Antibiotic pharmacokinetics in the elderly require altered dosing due to reduced renal clearance.
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Peer-reviewed literature demonstrates that physiological aging and reduced renal clearance in elderly patients frequently necessitate antibiotic dosage adjustments, though exceptions exist depending on the specific drug and patient health status.
Linezolid is an antibiotic used to treat infections caused by drug-resistant gram-positive organisms, including vancomycin-resistant Enterococcus faecium, multi-drug resistant Streptococcus pneumoniae, and methicillin-resistant Staphylococcus aureus. The adverse effects of linezolid can include thrombocytopenia and neuropathy, which are more prevalent with higher exposures and longer treatment durations. Although linezolid is traditionally administered at a standard 600 mg dose every 12 hours, the resulting exposure can vary greatly between patients and can lead to treatment failure or toxicity. The efficacy and toxicity of linezolid are determined by the exposure achieved in the patient; numerous clinical and population pharmacokinetics (popPK) studies have identified threshold measurements for both parameters. Several special populations with an increased need for linezolid dose adjustments have also been identified. Therapeutic Drug Monitoring (TDM) is a clinical strategy that assesses the response of an individual patient and helps adjust the dosing regimen to maximize efficacy while minimizing toxicity. Adaptive feedback control and model-informed precision dosing are additional strategies that use Bayesian algorithms and PK models to predict patient-specific drug exposure. TDM is a very useful tool for patient populations with sparse clinical data or known alterations in pharmacokinetics, including children, patients with renal insufficiency or those receiving renal replacement therapy, and patients taking co-medications known to interact with linezolid. As part of the clinical workflow, clinicians can use TDM with the thresholds summarized from the current literature to improve linezolid dosing for patients and maximize the probability of treatment success.
To summarize the pharmacokinetics of linezolid to optimize the dosing regimen in special populations. A literature search was performed in three largest medical databases, including Embase, Scopus, and PubMed. The main applied keywords were linezolid and pharmacokinetics. Of 3663 retrieved publications in the English language, 35 original research articles, clinical studies, and case reports about linezolid pharmacokinetics in different populations such as pregnant women, pediatrics, elderly subjects, obese people, individuals with organ dysfunction, and critically ill patients were included. RESULTS AND CONCLUSION: Dose adjustment is not currently recommended for linezolid in patients with mild to moderate renal or hepatic impairment, older adults, and pregnant women. Although dose adjustment is not recommended in patients with severe renal or hepatic impairment, it should be considered that these patients are more vulnerable to linezolid adverse effects and drug interactions. In pediatrics, reducing the linezolid dosing interval to 8 h is suggested. Despite the lack of sufficient information in obese individuals, dosing based on body weight or use of higher dose seems to be justifiable to prevent sub-therapeutic concentrations. Although dose adjustment of linezolid is not recommended in critically ill patients, administration of linezolid as continuous intravenous infusion is suggested in this population. Blood level monitoring should be considered in populations that are vulnerable to linezolid underexposure (such as critically ill patients with augmented renal clearance, pediatrics, overweight, and obese patients) or overexposure (such as elderly, patients with hepatic and renal impairment). To assess the efficacy and safety of linezolid, the area under the concentration-time curve over 24 h to minimum inhibitory concentration (AUC0-24 h/MIC) equal to 80-120, percentage of time above the MIC ≥ 85%, and serum trough concentration between 2 and 7 mg/L are suggested.
Augmented renal clearance (ARC), defined as a creatinine clearance (CrCl) > 130 mL/min/1.73 m2, is observed in 30–65% of critically ill patients. When following standard dosage guidelines, patients with ARC often experience subtherapeutic vancomycin levels, resulting in treatment failure due to accelerated drug elimination. This review aims to explore ARC’s impact on vancomycin pharmacokinetics and pharmacodynamics (PK/PD) indices in ARC patients, seeking to identify an accurate dose adjustment method for this patient population. In September 2023, a comprehensive literature search was conducted on the MEDLINE and EMBASE databases to include all available studies providing information on the impact of ARC on vancomycin therapy in critically ill adults. Articles that studied the pediatric population and those with insufficient PK data were excluded. A total of 21 articles met the inclusion criteria. The findings revealed a positive correlation between CrCl and vancomycin clearance, indicating low serum concentrations. Therefore, upward dosing adjustments are necessary to improve treatment success. Younger age consistently emerged as a major contributor to ARC and vancomycin PK/PD alterations. This study summarizes the PK/PD alterations, current dosage recommendations and proposes preliminary recommendations on possible dosing approaches to decrease the risk of subtherapeutic exposure in this patient population.
<h4>Background</h4>Imipenem is a broad-spectrum carbapenem antibiotic for severe infections with significant pharmacokinetic (PK) variability. This review systematically synthesized published population pharmacokinetic (popPK) studies to identify key covariates and guide individualized dosing for patients with various conditions.<h4>Methods</h4>A systematic PubMed and Web of Science search identified imipenem popPK models. Studies employing nonlinear mixed-effects modeling in patients with various conditions were included, and data were extracted independently by two reviewers via a standardized form. The study characteristics and PK parameter estimates were compared.<h4>Results</h4>This systematic review of 18 popPK studies revealed that imipenem PKs were predominantly characterized by two-compartment models. The clearance of imipenem varied from 4.79 to 16.2 L/h in adults. Creatinine clearance (CLcr) was the most consistent and significant covariate for imipenem clearance, whereas body weight (BW) was frequently identified for volume of distribution. Other clinically relevant covariates, including the glomerular filtration rate (GFR), age, and serum ALB level, were also incorporated into the final models for specific patient subpopulations. All models applied internal validations, such as bootstrap and visual predicative check, but only three studies performed external validation.<h4>Conclusion</h4>This review systematically integrates existing popPK models of imipenem, highlighting renal function and BW as key covariates. This study provides valuable insights for individualized dosing while identifying critical research gaps, particularly the need for external validation and focused studies in special populations.
The effect of age on the pharmacokinetics of pentisomide.
The effects of age on the pharmacokinetics of pentisomide (CM7857), an orally effective antiarrhythmic agent, were studied in two groups of volunteers. Sixteen young volunteers (mean age 26.4 years) and 10 elderly volunteers (mean age 67.8 years) received a single 200 mg oral dose of pentisomide. Mean AUC was larger and terminal elimination half-life longer in the elderly subjects, due to a decrease in total plasma clearance of pentisomide in the elderly. This decrease was due to a reduction in renal clearance of the drug which was paralleled by a significantly lower creatinine clearance in the elderly subjects. Dosage reduction, or a reduced frequency of dosing of pentisomide would be necessary in the elderly or those with impaired renal function.
Published in Biopharmaceutics & drug disposition (1991)
Quinolone disposition in the elderly. Practical implications. The fluoroquinolones are antibiotics frequently used in infections that affect elderly individuals. The physiological aging process can profoundly affect the pharmacokinetics of drugs, necessitating adjustment of dosage regimens in the elderly. Changes in pharmacokinetics with age are mainly due to the progressive deterioration of renal function, with resultant lower clearance of drugs which are eliminated by the kidneys. Ofloxacin is almost totally renally excreted and elimination is slower in older age groups; a dose reduction is therefore recommended for this quinolone. Unexpected alterations in pharmacokinetics may occur, as exemplified by the increased bioavailability of oral ciprofloxacin in elderly subjects. This is a well-documented phenomenon of such significance that lower oral doses are advisable for the elderly. Renal clearance of ciprofloxacin decreases in old age, but because of substantial nonrenal elimination the total clearance is affected less. Studies of the pharmacokinetics of the other quinolones in old age are scarce.
Comparative pharmacokinetics of ceftazidime in young, healthy and elderly, acutely ill males.
The pharmacokinetics of ceftazidime have been investigated after single and multiple i.v. doses in 9 young healthy male volunteers and 15 elderly male patients with acute bacterial infections. All subjects had normal, age-correlated glomerular function. Distribution and elimination in young volunteers were unaffected by posture and were similar to what has been reported earlier. In contrast, elderly patients had longer t1/2 beta (3.1 vs 1.9 h), larger AUC (414.0 vs 276.6 h.mg/l), lower total and renal clearances, reduced urinary recovery over 12 h and enlarged Vss. Total serum clearance of ceftazidime was closely correlated with the 51Cr-EDTA clearance. There was no significant change in 51Cr-EDTA clearance after seven days of treatment. A reduction in the dose of beta-lactam antibiotics eliminated by the kidney is advisable in elderly patients with an acute bacterial infection.
Published in European journal of clinical pharmacology (1988)
This single-case report describes severe neurotoxicity manifesting as seizure in an older, critically ill patient with acute kidney injury during treatment with ceftazidime-avibactam (CZA-AVI), a combination antibiotic used for multidrug-resistant Gram-negative infections. Although generally safe, neurotoxicity from CZA-AVI, while uncommon, can be severe. The patient, a 78-year-old woman with multiple comorbidities and acute kidney injury, developed impaired consciousness progressing to generalized seizures a few days after initiating CZA-AVI. Electroencephalography confirmed seizure activity. All other potential causes were excluded. Her neurological symptoms resolved completely after discontinuation of CZA-AVI and initiation of antiepileptic therapy. This case highlights that CZA-AVI carries a risk of serious neurotoxicity, particularly in vulnerable populations such as older, critically ill patients with renal impairment. It underscores the imperative for strict adherence to renal dose adjustment guidelines, vigilant neurological monitoring, and immediate consideration of drug-induced encephalopathy in the differential diagnosis of mental status changes in such patients. Awareness of this potential adverse event should be integrated into antimicrobial stewardship programs to optimize patient safety.
Pharmacokinetics of ceftazidime in elderly volunteers.
The pharmacokinetics of ceftazidime after a 1-g bolus dose were studied in six elderly volunteers and 12 young subjects. Serum and urine samples were collected in serial order for 24 h and assayed by high-pressure liquid chromatography. The ceftazidime renal clearance was reduced in elderly subjects, a symptom related to normal aging of the kidneys. The decrease in volume of distribution in the elderly group may be explained by a reduction in total body water and an increase in fat tissue. Dosage adjustment is probably not necessary for otherwise healthy elderly patients requiring ceftazidime.
Published in Antimicrobial agents and chemotherapy (1985)
44 percent of the drug is lost due to the first pass effect through the liver. Age and renal function do not affect the pharmacokinetics of moclobemide
Moclobemide, sold under the brand names Amira, Aurorix, Clobemix, Depnil and Manerix among others, is a reversible inhibitor of monoamine oxidase A (RIMA) drug primarily used to treat depression and social anxiety. It is not approved for use in the United States, but is approved in other Western countries such as Canada, the United Kingdom and Australia. It is produced by affiliates of the Hoffman
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