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4 pages, 203 KiB

Open AccessEditorial

Editorial: Antibiotics Special Issue on Pharmacokinetic/Pharmacodynamic Models of Antibiotics

by Razieh Kebriaei and Andrew D. Berti

Antibiotics 2022, 11(11), 1540; https://doi.org/10.3390/antibiotics11111540 - 3 Nov 2022

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Abstract

Pharmacokinetic/pharmacodynamic (PK/PD) modeling is an essential tool for rational drug development and treatment design [...] Full article

(This article belongs to the Special Issue Pharmacokinetic/Pharmacodynamic Models of Antibiotics)

Research

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15 pages, 1480 KiB

Open AccessArticle

Pharmacokinetics of Vancomycin among Patients with Chemotherapy-Associated Febrile Neutropenia: Which Would Be the Best Dosing to Obtain Appropriate Exposure?

by Daniel Parra González, Jefferson Alejandro Pérez Mesa, Sonia Isabel Cuervo Maldonado, Jorge Augusto Díaz Rojas, Jorge Alberto Cortés, Edelberto Silva Gómez, Carlos Humberto Saavedra Trujillo and Julio Gómez

Antibiotics 2022, 11(11), 1523; https://doi.org/10.3390/antibiotics11111523 - 1 Nov 2022

Cited by 4 | Viewed by 2246

Abstract

Previous research has determined that the required doses for treating febrile neutropenia with vancomycin are higher than the doses used conventionally. These recommendations have been made considering pharmacotherapeutic goals based on minimum concentration (

C_{\min}

) between 15–20

mg / L

. [...] Read more.

Previous research has determined that the required doses for treating febrile neutropenia with vancomycin are higher than the doses used conventionally. These recommendations have been made considering pharmacotherapeutic goals based on minimum concentration (

C_{\min}

) between 15–20

mg / L

. This study was developed to evaluate dose recommendations based on the achievement of a target consisting of ratio of area under the curve over minimum inhibitory concentration (

{AUC}_{24 h} / MIC

)

\geq 400

in this population of individuals. This study was conducted in a referral hospital for cancer treatment, study participants received vancomycin doses of

1 g

every 12 h in 2-4-h infusions. Vancomycin was described by a two-compartment pharmacokinetic model with clearance dependent on the estimated glomerular filtration rate. Simulations were performed taking into account a reduced version of the model to establish the influence of controllable and non-controllable variables on the probability of achieving several PK-PD targets. A dose of

2.5 g / day

in patients with estimated glomerular filtration rate (

eGFR

) between 80 and

122 mL / \min / 1.73 m^{2}

was adequate to achieve the pharmacotherapeutic target. A discrepancy was found between

AUC

-based and

C_{\min}

-based PK/PD indices, the former being affected by the dose and creatinine clearance while the latter highly influenced by the interval between doses. Full article

(This article belongs to the Special Issue Pharmacokinetic/Pharmacodynamic Models of Antibiotics)

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13 pages, 1433 KiB

Open AccessArticle

In Vitro Assessment of the Combination of Antibiotics against Some Integron-Harbouring Enterobacteriaceae from Environmental Sources

by Folake Temitope Fadare, Elsiddig A. E. Elsheikh and Anthony Ifeanyin Okoh

Antibiotics 2022, 11(8), 1090; https://doi.org/10.3390/antibiotics11081090 - 11 Aug 2022

Cited by 6 | Viewed by 2124

Abstract

One strategy for combating antimicrobial resistance in many infections is to combine antibacterial compounds to create combinations that outperform each molecule alone. In this study, we examine and study the inhibitory effect of combining two drugs belonging to different antibiotic classes to obtain [...] Read more.

One strategy for combating antimicrobial resistance in many infections is to combine antibacterial compounds to create combinations that outperform each molecule alone. In this study, we examine and study the inhibitory effect of combining two drugs belonging to different antibiotic classes to obtain a possible potentiating effect against some Enterobacteriaceae isolates harbouring integrons recovered from rivers and effluents of hospital and wastewater treatment plants in Eastern Cape Province, South Africa. These integrons could easily enable the isolates to acquire genes that confer additional resistance against conventional antibiotics. The minimum inhibitory concentration of the various antibiotics was determined using the broth microdilution, while the checkerboard method was used to determine the fractional inhibitory concentration indices (FICIs). A total of 26.3% (10/38) of the interactions were categorised as synergistic, while 73.7% (28/38) were indifferent. None of the combinations were antagonistic. The time–kill assays revealed all the synergistic interactions as bactericidal. Therefore, the combinations of gentamicin with tetracycline, ciprofloxacin, and ceftazidime against multidrug-resistant (MDR) Klebsiella pneumoniae, tetracycline–ceftazidime combination against MDR Escherichia coli, colistin combinations with ceftazidime and gentamicin, and tetracycline–gentamicin combinations against MDR Citrobacter freundii may be future therapeutic alternatives. Hence, the synergistic combinations reported in this study must be assessed further in vivo before their clinical applications. Full article

(This article belongs to the Special Issue Pharmacokinetic/Pharmacodynamic Models of Antibiotics)

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12 pages, 1241 KiB

Open AccessArticle

Predicting Antibiotic Effect of Vancomycin Using Pharmacokinetic/Pharmacodynamic Modeling and Simulation: Dense Sampling versus Sparse Sampling

by Yong Kyun Kim, Jae Ha Lee, Hang-Jea Jang, Dae Young Zang and Dong-Hwan Lee

Antibiotics 2022, 11(6), 743; https://doi.org/10.3390/antibiotics11060743 - 31 May 2022

Cited by 7 | Viewed by 2017

Abstract

This study aimed to investigate the effect of a structural pharmacokinetic (PK) model with fewer compartments developed following sparse sampling on the PK parameter estimation and the probability of target attainment (PTA) prediction of vancomycin. Two- and three-compartment PK models of vancomycin were [...] Read more.

This study aimed to investigate the effect of a structural pharmacokinetic (PK) model with fewer compartments developed following sparse sampling on the PK parameter estimation and the probability of target attainment (PTA) prediction of vancomycin. Two- and three-compartment PK models of vancomycin were used for the virtual concentration–time profile simulation. Datasets with reduced blood sampling times were generated to support a model with a lesser number of compartments. Monte Carlo simulation was conducted to evaluate the PTA. For the two-compartment PK profile, the total clearance (CL) of the reduced one-compartment model showed a relative bias (RBias) and relative root mean square error (RRMSE) over 90%. For the three-compartment PK profile, the CL of the reduced one-compartment model represented the largest RBias and RRMSE, while the steady-state volume of distribution of the reduced two-compartment model represented the largest absolute RBias and RRMSE. A lesser number of compartments corresponded to a lower predicted area under the concentration–time curve of vancomycin. The estimated PK parameters and predicted PK/PD index from models built with sparse sampling designs that cannot support the PK profile can be significantly inaccurate and unprecise. This might lead to the misprediction of the PTA and selection of improper dosage regimens when clinicians prescribe antibiotics. Full article

(This article belongs to the Special Issue Pharmacokinetic/Pharmacodynamic Models of Antibiotics)

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18 pages, 1472 KiB

Open AccessArticle

Combined PK/PD Index May Be a More Appropriate PK/PD Index for Cefoperazone/Sulbactam against Acinetobacter baumannii in Patients with Hospital-Acquired Pneumonia

by Yingjie Zhou, Jing Zhang, Yuancheng Chen, Jufang Wu, Beining Guo, Xiaojie Wu, Yingyuan Zhang, Minggui Wang, Ru Ya and Hao Huang

Antibiotics 2022, 11(5), 703; https://doi.org/10.3390/antibiotics11050703 - 23 May 2022

Cited by 5 | Viewed by 3541

Abstract

Cefoperazone/sulbactam (CPZ/SUL) is a β-lactam and β-lactamase inhibitor combination therapy for the treatment of respiratory tract infections. Using data from a prospective, multiple-center, open-label clinical trial in 54 patients with hospital-acquired pneumonia or ventilator-associated pneumonia caused by multidrug-resistant Acinetobacter baumannii (Ab), we showed [...] Read more.

Cefoperazone/sulbactam (CPZ/SUL) is a β-lactam and β-lactamase inhibitor combination therapy for the treatment of respiratory tract infections. Using data from a prospective, multiple-center, open-label clinical trial in 54 patients with hospital-acquired pneumonia or ventilator-associated pneumonia caused by multidrug-resistant Acinetobacter baumannii (Ab), we showed that a combined PK/PD index %(T > MIC_cpz*T > MIC_sul) is a more appropriate PK/PD index against Ab, compared to the PK/PD index (%T > MIC) for a single drug. For a 2 h infusion, the PK/PD cutoff of CPZ/SUL (2 g/1 g, q8h) for clinical and microbiological efficacy was 4/2 and 1/0.5 mg/L, respectively. The corresponding cumulative fraction of response was 46.5% and 25.3%, respectively. Results based on the combined PK/PD index were quite similar to that based on the joint probability of target attainment. The two drugs have interaction from the viewpoint of PK/PD. When the dose of one drug was too high, the PK/PD cutoff was often determined by another drug in which the dose was maintained. In most cases, sulbactam exerted the main effect against infection by Ab in the complex CPZ/SUL, which was similar to the literature reports. When the MIC of CPZ was 8, 16, or 32 mg/L, a CPZ/SUL 2 g/1 g (q8h), 2 g/2 g (q8h), or 2 g/2 g (q6h) (infusion was all 3 h) was recommended, respectively. A clinical efficacy and safety study to confirm simulation results is warranted. Full article

(This article belongs to the Special Issue Pharmacokinetic/Pharmacodynamic Models of Antibiotics)

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15 pages, 4795 KiB

Open AccessArticle

Pharmacodynamics of Ceftriaxone, Ertapenem, Fosfomycin and Gentamicin in Neisseria gonorrhoeae

by Urša Gubenšek, Myrthe de Laat, Sunniva Foerster, Anders Boyd and Alje Pieter van Dam

Antibiotics 2022, 11(3), 299; https://doi.org/10.3390/antibiotics11030299 - 23 Feb 2022

Cited by 6 | Viewed by 2753

Abstract

Objectives: To assess the in vitro effect of select antimicrobials on the growth of N. gonorrhoeae and its pharmacodynamic parameters. Methods: Time–kill assays were performed on two reference N. gonorrhoeae strains (ceftriaxone-resistant WHO X and ceftriaxone-susceptible WHO F) and one clinical N. gonorrhoeae [...] Read more.

Objectives: To assess the in vitro effect of select antimicrobials on the growth of N. gonorrhoeae and its pharmacodynamic parameters. Methods: Time–kill assays were performed on two reference N. gonorrhoeae strains (ceftriaxone-resistant WHO X and ceftriaxone-susceptible WHO F) and one clinical N. gonorrhoeae strain (ceftriaxone-susceptible CS03307). Time–kill curves were constructed for each strain by measuring bacterial growth rates at doubling antimicrobial concentrations of ceftriaxone, ertapenem, fosfomycin and gentamicin. Inputs from these curves were used to estimate minimal bacterial growth rates at high antimicrobial concentrations (ψ_min), maximum bacterial growth rates in the absence of antimicrobials (ψ_max), pharmacodynamic minimum inhibitory concentrations (zMIC), and Hill’s coefficients (κ). Results: Ceftriaxone, ertapenem and fosfomycin showed gradual death overtime at higher antimicrobial concentrations with a relatively high ψ_min, demonstrating time-dependent activity. Compared to WHO F, the ψ_min for WHO X was significantly increased, reflecting decreased killing activity for ceftriaxone, ertapenem and fosfomycin. At high ceftriaxone concentrations, WHO X was still efficiently killed. CS03307 also showed a high ψ_min for ceftriaxone in spite of a low MIC and no difference in ψ_min for fosfomycin in spite of significant MIC and zMIC differences. Gentamicin showed rapid killing for all three strains at high concentrations, demonstrating concentration-dependent activity. Conclusions: Based on time–kill assays, high-dosage ceftriaxone could be used to treat N. gonorrhoeae strains with MIC above breakpoint, with gentamicin as a potential alternative. Whether ertapenem or fosfomycin would be effective to treat strains with a high MIC to ceftriaxone is questionable. Full article

(This article belongs to the Special Issue Pharmacokinetic/Pharmacodynamic Models of Antibiotics)

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8 pages, 1189 KiB

Open AccessArticle

Bacterial Mixology: Combining Pharmacodynamic Models to Predict In Vitro Competition of MCR-1-Harboring E. coli

by Nicholas M. Smith, Arthur Chan, Thomas D. Nguyen and Jacob T. Dumbleton

Antibiotics 2022, 11(1), 34; https://doi.org/10.3390/antibiotics11010034 - 28 Dec 2021

Cited by 1 | Viewed by 1615

Abstract

The emergence of mobile colistin resistance (mcr)-mediated polymyxin resistance has resulted in a significant detriment to the utility of the polymyxins in the clinical setting. Though the risk for horizontal transfer of an mcr-containing plasmid is a major component of [...] Read more.

The emergence of mobile colistin resistance (mcr)-mediated polymyxin resistance has resulted in a significant detriment to the utility of the polymyxins in the clinical setting. Though the risk for horizontal transfer of an mcr-containing plasmid is a major component of the transmissibility, selection of polymyxin resistant subpopulations is still a major risk factor for developing polymyxin-resistant infections. Using static time-kills over 24 h (h), we performed competition studies by mixing known inocula of isogenic Escherichia coli strains (wildtype [WT] and mcr-1-harboring) and treating with a concentration array of polymyxin B. These results were then compared to a priori predictions of bacterial-killing effects by polymyxin B on a mixed population of E. coli cells using a previously published mechanism-based model. The data showed that both selective pressure between WT and mcr-1-harboring strains as well as underlying polymyxin B heteroresistance within each of the two strains contributed to bacterial regrowth despite treatment with high concentration polymyxin B. Moreover, the simulations showed that when mcr-1-harboring cells were 1% or 10% of the total population, regrowth by 24 h was still observed in ≥50% of the simulated subjects for both a 10⁶ and 10⁸ inoculum. These results indicate that at lower inoculums with a low proportion of mcr-1-harboring cells, selective pressure from a pharmacokinetic-optimized regimen of polymyxin B still results in regrowth and selection of polymyxin-resistant cells. Full article

(This article belongs to the Special Issue Pharmacokinetic/Pharmacodynamic Models of Antibiotics)

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10 pages, 1225 KiB

Open AccessArticle

MPC-Based Prediction of Anti-Mutant Effectiveness of Antibiotic Combinations: In Vitro Model Study with Daptomycin and Gentamicin against Staphylococcus aureus

by Maria V. Golikova, Elena N. Strukova, Yury A. Portnoy, Stephen H. Zinner and Alexander A. Firsov

Antibiotics 2021, 10(10), 1148; https://doi.org/10.3390/antibiotics10101148 - 23 Sep 2021

Cited by 1 | Viewed by 1836

Abstract

To explore whether combined treatments with daptomycin and gentamicin can prevent the development of Staphylococcus aureus resistance, and whether the possible restriction is associated with changes in antibiotic mutant prevention concentrations (MPCs), the enrichment of daptomycin- and gentamicin-resistant mutants was studied by simulating [...] Read more.

To explore whether combined treatments with daptomycin and gentamicin can prevent the development of Staphylococcus aureus resistance, and whether the possible restriction is associated with changes in antibiotic mutant prevention concentrations (MPCs), the enrichment of daptomycin- and gentamicin-resistant mutants was studied by simulating 5-day single and combined treatments in an in vitro dynamic model. The MPCs of the antibiotics in the combination were determined at concentration ratios equal to the ratios of 24 h areas, under the concentration–time curve (AUCs) of the antibiotics, as simulated in pharmacodynamic experiments. The MPCs of both daptomycin and gentamicin decreased in the presence of each other; this led to an increase in the time when antibiotic concentrations were above the MPC (T_>MPC). The increases in T_>MPCs were concurrent with increases of the anti-mutant effects of the combined antibiotics. When anti-mutant effects of the antibiotics in single and combined treatments were plotted against the T_>MPCs, significant sigmoid relationships were obtained. These findings suggest that (1) daptomycin–gentamicin combinations prevent the development of S. aureus resistance to each antibiotic; (2) the anti-mutant effects of antibiotic combinations can be predicted using MPCs determined at pharmacokinetic-based antibiotic concentration ratios; (3) T_>MPC is a reliable predictor of the anti-mutant efficacy of antibiotic combinations. Full article

(This article belongs to the Special Issue Pharmacokinetic/Pharmacodynamic Models of Antibiotics)

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