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PBPK Modeling and Simulation of Antibiotics Amikacin, Gentamicin, Tobramycin, and Vancomycin Used in Hospital Practice.

ABSTRACT: The importance of closely observing patients receiving antibiotic therapy, performing therapeutic drug monitoring (TDM), and regularly adjusting dosing regimens has been extensively demonstrated. Additionally, antibiotic resistance is a contemporary concerningly dangerous issue. Optimizing the use of antibiotics is crucial to ensure treatment efficacy and prevent toxicity caused by overdosing, as well as to combat the prevalence and wide spread of resistant strains. Some antibiotics have been selected and reserved for the treatment of severe infections, including amikacin, gentamicin, tobramycin, and vancomycin. Critically ill patients often require long treatments, hospitalization, and require particular attention regarding TDM and dosing adjustments. As these antibiotics are eliminated by the kidneys, critical deterioration of renal function and toxic effects must be prevented. In this work, clinical data from a Portuguese cohort of 82 inpatients was analyzed and physiologically based pharmacokinetic (PBPK) modeling and simulation was used to study the influence of different therapeutic regimens and parameters as biological sex, body weight, and renal function on the biodistribution and pharmacokinetic (PK) profile of these four antibiotics. Renal function demonstrated the greatest impact on plasma concentration of these antibiotics, and vancomycin had the most considerable accumulation in plasma over time, particularly in patients with impaired renal function. Thus, through a PBPK study, it is possible to understand which pharmacokinetic parameters will have the greatest variation in a given population receiving antibiotic administrations in hospital context.

SUBMITTER: Ferreira A

PROVIDER: S-EPMC8620954 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundThe use of high-dose, extended-interval aminoglycosides, a common practice in adult populations, is less well established for pediatric patients. In younger populations, these drugs are often administered according to a multiple daily dosing method.ObjectiveTo characterize prescribing practices for aminoglycosides in pediatric inpatients across Canada, with a focus on high-dose, extended-interval regimens.MethodsThis study was based on an electronic survey of pharmacists representing Canadian health care delivery organizations that provided pediatric inpatient services, which was distributed in March 2015. Questions focused on demographic characteristics; indications for high-dose, extended-interval tobramycin or gentamicin; use of these regimens in patients with particular comorbidities; empiric dosing; monitoring parameters; and the extent of pharmacists' authority to independently prescribe doses and order monitoring parameters for aminoglycosides at their respective institutions.ResultsForty-five (48%) of the 94 prospective participants responded to the survey. Of these 45 respondents, 35 (78%) indicated that their respective health regions used high-dose, extended-interval tobramycin or gentamicin in pediatric inpatients. The patient characteristics for use of such regimens were varied. The median reported doses were 10 mg/kg for pulmonary exacerbation in cystic fibrosis, 7 mg/kg for urinary tract infection, and 8 mg/kg for febrile neutropenia. Thirty-one (89%) of the 35 respondents using these regimens reported that they monitored serum levels, and 27 (77%) reported monitoring for nephrotoxicity. With regard to prescriptive authority, 7 (16%) of the 45 respondents indicated that pharmacists were authorized to independently adjust dosing at their institutions, and pharmacists at 14 (31%) of 45 sites were authorized to order monitoring parameters.ConclusionsHigh-dose, extended-interval aminoglycoside therapy was frequently used for pediatric patients across Canada, although the dosages and monitoring practices varied greatly. The information from this study can be used for cross-comparison of practice by other centres across Canada.

Project description:BackgroundThe treatment of grafts with vancomycin for ligament reconstruction in knee surgery is the current standard. However, high antibiotic concentrations have chondrotoxic effects.PurposeTo test the chondrotoxicity of clindamycin, gentamicin and vancomycin in comparable concentrations. In vitro and in vivo effective concentrations hugely vary from drug to drug. To allow for comparisons between these three commonly used antibiotics, the concentration ranges frequently used in orthopedic surgical settings were tested.Study designControlled laboratory study.MethodsHuman cartilage from 10 specimens was used to isolate chondrocytes. The chondrocytes were treated with clindamycin (1 mg/mL and 0.5 mg/mL), gentamicin (10 mg/mL and 5 mg/mL) or vancomycin (10 mg/mL and 5 mg/mL), at concentrations used for preoperative infection prophylaxis in ligament surgery. Observations were taken over a period of 7 days. A control of untreated chondrocytes was included. To test the chondrotoxicity, a lactate dehydrogenase (LDH) test and a water-soluble tetrazolium salt (WST-1) assay were performed on days 1, 3 and 7. In addition, microscopic examinations were performed after fluorescence staining of the cells at the same time intervals.ResultsAll samples showed a reasonable vitality of the cartilage cells after 72 h. However, clindamycin and gentamicin both showed higher chondrotoxicity in all investigations compared to vancomycin. After a period of 7 days, only chondrocytes treated with vancomycin showed reasonable vitality.ConclusionsThe preoperative treatment of ligament grafts with vancomycin is the most reasonable method for infection prophylaxis, in accordance with the current study results regarding chondrotoxicity; however, clindamycin and gentamicin cover a wider anti-bacterial spectrum.Clinical relevanceThe prophylactic antibiotic treatment of ligament grafts at concentrations of 5 mg/mL or 10 mg/mL vancomycin is justifiable and reasonable. In specific cases, even the use of gentamicin and clindamycin is appropriate.

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PBPK Modeling and Simulation of Antibiotics Amikacin, Gentamicin, Tobramycin, and Vancomycin Used in Hospital Practice.

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