimens. The %T > MIC corresponding to maximal bactericidal activity was ∼40%. The percentages of target attainment were >90%, 61%-83%, 23%-33%, and <3% with the short infusion regimen and >90%, 98%-99%, 55%-79%, and <5% with the prolonged infusion regimen for isolates with MIC ≤2, 4, 8, and ≥16 mg/L, respectively. The lowest target attainment rates were observed for the ICU patients and the highest for internal medicine patients. The prolonged infusion regimen was more effective than the short infusion regimen against isolates with MIC 4-8 mg/L.

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Section: In Vitro Pharmacokineticepharmacodynamic Modelmentioning

confidence: 99%

Comparison of Short Versus Prolonged Infusion of Standard Dose of Meropenem Against Carbapenemase-Producing Klebsiella pneumoniae Isolates in Different Patient Groups: A Pharmacokinetic–Pharmacodynamic Approach

Vourli

Tsala

Kotsakis

et al. 2016

Journal of Pharmaceutical Sciences

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“…5,6 A dosefractionation design was followed with nine dosing regimens of colistin targeting fC max 9, 3 and 1.5 mg/L administered every 8, 12 and 24 h for 24 h. High drug exposures were included in order to better describe the exposure-effect relationships with effects ranging from low to high. Colistin was added to both compartments of the in vitro model in order to reach a peak concentration within 1.5 h, simulating exposures achieved with a loading dose followed by maintenance doses.…”

Section: In Vitro Pk/pd Modelmentioning

confidence: 99%

Exploring colistin pharmacodynamics against Klebsiella pneumoniae: a need to revise current susceptibility breakpoints

Tsala

Vourli

Georgiou

et al. 2018

Journal of Antimicrobial Chemotherapy

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Objectives: Because the pharmacokinetic/pharmacodynamic (PK/PD) characteristics of colistin against Enterobacteriaceae are not well explored, we studied the activity of colistin against K. pneumoniae in an in vitro PK/PD model simulating different dosing regimens.Methods: Three clinical isolates of K. pneumoniae with MICs of 0.5, 1 and 4 mg/L were tested in an in vitro PK/PD model following a dose-fractionation design over a period of 24 h. A high and low inoculum of 10 7 and 10 4 cfu/mL with and without a heteroresistant subpopulation, respectively, were used. PK/PD indices associated with colistin activity were explored and Monte Carlo analysis was performed in order to determine the PTA for achieving a bactericidal effect (2 log kill). Results:The fAUC/MIC (R 2 " 0.64-0.68) followed by fC max /MIC (R 2 " 0.55-0.63) best described colistin's 24 h log 10 cfu/mL reduction for both low and high inocula. Dosing regimens with fC max /MIC !6 were always associated with a bactericidal effect (P " 0.0025). However, at clinically achievable concentrations, usually below fC max /MIC " 6, an fAUC/MIC !25 was more predictive of a bactericidal effect. Using a dosing regimen of 9 MU/ day, the PTA for this pharmacodynamic target was 100%, 5%-70% and 0%, for isolates with MICs of 0.5, 1 and !2 mg/L, respectively. Dosing regimens that aim for a trough level of 1 mg/L achieve coverage of strains up to 0.5 mg/L (target trough/MIC " 2 mg/L).Conclusions: Characterization of the pharmacodynamics of colistin against Enterobacteriaceae in an in vitro model of infection indicates that a revision of current susceptibility breakpoints is needed. Therapeutic drug monitoring of colistin to achieve pharmacodynamic targets in individual patients is highly recommended.

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“…Therefore, only preclinical data from thigh and lung infection models were utilized for determining PK/PD targets and when not available, data from in vitro dynamic models were used. The PK/PD target of 3-log kill was used from in vitro models as this seems to correlate with 1-log kill in animals [10].…”

Section: Methodsmentioning

confidence: 99%

Assessing Clinical Potential of Old Antibiotics against Severe Infections by Multi-Drug-Resistant Gram-Negative Bacteria Using In Silico Modelling

et al. 2022

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In the light of increasing antimicrobial resistance among gram-negative bacteria and the lack of new more potent antimicrobial agents, new strategies have been explored. Old antibiotics, such as colistin, temocillin, fosfomycin, mecillinam, nitrofurantoin, minocycline, and chloramphenicol, have attracted the attention since they often exhibit in vitro activity against multi-drug-resistant (MDR) gram-negative bacteria, such as Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Acinetobacter baumannii. The current review provides a summary of the in vitro activity, pharmacokinetics and PK/PD characteristics of old antibiotics. In silico modelling was then performed using Monte Carlo simulation in order to combine all preclinical data with human pharmacokinetics and determine the probability of target (1-log kill in thigh/lung infection animal models) attainment (PTA) of different dosing regimens. The potential of clinical efficacy of a drug against severe infections by MDR gram-negative bacteria was considered when PTA was >95% at the epidemiological cutoff values of corresponding species. In vitro potent activity against MDR gram-negative pathogens has been shown for colistin, polymyxin B, temocillin (against E. coli and K. pneumoniae), fosfomycin (against E. coli), mecillinam (against E. coli), minocycline (against E. coli, K. pneumoniae, A. baumannii), and chloramphenicol (against E. coli) with ECOFF or MIC90 ≤ 16 mg/L. When preclinical PK/PD targets were combined with human pharmacokinetics, Monte Carlo analysis showed that among the old antibiotics analyzed, there is clinical potential for polymyxin B against E. coli, K. pneumoniae, and A. baumannii; for temocillin against K. pneumoniae and E. coli; for fosfomycin against E. coli and K. pneumoniae; and for mecillinam against E. coli. Clinical studies are needed to verify the potential of those antibiotics to effectively treat infections by multi-drug resistant gram-negative bacteria.

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Pharmacokinetic–pharmacodynamic modelling of meropenem against VIM-producing Klebsiella pneumoniae isolates: clinical implications

Cited by 12 publications

References 26 publications

Comparison of Short Versus Prolonged Infusion of Standard Dose of Meropenem Against Carbapenemase-Producing Klebsiella pneumoniae Isolates in Different Patient Groups: A Pharmacokinetic–Pharmacodynamic Approach

Comparison of Short Versus Prolonged Infusion of Standard Dose of Meropenem Against Carbapenemase-Producing Klebsiella pneumoniae Isolates in Different Patient Groups: A Pharmacokinetic–Pharmacodynamic Approach

Exploring colistin pharmacodynamics against Klebsiella pneumoniae: a need to revise current susceptibility breakpoints

Assessing Clinical Potential of Old Antibiotics against Severe Infections by Multi-Drug-Resistant Gram-Negative Bacteria Using In Silico Modelling

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