Minor Fluctuations in Renal Function May Alter Therapeutic Drug Concentrations Substantially during High-Dose, Continuous-Infusion Beta-Lactam Therapy for Multi-Drug-Resistant Gram-Negative Bacilli

2012 ◽  
Vol 13 (6) ◽  
pp. 415-417 ◽  
Author(s):  
Cheguevara I. Afaneh ◽  
Vanessa P. Ho ◽  
Peter McWhorter ◽  
David P. Nicolau ◽  
Philip S. Barie
Keyword(s):  
Renal Function ◽  
Continuous Infusion ◽  
Therapeutic Drug ◽  
High Dose ◽  
Drug Resistant ◽  
Beta Lactam ◽  
Gram Negative ◽  
Drug Concentrations

scholarly journals Assessment of a PK/PD Target of Continuous Infusion Beta-Lactams Useful for Preventing Microbiological Failure and/or Resistance Development in Critically Ill Patients Affected by Documented Gram-Negative Infections

Antibiotics ◽  
2021 ◽  
Vol 10 (11) ◽  
pp. 1311
Author(s):  
Milo Gatti ◽  
Pier Giorgio Cojutti ◽  
Renato Pascale ◽  
Tommaso Tonetti ◽  
Cristiana Laici ◽  
...  
Keyword(s):  
Continuous Infusion ◽  
Critically Ill ◽  
Critically Ill Patients ◽  
Area Under The Curve ◽  
Therapeutic Drug ◽  
Beta Lactam ◽  
Beta Lactams ◽  
Roc Curve Analysis ◽  
Resistance Development ◽  
Gram Negative

Background: Emerging data suggest that more aggressive beta-lactam PK/PD targets could minimize the occurrence of microbiological failure and/or resistance development. This study aims to assess whether a PK/PD target threshold of continuous infusion (CI) beta-lactams may be useful in preventing microbiological failure and/or resistance development in critically ill patients affected by documented Gram-negative infections. Methods: Patients admitted to intensive care units from December 2020 to July 2021 receiving continuous infusion beta-lactams for documented Gram-negative infections and having at least one therapeutic drug monitoring in the first 72 h of treatment were included. A receiver operating characteristic (ROC) curve analysis was performed using the ratio between steady-state concentration and minimum inhibitory concentration (Css/MIC) ratio as the test variable and occurrence of microbiological failure as the state variable. Area under the curve (AUC) and 95% confidence interval (CI) were calculated. Independent risk factors for the occurrence of microbiological failure were investigated using logistic regression. Results: Overall, 116 patients were included. Microbiological failure occurred in 26 cases (22.4%). A Css/MIC ratio ≤ 5 was identified as PK/PD target cut-off with sensitivity of 80.8% (CI 60.6–93.4%) and specificity of 90.5% (CI 74.2–94.4%), and with an AUC of 0.868 (95%CI 0.793–0.924; p < 0.001). At multivariate regression, independent predictors of microbiological failure were Css/MIC ratio ≤ 5 (odds ratio [OR] 34.54; 95%CI 7.45–160.11; p < 0.001) and Pseudomonas aeruginosa infection (OR 4.79; 95%CI 1.11–20.79; p = 0.036). Conclusions: Early targeting of CI beta-lactams at Css/MIC ratio > 5 during the treatment of documented Gram-negative infections may be helpful in preventing microbiological failure and/or resistance development in critically ill patients.

scholarly journals Population Pharmacokinetics of High-Dose Continuous-Infusion Meropenem and Considerations for Use in the Treatment of Infections Due to KPC-Producing Klebsiella pneumoniae

2017 ◽  
Vol 61 (10) ◽  
Author(s):  
Piergiorgio Cojutti ◽  
Assunta Sartor ◽  
Elda Righi ◽  
Claudio Scarparo ◽  
Matteo Bassetti ◽  
...  
Keyword(s):  
Monte Carlo ◽  
Renal Function ◽  
Klebsiella Pneumoniae ◽  
Monte Carlo Simulations ◽  
Continuous Infusion ◽  
Population Pharmacokinetics ◽  
University Hospital ◽  
Therapeutic Drug ◽  
High Dose ◽  
Content Type

ABSTRACT We assessed the population pharmacokinetics of high-dose continuous-infusion (HDCI) meropenem in a cohort of patients with Klebsiella pneumoniae carbapenemase (KPC)-producing Klebsiella pneumoniae (KPC-Kp) infections. Monte Carlo simulations were used to define the permissible HDCI meropenem regimens that could be safely considered for the treatment of KPC-Kp infections due to meropenem-resistant strains. Permissible doses were arbitrarily defined as those associated with a ≤10% to 15% likelihood of meropenem steady-state concentrations (C ss) of >100 mg/liter. Probabilities of target attainment (PTA) of four incremental pharmacodynamic determinants for meropenem efficacy (100% T>1×MIC, 100% T>2×MIC, 100% T>3×MIC, and 100% T>4×MIC, where “T>MIC” represents the time during which the plasma concentration of this time-dependent antibacterial agent is maintained above the MIC for the pathogen) in relation to different classes of renal function were calculated. The cumulative fractions of response (CFR) for the permissible HDCI meropenem regimens were calculated against the MIC distribution of the KPC-Kp clinical isolates that were collected routinely at our University Hospital between 2013 and 2016 (n = 169). Ninety-seven meropenem C ss were included in the analysis. The final model included creatinine clearance (CrCL) as a covariate and explained 94% of the population variability. Monte Carlo simulations based on licensed dosages of up to 6 g/day predicted an acceptable PTA (>80%) of 100% T>1×MIC against KPC-Kp with a meropenem MIC of ≤32 mg/liter in patients with a CrCL level of <130 ml/min. Dosages of 8 g/day were needed for achieving the same target in patients with CrCL at levels of 130 to 200 ml/min. In dealing with pathogens with a meropenem MIC of 64 mg/liter, HDCI regimens using meropenem at higher than licensed levels should be considered. In these cases, real-time therapeutic drug monitoring could be a useful adjunct for optimized care. The predicted CFR were >75% in all of the classes of renal function.

scholarly journals Outcomes in patients with gram-negative sepsis treated with gentamicin

2012 ◽  
Vol 3 (3) ◽  
pp. 109-113 ◽  
Author(s):  
Peter Pillans ◽  
Joel Iedema ◽  
Peter Donovan ◽  
Robert Newbery ◽  
Venetia Whitehead ◽  
...  
Keyword(s):  
Renal Function ◽  
Elderly Population ◽  
Total Body Weight ◽  
Therapeutic Drug ◽  
Gram Negative ◽  
Clinical Endpoints ◽  
Patient Demographics ◽  
Antimicrobial Sensitivity ◽  
Total Body ◽  
Baseline Renal Function

Objective: Recent changes to therapeutic drug monitoring (TDM) of gentamicin have been advocated in Australia. It remains uncertain whether these will have an effect on hard clinical endpoints. The aim of this study was to determine clinical outcomes in patients with gram-negative infections treated with gentamicin. Methods: Microbiology results of patients with confirmed gram-negative cultures were retrospectively reviewed and those treated with gentamicin included. Medical records were reviewed and patient demographics, diagnosis, renal function, comorbidities, gentamicin doses, duration, monitoring, concomitant antibiotics, antimicrobial sensitivity and clinical and microbiological outcomes recorded. Results: A total of 100 patients were included in the study: 52% were male, median age 64 years (17–97). Total body weight was recorded in 56% (median 74.5 kg, range 35–134 kg). Most patients had two or more important comorbidities. A total of 72% received empiric and 28% directed treatment. The organism was identified on blood culture in 45%, urine culture in 43% and aspiration of liver abscess in 12%; 95% of organisms were sensitive to gentamicin. Baseline renal function was normal in 62%. Mean gentamicin dose was 3.9 ± 0.9 mg/kg and mean duration 2.9 ± 2.5 days. Only 21% had optimal TDM. Clinical outcome was favourable in 90%. There were no cases of preventable serious toxicity. Conclusions: Despite the modest doses of gentamicin used in an elderly population with comorbidities, as well as the absence of optimal TDM, outcomes were favourable without preventable serious toxicity.

scholarly journals Vancomycin Dosing in Pediatric Extracorporeal Membrane Oxygenation: Potential Impacts of New Technologies

2017 ◽  
Vol 22 (5) ◽  
pp. 358-363
Author(s):  
Kevin P. Lonabaugh ◽  
Kelly J. Lunsford ◽  
Gary Y. Fang ◽  
David A. Kaufman ◽  
Samuel D. Addison ◽  
...  
Keyword(s):  
Renal Function ◽  
Extracorporeal Membrane Oxygenation ◽  
Pediatric Patients ◽  
New Technologies ◽  
Total Daily Dose ◽  
Therapeutic Drug ◽  
Membrane Oxygenation ◽  
Drug Concentrations ◽  
Daily Dose ◽  
Serum Vancomycin

OBJECTIVES The objective of the current study was to evaluate the doses of vancomycin used to obtain therapeutic drug concentrations in pediatric patients on extracorporeal membrane oxygenation (ECMO), using new ECMO technologies. METHODS This was a single-center, retrospective study of patients treated with vancomycin while receiving ECMO using low-volume circuit technology. RESULTS A total of 28 patients were included in the analysis of the primary endpoint. Patients had a median age of 6 weeks (0–11 years) and a median weight of 3.45 kg (2.44–37.2 kg). Ultrafiltration was used in 89.3% of patients at initiation of ECMO regardless of baseline renal function, resulting in a median urine output of 2 mL/kg/hr at the time of the final vancomycin dose. Most patients started vancomycin at the same time as ECMO. The median total daily dose was 30 mg/kg/day. The median total daily dose in a subset of patients less than one year of age was 20 mg/kg/day. Nearly all patients had at least 1 therapeutic trough serum vancomycin concentration. A total of 16 patients completed their vancomycin course using an interval of every 12 hours or shorter. Half-life was calculated in a subset of 11 patients and the mean was found to be 12.3 ± 2.8 hours. CONCLUSIONS An initial dosing interval of every 12 hours to provide a total daily dose of 30 mg/kg/day is a possible option in pediatric patients on ECMO provided that renal function is normal at baseline. Monitoring of serum vancomycin concentrations for adjustment of dosing is required throughout therapy and is still warranted.

scholarly journals 1101. Implementing a Beta-Lactam Therapeutic Drug Monitoring Program: Experience from a Large Academic Medical Center

2021 ◽  
Vol 8 (Supplement_1) ◽  
pp. S642-S642
Author(s):  
Venugopalan Veena ◽  
Malva Hamza ◽  
Barbara A Santevecchi ◽  
Kathryn DeSear ◽  
Kartikeya Cherabuddi ◽  
...  
Keyword(s):  
Therapeutic Drug Monitoring ◽  
Drug Monitoring ◽  
Dosage Adjustment ◽  
Total Serum ◽  
Therapeutic Drug ◽  
Beta Lactam ◽  
Dose Individualization ◽  
Material Support ◽  
Drug Concentrations ◽  
Drug Registry

Abstract Background Beta-lactams (BL) are the cornerstone of antimicrobial treatment for infections. Beta-lactam therapeutic drug monitoring (BL-TDM) optimizes drug concentrations to ensure maximal efficacy and minimal toxicity. The goals of this study were to describe the implementation process of a BL-TDM program and to further describe our experience using BL-TDM in clinical practice. Methods This was a retrospective review of adult patients with available BL-TDM between January 2016 and November 2019 at the University of Florida (UF) Health Shands Hospital. Total serum concentrations of BL were measured in the Infectious Diseases Pharmacokinetics Lab (IDPL) at UF, using a validated ultrahigh pressure liquid chromatography assay with triple quadrupole mass spectroscopy (LC-MS-MS). At our institution, TDM is available for 11 BLs and in-house assays are performed from Mon-Fri for most BLs. Results A total of 3,030 BL concentrations were obtained. An analysis was performed on the first BL-TDM encounter in 1,438 patients. The median age was 57 years (IQR, 41-69) and the median BMI was 27.5 kg/m2 (IQR, 22.5-34.5). On the day of BL-TDM, the median serum creatinine was 0.83 (IQR, 0.59-1.30). Fifty-one percent of patients (n=735) were in an ICU at the time of BL-TDM with a median SOFA score of 6 (IQR, 3-9). BL-TDM was most frequently performed on cefepime (61%, n=882), piperacillin (15%, n=218), and meropenem (11%, n=151). The BL was administered as a continuous infusion in 211 (15%) patients. An interim analysis of 548 patients showed that BL-TDM was performed a median of 2 days (IQR, 1-4) from the start of BL therapy and resulted in a dosage adjustment in 26% (n=145). Conclusion BL-TDM was performed in older, non-obese patients with normal renal function. Over half of the evaluated patients were in an ICU at the time of TDM. This finding emphasizes the value of BL-TDM in the ICU setting because altered pharmacokinetics during critical illness has been linked to enhanced BL clearance. Interestingly, BL-TDM resulted in dosage adjustment in 1 in 4 patients who were receiving licensed BL dosing regimens, thus highlighting the role of TDM in dose individualization. BL-TDM was performed most commonly within the 72-hours of therapy initiation. Early BL-TDM has been shown to improve patient outcomes and should be promoted. Disclosures Venugopalan Veena, PharmD, Melinta (Other Financial or Material Support, Received a stipend for participation in a drug registry)Merck (Other Financial or Material Support, Received a stipend for participation in a drug registry) Charles A. Peloquin, Pharm.D., Nothing to disclose

Probable Nonconvulsive Status Epilepticus With the Use of High-Dose Continuous Infusion Ceftazidime

2016 ◽  
Vol 29 (6) ◽  
pp. 564-568 ◽  
Author(s):  
Reagan D. Collins ◽  
Frank P. Tverdek ◽  
Jeffrey J. Bruno ◽  
Elizabeth A. Coyle
Keyword(s):  
Status Epilepticus ◽  
Continuous Infusion ◽  
Health Care Providers ◽  
Bacterial Infections ◽  
Multidrug Resistant ◽  
Nonconvulsive Status Epilepticus ◽  
High Dose ◽  
Care Providers ◽  
Beta Lactam ◽  
Beta Lactams

Multidrug resistant (MDR) bacterial infections are a major concern of health care providers due to their increasing incidence and associated mortality. In some cases, few or no antibiotics have preserved activity. Beta-lactam administration via continuous infusion can optimize time over minimum inhibitory concentration (MIC). In some cases, use of high-dose continuous infusion (HDCI) may be necessary to achieve serum levels in excess of nonsusceptible MIC values. The use of HDCI beta-lactams is not without risk, specifically neurotoxic adverse effects, which appear dose related. We describe a 64-year-old male who experienced myoclonus and nonconvulsive status epilepticus while receiving HDCI ceftazidime for treatment of multidrug resistant Pseudomonas aeruginosa bacteremia. This report serves as a cautionary example of the potential toxicities associated with HDCI beta-lactams and supports the importance of risk–benefit analysis prior to and during treatment. Additionally, the use of serum drug level monitoring may be necessary to better prevent or predict toxicity.

P-glycoprotein expression in malignant lymphoma and reversal of clinical drug resistance with chemotherapy plus high-dose verapamil.

1991 ◽  
Vol 9 (1) ◽  
pp. 17-24 ◽  
Author(s):  
T P Miller ◽  
T M Grogan ◽  
W S Dalton ◽  
C M Spier ◽  
R J Scheper ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Continuous Infusion ◽  
Efflux Pump ◽  
Competitive Inhibition ◽  
Transmembrane Protein ◽  
Immunohistochemical Method ◽  
High Dose ◽  
Drug Resistant ◽  
P Glycoprotein ◽  
Clinical Drug

P-glycoprotein is a transmembrane protein thought to function as an efflux pump to detoxify cells. It is associated with multidrug resistance in laboratory systems and has recently been found in human tumors associated with in vitro and clinical drug resistance. We used an immunohistochemical method employing two monoclonal antibodies, JSB-1 and C-219, to detect expression of P-glycoprotein in lymphoma patients. One of 42 newly diagnosed and untreated lymphoma patients (2%) and seven of 11 previously treated and drug-resistant patients (64%) had detectable levels of P-glycoprotein (P less than .001). Based on prior reports suggesting that verapamil sensitizes drug-resistant cancer cells to chemotherapy by competitive inhibition of the P-glycoprotein, we tested the efficacy of verapamil as a chemosensitizer in 18 patients with drug-refractory disease. All patients had previously failed or relapsed within 3 months of a doxorubicin-vincristine-containing drug regimen. Patients received day-1 cyclophosphamide, and 4-day continuous infusion doxorubicin and vincristine and oral dexamethasone (CVAD). CVAD was combined with 5-day continuous infusion verapamil given at maximally tolerated dose. Overall, 13 of 18 patients (72%) responded to treatment including five complete remissions (CRs; 28%). The median duration of response was 200 days and median survival was 242 days. The dose-limiting toxicity of the verapamil infusion was temporary cardiac dysfunction including hypotension, congestive heart failure, and cardiac arrhythmia. We conclude that the P-glycoprotein is uncommonly expressed in untreated lymphomas and frequently expressed in clinically drug-resistant disease, and that chemotherapy using CVAD plus maximally tolerated doses of verapamil results in a high response rate in patients carefully selected for clinical drug resistance.

Plasma concentrations resulting from continuous infusion of meropenem in a community-based outpatient program: A case series

2020 ◽  
Vol 77 (24) ◽  
pp. 2074-2080
Author(s):  
Amy Legg ◽  
Melanie Halford ◽  
Kate McCarthy
Keyword(s):  
Continuous Infusion ◽  
Drug Exposure ◽  
Plasma Concentrations ◽  
Case Series ◽  
Infectious Complications ◽  
Antimicrobial Treatment ◽  
Therapeutic Drug ◽  
Community Based ◽  
Drug Concentrations ◽  
Tertiary Center

Abstract Purpose Traditionally meropenem has been considered too unstable in solution for continuous infusion. However, in the era of increasing antimicrobial resistance, use of meropenem is becoming more frequently required, and the ability to facilitate its administration via community-based programs would be beneficial. There are some reassuring data about meropenem stability in solution, but data about actual drug exposure in patients and subsequent clinical outcomes are lacking. Summary Here we present a case series of 4 patients at a single tertiary center who received meropenem via continuous infusion coordinated through an outpatient parenteral antimicrobial treatment (OPAT) program. We provide plasma drug concentrations achieved and report on the patients’ clinical progress. All patients achieved drug concentrations of at least 2 times the minimum inhibitory concentration (MIC) while receiving meropenem via continuous infusion and had resolution of their infectious complications. No adverse effects of meropenem continuous infusion were noted. Conclusion Meropenem continuous infusion along with therapeutic drug monitoring was used successfully in a community-based program. Due to interpatient pharmacokinetic variability, we consider meropenem concentration monitoring compulsory during continuous-infusion meropenem therapy.

Successful treatment of meningeal leukemia using systemic high-dose cytosine arabinoside.

1984 ◽  
Vol 2 (5) ◽  
pp. 365-368 ◽  
Author(s):  
J Frick ◽  
P S Ritch ◽  
R M Hansen ◽  
T Anderson
Keyword(s):  
Cerebrospinal Fluid ◽  
Cytosine Arabinoside ◽  
Systemic Disease ◽  
Therapeutic Drug ◽  
High Dose ◽  
Pharmacokinetic Studies ◽  
Meningeal Involvement ◽  
Drug Concentrations ◽  
High Doses ◽  
Meningeal Leukemia

Conventional therapy for leukemic meningitis includes cranial irradiation and intrathecal chemotherapy administered by repeated lumbar punctures or direct intraventricular instillation via an Ommaya reservoir. Several clinical reports have indicated that high doses of cytosine arabinoside (ara-C) are effective in the treatment of acute leukemia refractory to standard induction therapy. Pharmacokinetic studies have demonstrated that high doses of ara-C given intravenously obtain sustained therapeutic drug concentrations in the cerebrospinal fluid, suggesting that this approach may be useful in the treatment of systemic disease associated with meningeal involvement. Five consecutive patients with overt meningeal leukemia were treated using only systemic chemotherapy containing high-dose ara-C. In all patients there was prompt resolution of neurologic symptoms and signs accompanied by cytologic clearing of leukemic cells from the cerebrospinal fluid.

scholarly journals Association of anti-tuberculosis drug concentrations in hair and treatment outcomes in MDR- and XDR-TB

2019 ◽  
Vol 5 (2) ◽  
pp. 00046-2019 ◽  
Author(s):  
John Metcalfe ◽  
Peter Bacchetti ◽  
Roy Gerona ◽  
Ali Esmail ◽  
Keertan Dheda ◽  
...  
Keyword(s):  
Treatment Outcomes ◽  
Drug Exposure ◽  
Cold Chain ◽  
Therapeutic Drug ◽  
Drug Resistant ◽  
Pharmacokinetic Variability ◽  
Resistant Tuberculosis ◽  
Extensively Drug Resistant ◽  
Drug Concentrations ◽  
Trial Participants

Therapeutic drug monitoring for drug-resistant tuberculosis (TB) is likely to improve treatment outcomes. While assessments of plasma drug levels can explain pharmacokinetic variability among trial participants, these measures require phlebotomy and a cold chain, and are generally not repeated frequently enough to characterise drug exposure over time. Using a novel multi-analyte assay, we found evidence that higher anti-TB drug concentrations in hair, a non-biohazardous and noninvasively collected biomatrix, predict extensively-drug resistant-TB clinical outcomes in a high-burden setting.

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