Population pharmacokinetics of intra-peritoneal gentamicin and the impact of varying dwell times on pharmacodynamic target attainment in patients with acute peritonitis undergoing peritoneal dialysis

2021 ◽  
Author(s):  
Andras Farkas ◽  
Katerina Oikonomou ◽  
Mohammad Ghanbar ◽  
Phillip Villasurda ◽  
Julie Varghese ◽  
...  
Keyword(s):  
Body Weight ◽  
Peritoneal Dialysis ◽  
Population Pharmacokinetics ◽  
Multiple Dose ◽  
Treatment Success ◽  
Systemic Exposure ◽  
Break Point ◽  
Target Attainment ◽  
Acute Peritonitis ◽  
The Impact

While the use of intraperitoneal (i.p.) gentamicin is common in the treatment of peritoneal dialysis (PD)-related infections, the ability of these regimens to attain pharmacodynamic target indices of interest in blood and dialysate has not been widely reported. Pharmacokinetic (PK) data was obtained and analyzed from a multiple-dose PK study of i.p. gentamicin with 24 patients who received the drug at 0.6 mg/kg dose of body weight. The probability of target attainment (PTA) for indices of treatment success (i.p. peak/MIC ratio >10) and toxicity (plasma AUC < 120 mg*h/L) was determined for 0.3 to 1.2 mg/kg i.p. regimens every 24 h for dwell times of 2 to 6 hours and for the duration of 2-week course. In the peritoneum, successful PTA was achieved by all of the simulated regimens up to an MIC of 1 mg/L, and by doses equal to or greater than 0.6 mg/kg up to the MIC of 2 mg/L. At the susceptibility break point of 4 mg/L only the highest dose of 1.2 mg/kg is likely to provide adequate PTA. Probability of achieving exposure below the threshold of 120 mg*h/L in the daily AUC in plasma seems acceptable for all regimens at or below 0.6 mg/kg. Based on the model we developed, a gentamicin dose of 0.6 mg/kg is sufficient to treat organisms with an MIC of ≤2 mg/L without the risk of significant systemic exposure. The 1.2 mg/kg dose necessary to reach the pharmacodynamic target for efficacy at the clinical break point of 4 mg/L is likely to produce early toxic levels of exposure that is expected to be detrimental to the renal system.

Multiple-Dose-Kinetics of Ofloxacin after Intraperitoneal Application in CAPD Patients

1991 ◽  
Vol 11 (4) ◽  
pp. 317-321 ◽  
Author(s):  
Dieter Kampf ◽  
Klaus Borner ◽  
Hannelore Hain ◽  
Wolfgang Conrad
Keyword(s):  
Peritoneal Dialysis ◽  
Staphylococcus Epidermidis ◽  
Peritoneal Fluid ◽  
Multiple Dose ◽  
Plasma Concentrations ◽  
Drug Application ◽  
E Coli ◽  
Acute Peritonitis ◽  
The Mean ◽  
Kinetics Of

Pharmacokinetics of ofloxacin in plasma and peritoneal fluid were studied in 11 patients on continuous ambulatory peritoneal dialysis (CAPD). Seven patients without peritonitis received 20 mg ofloxacin added to 2L dialysate i.p. every 6 h for one day only, while 4 patients with acute peritonitis were treated with this same dosage every 4 h for 3 days, then every 6 h for the next 7 days. Ofloxacin concentrations in plasma and dialysate were determined by HPLC. After i.p. drug application there was a rapid elimination of ofloxacin from dialysate, this being significantly faster in patients with peritonitis as compared to those without. Likewise, the total amount lost from the first bag after a 3 h dwell was higher in the peritonitis group (84.7±1.5%; mean±SEM) than in the non-peritonitis group (75.6±2.1 %). Twenty-four h after start of ofloxacin treatment, the mean peritoneal fluid concentrations at the end of each exchange studied were all above 3 mg/L. In patients with peritonitis, plasma concentrations of ofloxacin rose to 0.94±0.05 mg/L after 24 h reaching a Cmax of 1.8±0.2 mg/L after a tmax of 84±23 h.lntraperitoneal administration of ofloxacin was well tolerated, and no local or systemic adverse events were observed. Peritonitis episodes that were caused by Staphylococcus epidermidis (3) and by E. coli (1) were cured in all patients.

scholarly journals Population pharmacokinetics of piperacillin in febrile children receiving cancer chemotherapy: the impact of body weight and target on an optimal dosing regimen

2019 ◽  
Vol 74 (10) ◽  
pp. 2984-2993
Author(s):  
Anders Thorsted ◽  
Anders N Kristoffersson ◽  
Sabine F Maarbjerg ◽  
Henrik Schrøder ◽  
Mikala Wang ◽  
...  
Keyword(s):  
Body Weight ◽  
Continuous Infusion ◽  
Cancer Chemotherapy ◽  
Pharmacokinetic Analysis ◽  
Population Pharmacokinetic ◽  
Dosing Regimen ◽  
Target Attainment ◽  
Body Weights ◽  
Dosing Regimens ◽  
The Impact

Abstract Background The β-lactam antibiotic piperacillin (in combination with tazobactam) is commonly chosen for empirical treatment of suspected bacterial infections. However, pharmacokinetic variability among patient populations and across ages leads to uncertainty when selecting a dosing regimen to achieve an appropriate pharmacodynamic target. Objectives To guide dosing by establishing a population pharmacokinetic model for unbound piperacillin in febrile children receiving cancer chemotherapy, and to assess pharmacokinetic/pharmacodynamic target attainment (100% fT &gt; 1×MIC and 50% fT &gt; 4×MIC) and resultant exposure, across body weights. Methods Forty-three children admitted for 89 febrile episodes contributed 482 samples to the pharmacokinetic analysis. The typical doses required for target attainment were compared for various dosing regimens, in particular prolonged infusions, across MICs and body weights. Results A two-compartment model with inter-fever-episode variability in CL, and body weight included through allometry, described the data. A high CL of 15.4 L/h (70 kg) combined with high glomerular filtration rate (GFR) values indicated rapid elimination and hyperfiltration. The target of 50% fT &gt; 4×MIC was achieved for an MIC of 4.0 mg/L in a typical patient with extended infusions of 2–3 (q6h) or 3–4 (q8h) h, at or below the standard adult dose (75 and 100 mg/kg/dose for q6h and q8h, respectively). Higher doses or continuous infusion were needed to achieve 100% fT &gt; 1×MIC due to the rapid piperacillin elimination. Conclusions The licensed dose for children with febrile neutropenia (80 mg/kg q6h as a 30 min infusion) performs poorly for attainment of fT&gt;MIC pharmacokinetic/pharmacodynamic targets. Given the population pharmacokinetic profile, feasible dosing regimens with reasonable exposure are continuous infusion (100% fT &gt; 1×MIC) or prolonged infusions (50% fT &gt; 4×MIC).

scholarly journals Dose Optimization of Cefpirome Based on Population Pharmacokinetics and Target Attainment during Extracorporeal Membrane Oxygenation

2020 ◽  
Vol 64 (5) ◽  
Author(s):  
Soyoung Kang ◽  
June Young Jang ◽  
Jongsung Hahn ◽  
Dasohm Kim ◽  
Jun Yeong Lee ◽  
...  
Keyword(s):  
Extracorporeal Membrane Oxygenation ◽  
Population Pharmacokinetics ◽  
Population Pharmacokinetic Model ◽  
Pharmacokinetic Model ◽  
Dose Optimization ◽  
Population Pharmacokinetic ◽  
Optimal Dosage ◽  
Target Attainment ◽  
Membrane Oxygenation ◽  
The Impact

ABSTRACT To obtain the optimal dosage regimen in patients receiving extracorporeal membrane oxygenation (ECMO), we developed a population pharmacokinetics model for cefpirome and performed pharmacodynamic analyses. This prospective study included 15 patients treated with cefpirome during ECMO. Blood samples were collected during ECMO (ECMO-ON) and after ECMO (ECMO-OFF) at predose and 0.5 to 1, 2 to 3, 4 to 6, 8 to 10, and 12 h after cefpirome administration. The population pharmacokinetic model was developed using nonlinear mixed effects modeling and stepwise covariate modeling. Monte Carlo simulation was used to assess the probability of target attainment (PTA) and cumulative fraction of response (CFR) according to the MIC distribution. Cefpirome pharmacokinetics were best described by a two-compartment model. Covariate analysis indicated that serum creatinine concentration (SCr) was negatively correlated with clearance, and the presence of ECMO increased clearance and the central volume of distribution. The simulations showed that patients with low SCr during ECMO-ON had lower PTA than patients with high SCr during ECMO-OFF; so, a higher dosage of cefpirome was required. Cefpirome of 2 g every 8 h for intravenous bolus injection or 2 g every 12 h for extended infusion over 4 h was recommended with normal kidney function receiving ECMO. We established a population pharmacokinetic model for cefpirome in patients with ECMO, and appropriate cefpirome dosage regimens were recommended. The impact of ECMO could be due to the change in patient status on consideration of the small population and uncertainty in covariate relationships. Dose optimization of cefpirome may improve treatment success and survival in patients receiving ECMO. (This study has been registered at ClinicalTrials.gov under identifier NCT02581280.)

scholarly journals Population Pharmacokinetics of Polymyxin B in Obese Patients for Resistant Gram-Negative Infections

2021 ◽  
Vol 12 ◽  
Author(s):  
Peile Wang ◽  
Qiwen Zhang ◽  
Min Feng ◽  
Tongwen Sun ◽  
Jing Yang ◽  
...  
Keyword(s):  
Body Weight ◽  
Population Pharmacokinetics ◽  
Ideal Body Weight ◽  
Total Body Weight ◽  
Polymyxin B ◽  
Fixed Dose ◽  
Obese Patients ◽  
Target Attainment ◽  
Gram Negative ◽  
Toxicity Risk

Polymyxin B is an effective but potentially nephrotoxic antibiotic that is commonly used to treat resistant Gram-negative infections. As a weight-based dosing drug, obese patients may be at a high risk of nephrotoxicity. However, the pharmacokinetics and dosing recommendations for this population are currently lacking. This study aimed to describe the polymyxin B population pharmacokinetics and to evaluate pharmacokinetic/pharmacodynamics (PK/PD) target attainment for obese patients. This study included 26 patients (body mass index, BMI &gt;30) who received polymyxin B for ≥3 days. The total body weight (TBW) ranged from 75 to 125 kg, and the BMI ranged from 30.04 to 40.35. A two-compartment model adequately described the data using Phoenix NLME software. Monte Carlo simulation was used to assess polymyxin B exposure and the probability of target attainment (PTA). As a result, body weight had no significant effect on polymyxin B pharmacokinetics. According to model-based simulation, adjusted body weight (ABW)-based regimens had a high probability of achieving optimal exposure with minimal toxicity risk by comparing TBW and ideal body weight (IBW)-based regimens. The fixed dose of 125 mg or 150 mg q12h had a high toxicity risk. PTA results showed that TBW, IBW, and ABW-based regimens had similar PTA values. Therefore, for obese patients, ABW-based regimens but with a daily dose &lt;250 mg have a high likelihood of achieving an AUCss,24h of 50–100 mg h/L and attaining PK/PD targets with the MIC ≤0.5 mg/L.

scholarly journals Body Mass, Physical Activity and Eating Habits Changes during the First COVID-19 Pandemic Lockdown in Poland

2021 ◽  
Vol 18 (11) ◽  
pp. 5682
Author(s):  
Hubert Dobrowolski ◽  
Dariusz Włodarek
Keyword(s):  
Physical Activity ◽  
Body Weight ◽  
Body Mass ◽  
Social Life ◽  
Eating Habits ◽  
High Energy ◽  
High Energy Density ◽  
Average Weight ◽  
Study Participants ◽  
The Impact

The outbreak of the COVID-19 pandemic caused a number of changes in social life around the world. In response to the growing number of infections, some countries have introduced restrictions that may have resulted in the change of the lifestyle. The aim of our study was to investigate the impact of the lockdown on body weight, physical activity and some eating habits of the society. The survey involving 183 people was conducted using a proprietary questionnaire. The mean age of the study participants was 33 ± 11 and mean height 169 ± 8 cm. An average increase in body weight was observed in 49.18% by 0.63 ± 3.7 kg which was the result of a decrease in physical activity and an increase in food consumption. We also observed a decrease in PAL from 1.64 ± 0.15 to 1.58 ± 0.13 and changes in the amount of food and individual groups of products consumption, including alcohol. Among the study participants who did not lose body mass, there was an average weight gain of 2.25 ± 2.5 kg. In conclusion, an increase of weight was shown in about half of the respondents in the study group which was associated with a decrease in physical activity and an increase in the consumption of total food and high energy density products.

scholarly journals Pharmacokinetic/Pharmacodynamic Target Attainment Based on Measured Versus Predicted Unbound Ceftriaxone Concentrations in Critically Ill Patients with Pneumonia: An Observational Cohort Study

Antibiotics ◽  
2021 ◽  
Vol 10 (5) ◽  
pp. 557
Author(s):  
Matthias Gijsen ◽  
Erwin Dreesen ◽  
Ruth Van Daele ◽  
Pieter Annaert ◽  
Yves Debaveye ◽  
...  
Keyword(s):  
Renal Function ◽  
Cohort Study ◽  
Protein Binding ◽  
Critically Ill ◽  
Critically Ill Patients ◽  
Observational Cohort Study ◽  
Target Attainment ◽  
Binding Model ◽  
Observational Cohort ◽  
The Impact

The impact of ceftriaxone pharmacokinetic alterations on protein binding and PK/PD target attainment still remains unclear. We evaluated pharmacokinetic/pharmacodynamic (PK/PD) target attainment of unbound ceftriaxone in critically ill patients with severe community-acquired pneumonia (CAP). Besides, we evaluated the accuracy of predicted vs. measured unbound ceftriaxone concentrations, and its impact on PK/PD target attainment. A prospective observational cohort study was carried out in adult patients admitted to the intensive care unit with severe CAP. Ceftriaxone 2 g q24h intermittent infusion was administered to all patients. Successful PK/PD target attainment was defined as unbound trough concentrations above 1 or 4 mg/L throughout the whole dosing interval. Acceptable overall PK/PD target attainment was defined as successful target attainment in ≥90% of all dosing intervals. Measured unbound ceftriaxone concentrations (CEFu) were compared to unbound concentrations predicted from various protein binding models. Thirty-one patients were included. The 1 mg/L and 4 mg/L targets were reached in 26/32 (81%) and 15/32 (47%) trough samples, respectively. Increased renal function was associated with the failure to attain both PK/PD targets. Unbound ceftriaxone concentrations predicted by the protein binding model developed in the present study showed acceptable bias and precision and had no major impact on PK/PD target attainment. We showed suboptimal (i.e., <90%) unbound ceftriaxone PK/PD target attainment when using a standard 2 g q24h dosing regimen in critically ill patients with severe CAP. Renal function was the major driver for the failure to attain the predefined targets, in accordance with results found in general and septic ICU patients. Interestingly, CEFu was reliably predicted from CEFt without major impact on clinical decisions regarding PK/PD target attainment. This suggests that, when carefully selecting a protein binding model, CEFu does not need to be measured. As a result, the turn-around time and cost for ceftriaxone quantification can be substantially reduced.

The Effect of a Nitric Oxide Inhibitor (L-Name) on Peritoneal Transport during Dialysis in Rats

1998 ◽  
Vol 18 (2) ◽  
pp. 188-192 ◽  
Author(s):  
Andrzej Breborowicz ◽  
Katarzyna Wieczorowska Tobis ◽  
Katarzyna Korybalska ◽  
Alicja Polubinska ◽  
Maciej Radkowski ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Peritoneal Dialysis ◽  
Significant Decline ◽  
Nitric Oxide Synthesis ◽  
Dialysis Fluid ◽  
Large Molecules ◽  
Acute Peritonitis ◽  
Important Mediator ◽  
Peritoneal Transport ◽  
Nitric Oxide Inhibitor

Objective To assess the effect of an inhibitor of nitric oxide synthesis [NG-nitro-L-arginine methyl ester (L-NAME)] on peritoneal transport during peritoneal dialysis (PD) and peritonitis in rats. Methods The authors studied peritoneal transport of small and large solutes, and net ultrafiltration (UF) in rats during PD with Dianeal 3.86 (Baxter, McGaw Park, IL, U.S.A.). They evaluated the effect of L-NAME used as an additive to dialysis fluid in concentrations 0.5 -5 mg/m L on peritoneal transport of small and large molecules and on transperitoneal UF. In addition, they studied the effect of L-NAME (5 mg/mL) during acute peritonitis induced by lipopolysaccharides (5 μg/mL) given intraperitoneally. Results The addition of L-NAME to dialysis fluid increased the selectivity of the peritoneum and net UF during dialysis. Lipopolysaccharides used as an additive to the dialysis fluid, together with L-NAME, did not induce changes in transperitoneal transport of small and large solutes and did not cause a significant decline in net UF. L-NAME given intraperitoneally reduced both local and systemic production of nitric oxide, which might explain its effects on peritoneal transport. Conclusions Nitric oxide is an important mediator of changes in peritoneal transport and its effect is especially significant during peritonitis.

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