Is the subcutaneous route an alternative for administering ertapenem to older patients? PHACINERTA study

2019 ◽  
Vol 74 (12) ◽  
pp. 3546-3554 ◽  
Author(s):  
Claire Roubaud Baudron ◽  
Rachel Legeron ◽  
Julien Ollivier ◽  
Fabrice Bonnet ◽  
Carine Greib ◽  
...  

Abstract Background Antibiotic administration by subcutaneous (SC) injection is common practice in French geriatric wards as an alternative to the intravenous (IV) route, but few pharmacokinetic/pharmacodynamic data are available. Ertapenem is useful for the treatment of infections with ESBL-producing enterobacteria. Objectives To report and compare ertapenem pharmacokinetic data between IV and SC routes in older persons. Methods Patients >65 years of age receiving ertapenem (1 g once daily) for at least 48 h (IV or SC, steady-state) were prospectively enrolled. Total ertapenem concentrations [residual (C0), IV peak (C0.5) and SC peak (C2.5)] were determined by UV HPLC. Individual-predicted AUC0–24 values were calculated and population pharmacokinetic analyses were performed. Using the final model, a Monte Carlo simulation involving 10 000 patients evaluated the influence of SC or IV administration on the PTA. Tolerance to ertapenem and recovery were also monitored. ClinicalTrials.gov identifier: NCT02505386. Results Ten (mean ± SD age=87±7 years) and 16 (age=88±5 years) patients were included in the IV and SC groups, respectively. The mean C0 and C2.5 values were not significantly different between the IV and SC groups (C0=12±5.9 versus 12±7.4 mg/L, P=0.97; C2.5=97±42 versus 67±41 mg/L, P=0.99). The mean C0.5 was higher in the IV group compared with the SC group (C0.5=184±90 versus 51±66 mg/L, P=0.001). The mean individual AUCs (1126.92±334.99 mg·h/L for IV versus 1005.3±266.0 mg·h/L for SC, P=0.38) and PTAs were not significantly different between groups. No severe antibiotic-related adverse effects were noted. Conclusions SC administration of ertapenem is an alternative to IV administration in older patients.

2019 ◽  
Vol 63 (4) ◽  
Author(s):  
Si-Chan Li ◽  
Qi Ye ◽  
Hua Xu ◽  
Long Zhang ◽  
Yang Wang

ABSTRACT Linezolid is a synthetic antibiotic very effective in the treatment of infections caused by Gram-positive pathogens. Although the clinical application of linezolid in children has increased progressively, data on linezolid pharmacokinetics in pediatric patients are very limited. The aim of this study was to develop a population pharmacokinetic model for linezolid in children and optimize the dosing strategy in order to improve therapeutic efficacy. We performed a prospective pharmacokinetic study of pediatric patients aged 0 to 12 years. The population pharmacokinetic model was developed using the NONMEM program. Goodness-of-fit plots, nonparametric bootstrap analysis, normalized prediction distribution errors, and a visual predictive check were employed to evaluate the final model. The dosing regimen was optimized based on the final model. The pharmacokinetic data from 112 pediatric patients ages 0.03 to 11.9 years were analyzed. The pharmacokinetics could best be described by a one-compartment model with first-order elimination along with body weight and the estimated glomerular filtration rate as significant covariates. Simulations demonstrated that the currently approved dosage of 10 mg/kg of body weight every 8 h (q8h) would lead to a high risk of underdosing for children in the presence of bacteria with MICs of ≥2 mg/liter. To reach the pharmacokinetic target, an elevated dosage of 15 or 20 mg/kg q8h may be required for them. The population pharmacokinetics of linezolid were characterized in pediatric patients, and simulations provide an evidence-based approach for linezolid dosage individualization.


2020 ◽  
Author(s):  
Athanase Benetos ◽  
Tsung-Po Lai ◽  
Simon Toupance ◽  
Carlos Labat ◽  
Simon Verhulst ◽  
...  

AbstractBackgroundLymphopenia due to a plummeting T-cell count is a major feature of severe COVID-19. T-cell proliferation is telomere length (TL)-dependent and TL shortens with age. Older persons are disproportionally affected by severe COVID-19, and we hypothesized that those with short TL have less capacity to mount an adequate T-cell proliferative response to SARS-CoV-2. This hypothesis predicts that among older patients with COVID-19, shorter telomeres of peripheral blood mononuclear cells (PBMCs) will be associated with a lower lymphocyte count.MethodsOur sample comprised 17 COVID-19 and 21 non-COVID-19 patients, aged 87 ± 8 (mean ± SD) and 87 ± 9 years, respectively. We measured TL by the Telomere Shortest Length Assay, a novel method that measures and tallies the short telomeres directly relevant to telomere-mediated biological processes. The primary analysis quantified TL as the proportion of telomeres shorter than 2 kilobases. For comparison, we also quantified TL by Southern blotting, which measures the mean length of telomeres.ResultsLymphocyte count (109/L) was 0.91 ± 0.42 in COVID-19 patients and 1.50 ± 0.50 in non-COVID-19 patients (P < 0.001). In COVID-19 patients, but not in non-COVID-19 patients, lymphocyte count was inversely correlated with the proportion of telomeres shorter than 2 kilobases (P = 0.005) and positively correlated with the mean of telomeres measured by TeSLA (P = 0.03). Lymphocyte counts showed no statistically significant correlations with Southern blotting results in COVID-19 or non-COVID-19 patients.ConclusionsThese results support the hypothesis that a compromised TL-dependent T-cell proliferative response contributes to lymphopenia and the resulting disproportionate severity of COVID-19 among old adults. We infer that infection with SARS-CoV-2 uncovers the limits of the TL reserves of older persons.


Author(s):  
Jasmina Milovanovic ◽  
Radica Živković Zaric ◽  
Nikola Rosic ◽  
Dejana Ruzić Zecevic ◽  
Dragan Milovanovic ◽  
...  

Abstract Vancomycin is a tricyclic glycopeptide antibiotic, mostly used in the treatment of severe staphylococcal and enterococcal infections, especially in orthopedic surgery. The purpose of this analysis was to develop a population pharmacokinetic (PPK) model of vancomycine in hospitalized patients with bone fractures and identify important factors which influence its clearance (CL). A total of ninety-nine measurements of vancomycin serum concentrations were used in our population modeling. A two-compartment model was applied to describe the pharmacokinetics of vancomycin using subroutines ADVAN3 and TRANS4. The study population included patients of both sexes, with the mean age of 62.12±14.69 years and body weight of 80.32±12.44kg. Vancomycin was administered as intravenous infusion with average daily dose of 1772.73±521.34mg. Out of twenty different factors evaluated in the study (including demographic, clinical and laboratory data), only daily dose of vancomycin (DD) and co-medication with piperacillin/tazobactam (PT) showed significant effect on clearance of vancomycin. The final model was described by the following equation: CL (l/h) = 0.03 + 0.000468 x DD + 0.675 x PT. Bootstrapping was used for validation of the final model. In conclusion, the main causes of variability in the clearance of vancomycin among adult patients with bone fractures are daily dose of vancomycin and co-medication with piperacillin/tazobactam.


2005 ◽  
Vol 23 (17) ◽  
pp. 3906-3911 ◽  
Author(s):  
Michelle A. Rudek ◽  
Ming Zhao ◽  
Ping He ◽  
Carol Hartke ◽  
Jill Gilbert ◽  
...  

PurposeTo characterize the pharmacokinetic behavior of 5-azacitidine (5-AC), a cytidine nucleoside analog, when given with phenylbutyrate, a histone deaceytlase inhibitor.Patients and MethodsPharmacokinetic data were obtained from two trials involving patients with solid tumor and hematologic malignancies. 5-AC at doses ranging from 10 to 75 mg/m2/d was administered once daily as a subcutaneous injection for 5 to 21 days in combination with phenylbutyrate administered as a continuous intravenous infusion for varying dose and duration every 28 or 35 days. Serial plasma samples were collected up to 24 hours after 5-AC administration. 5-AC was quantitated using a validated liquid chromatograph/tandem mass spectrometry method.Results5-AC was rapidly absorbed with the mean Tmaxoccurring at 0.47 hour. Average maximum concentration (Cmax) and area under the curve (AUC0-∞) values increased in a dose-proportionate manner with increasing dose from 10 to 75 mg/m2/d; the mean ± SD Cmaxand AUC0-∞at 10 mg/m2/d were 776 ± 459 nM and 1,355 ± 1,125 h*nM, respectively, and at 75 mg/m2/d were 4,871 ± 1,398 nM and 6,582 ± 2,560 h*nM, respectively. Despite a short terminal half-life of 1.5 ± 2.3 hours, inhibition of DNA methyl transferase activity in tumors of patients receiving 5-AC has been documented.Conclusion5-AC is rapidly absorbed and eliminated when administered subcutaneously. Sufficient 5-AC exposure is achieved to produce pharmacodynamic effects in tumors.


2019 ◽  
Vol 63 (4) ◽  
Author(s):  
Jeannet C. Bos ◽  
Jan M. Prins ◽  
Mabor C. Mistício ◽  
Ginto Nunguiane ◽  
Cláudia N. Lang ◽  
...  

ABSTRACT In sub-Saharan Africa (SSA), gentamicin is commonly used for severe infections in non-intensive-care-unit (ICU) settings, but pharmacokinetic and pharmacodynamic data for this specific population are lacking. We performed a population pharmacokinetic study in an adult Mozambican non-ICU hospital population treated with gentamicin (n = 48) and developed a pharmacokinetic model using nonlinear mixed-effects modeling. Simulations showed that non-ICU patient populations in SSA may be at substantial risk for underexposure to gentamicin during routine once-daily dosing.


1998 ◽  
Vol 42 (5) ◽  
pp. 1098-1104 ◽  
Author(s):  
Sandra L. Preston ◽  
George L. Drusano ◽  
Adam L. Berman ◽  
Cynthia L. Fowler ◽  
Andrew T. Chow ◽  
...  

ABSTRACT Population pharmacokinetic modeling is a useful approach to obtaining estimates of both population and individual pharmacokinetic parameter values. The potential for relating pharmacokinetic parameters to pharmacodynamic outcome variables, such as efficacy and toxicity, exists. A logistic regression relationship between the probability of a successful clinical and microbiological outcome and the peak concentration-to-MIC ratio (and also the area under the plasma concentration-time curve [AUC]/MIC ratio) has previously been developed for levofloxacin; however, levofloxacin assays for determination of the concentration in plasma are not readily available. We attempted to derive and validate demographic variable models to allow prediction of the peak concentration in plasma and clearance (CL) from plasma for levofloxacin. Two hundred seventy-two patients received levofloxacin intravenously for the treatment of community-acquired infection of the respiratory tract, skin or soft tissue, or urinary tract, and concentrations in plasma, guided by optimal sampling theory, were obtained. Patient data were analyzed by the Non-Parametric Expectation Maximization approach. Maximum a posteriori probability Bayesian estimation was used to generate individual parameter values, including CL. Peak concentrations were simulated from these estimates. The first 172 patients were used to produce demographic models for the prediction of CL and the peak concentration. The remaining 100 patients served as the validation group for the model. A median bias and median precision were calculated. A two-compartment model was used for the population pharmacokinetic analysis. The mean CL and the mean volume of distribution of the central compartment (V 1) were 9.27 liters/h and 0.836 liter/kg, respectively. The mean values for the intercompartmental rate constants, the rate constant from the central compartment to the peripheral compartment (K cp) and the rate constant from the peripheral compartment to the central compartment (K pc), were 0.487 and 0.647 h−1, respectively. The mean peak concentration and the mean AUC values normalized to a dosage of 500 mg every 24 h were 8.67 μg/ml and 72.53 μg · h/ml, respectively. The variables included in the final model for the prediction of CL were creatinine clearance (CLCR), race, and age. The median bias and median precision were 0.5 and 18.3%, respectively. Peak concentrations were predicted by using the demographic model-predicted parameters of CL,V 1, K cp, andK pc, in the simulation. The median bias and the median precision were 3.3 and 21.8%, respectively. A population model of the disposition of levofloxacin has been developed. Population demographic models for the prediction of peak concentration and CL from plasma have also been successfully developed. However, the performance of the model for the prediction of peak concentration was likely insufficient to be of adequate clinical utility. The model for the prediction of CL was relatively robust, with acceptable bias and precision, and explained a reasonable amount of the variance in the CL of levofloxacin from plasma in the population (r 2 = 0.396). Estimated CLCR, age, and race were the final model covariates, with CLCRexplaining most of the population variance in the CL of levofloxacin from plasma. This model can potentially optimize the benefit derived from the pharmacodynamic relationships previously developed for levofloxacin.


2012 ◽  
Vol 56 (4) ◽  
pp. 1892-1898 ◽  
Author(s):  
Jintanat Ananworanich ◽  
Meena Gorowara ◽  
Anchalee Avihingsanon ◽  
Stephen J. Kerr ◽  
Nadine van Heesch ◽  
...  

ABSTRACTBecause studies showed similar viral suppression with lower raltegravir doses and because Asians usually have high antiretroviral concentrations, we explored low-dose raltegravir therapy in Thais. Nineteen adults on raltegravir at 400 mg twice daily (BID) with HIV RNA loads of <50 copies/ml were randomized to receive 400 mg once daily (QD) or 800 mg QD for 2 weeks, followed by the other dosing for 2 weeks. Intensive pharmacokinetic analyses were performed, and HIV RNA was monitored. Two patients were excluded from the 400-mg QD analysis due to inevaluable pharmacokinetic data. The mean patient weight was 58 kg. Mean pharmacokinetic values were as follows: for raltegravir given at 400 mg BID, the area under the concentration-time curve from 0 to 12 h (AUC0-12) was 15.6 mg/liter-h and the minimum plasma drug concentration (Ctrough) was 0.22 mg/liter; for raltegravir given at 800 mg QD, the AUC0-24was 33.6 mg/liter-h and theCtroughwas 0.06 mg/liter; and for raltegravir given at 400 mg QD, the AUC0-24was 18.6 mg/liter-h and theCtroughwas 0.08 mg/liter. The HIV RNA load was <50 copies/ml at each dose level. Compared to the adjusted AUC0-24for Westerners on raltegravir at 400 mg BID, Thais on the same dose had double the AUC0-24and those on raltegravir at 400 mg QD had a similar AUC0-24. More patients had aCtroughof <0.021 mg/liter on raltegravir at 400 mg QD (9/17 patients) than on raltegravir at 800 mg QD (1/19 patients) or 400 mg BID (0/19 patients). Seventeen patients used raltegravir at 400 mg QD for a median of 35 weeks; two had confirmed HIV RNA loads between 50 and 200 copies/ml, and both had lowCtroughvalues. Low-dose raltegravir could be a cost-saving option for maintenance therapy in Asians or persons with low body weight. However, raltegravir at 400 mg QD was associated with a lowCtroughand with a risk for HIV viremia. Raltegravir at 200 or 300 mg BID should be studied, but new raltegravir formulations will be needed.


Author(s):  
Ab Rahman A F ◽  
Md Sahak N. ◽  
Ali A. M.

Objective: Once daily dosing (ODD) aminoglycoside is gaining wide acceptance as an alternative way of dosing. In our setting it is the regimen of choice whenever gentamicin is indicated. The objective of this study was to evaluate the practice of gentamicin ODD in a public hospital in Malaysia. Methods: We conducted a retrospective review of medical records of patients on gentamicin ODD who were admitted to Hospital Melaka during January 2002 until March 2010. All adult patients who were on ODD gentamicin with various level of renal function were included in the study. Patients on gentamicin less than 72 hours and pregnant women were excluded. Results: From 110 patients, 75 (68.2%) were male and 35 (31.8%) were female. Indications for ODD gentamicin included pneumonia, 34 (31.0%) neutropenic sepsis, 27 (24.5%) and sepsis, 11 (10.0%). The mean dose and duration of gentamicin was 3.2 mg/kg/day and 7 days, respectively. Almost all patients were on gentamicin combined with other antibiotics. Clinical cure based on fever resolution was found in 89.1% of patients treated with ODD. Resolution of fever took an average of 48 hours after initiation of therapy. The evaluation for bacteriologic cure could not be performed because of insufficient data on culture and sensitivity. Out of 38 patients with analyzable serum creatinine data, four patients might have developed nephrotoxicity. Conclusion: In our setting, lower dosages of ODD gentamicin when used in combination with other antibiotics seemed to be effective and safe in treating most gram negative infections.


2020 ◽  
pp. 1357633X1989388
Author(s):  
Anne-Sophie Boureau ◽  
Helene Masse ◽  
Guillaume Chapelet ◽  
Laure de Decker ◽  
Pascal Chevalet ◽  
...  

Introduction Population-based studies show a significant increase in the prevalence of visual impairment in older patients. However, older patients and patients with lower Mini-Mental State Examination (MMSE) scores have few ophthalmological assessments. The main objective of our study was to evaluate the feasibility of tele-ophthalmological screening for ophthalmological diseases in older patients referred for cognitive assessment. Methods This monocentric prospective study included patients referred to a memory clinic for cognitive assessment. All patients underwent a geriatric assessment comprising a cognitive assessment associated with tele-ophthalmological screening undertaken by an orthoptist, including undilated retinal photography. The retinal photographs were subsequently sent to an ophthalmologist. We identified patients who were not eligible for ophthalmological assessment, for patients that had to come back due to poor-quality retinal photographs and finally for detected eye diseases. The association between the geriatric variable and newly detected eye diseases was analysed in univariable and multivariable analyses. Results The mean age of the 298 patients included was 83.5 years  ± 5.65; 29.5% were male. The mean MMSE score was 20.8 ± 5.2; 66.3% of patients had a diagnosis of dementia. Eighteen patients (6.0%) were not eligible for ophthalmological examination and 13 patients (4.6%) were asked to come back owing to poor-quality retinal photographs. Forty-one patients (13.7%) had a newly detected eye disease. In multivariable analysis, patients with a lower MMSE had significantly more newly identified eye diseases. Discussion The tele-ophthalmological screening method identified unknown ophthalmological diseases requiring specialised management in this older population with cognitive complaints.


2019 ◽  
Vol 6 (Supplement_2) ◽  
pp. S335-S336
Author(s):  
Hyeri Seok ◽  
Ju-Hyun Song ◽  
Ji Hoon Jeon ◽  
Hee Kyoung Choi ◽  
Won Suk Choi ◽  
...  

Abstract Background Even after the introduction of the Sepsis-3 definition, there is still debate on the ideal antibiotic administration time in patients with sepsis. This study was performed to evaluate the association between the timing of antibiotic administration and mortality in sepsis patients who visited the emergency room. Methods A prospective cohort study was conducted on patients who were diagnosed as sepsis with Sepsis-3 definition among patients who visited the emergency department (ED) of Korea University Ansan Hospital from September 2017 to January 2019. The timing of antibiotic administration was defined as the time in hours from ED arrival until the first antibiotic administration. Cox logistic regression analysis was used to estimate the association between time to antibiotics and 7-, 14-, and 28-day mortality. Results During the study period, a total of 251 patients were enrolled with a 7-, 14-, and 28-day mortality of 16.7%, 36.3%, and 57.4%, respectively. The median time to antibiotic administration was 247 minutes (interquartile range 72 – 202 minutes). The mean age was 72 ± 15 years old and 122 patients (48.6%) were female. The most common site of infection was respiratory infection. The timing of antibiotic administration were not associated with 7-, 14-, and 28-day mortality. Female (adjusted hazard ratio [HR] 2.06 [95% confidence interval (CI) 1.21 – 3.53]; P value = 0.008), SOFA score (aHR 1.17 [95% CI 1.05 - 1.31]; P = 0.005), and initial lactate level (aHR 1.13 [95% CI 1.05 - 1.22]; P = 0.001) increased the risk of 7-day mortality. Female (aHR 2.07 [95% CI 1.48 – 2.89]; P ≤ 0.001), Charlson comorbidity index (aHR 1.12 [95% CI 1.02 - 1.24]; P = 0.025), and initial lactate level (aHR 1.19 [95% CI 1.02 - 1.16]; P = 0.011) increased the risk of 14-day mortality. Female (aHR 1.95 [95% CI 1.50 – 2.54]; P = 0.001) increased the risk of 28-day mortality in patients with sepsis. Conclusion The timing of antibiotic administration did not increase the risk of mortality in the treatment of sepsis patients who visited ED. Rather, the SOFA score, lactate, female, and comorbidity increased the mortality associated with sepsis. Disclosures All authors: No reported disclosures.


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