scholarly journals 2107. Azole Therapeutic Drug Monitoring (TDM) in a Multiracial Cohort with Varied Pharmacogenetics

2019 ◽  
Vol 6 (Supplement_2) ◽  
pp. S713-S713
Author(s):  
Peijun Yvonne Zhou ◽  
Tze Peng Lim ◽  
Si Lin Sarah Tang ◽  
Yixin Liew ◽  
Nathalie Grace Sy. Chua ◽  
...  
Keyword(s):  
Hematological Malignancy ◽  
Organ Transplant ◽  
Drug Formulation ◽  
Therapeutic Drug ◽  
Solid Organ ◽  
Efficacy And Safety ◽  
Breakthrough Infection ◽  
Southeast Asians ◽  
Anti Fungal ◽  
Trough Levels

Abstract Background Voriconazole (VOR) and posaconazole (POS) exhibit wide pharmacokinetic variability. Various factors including race and genetic polymorphisms are at play and this may affect treatment response. We aim to evaluate the utility of VOR/POS TDM among Southeast Asians that are predominantly intermediate/poor VOR metabolizers. Methods All adults with VOR/POS TDM performed at our institution from 2015 to 2018 were included. We determined proportion of patients and doses required to achieve TDM targets [(2 – 5.5 mg/L (VOR) or ≥ 0.7 and ≥ 1.0 mg/L (POS prophylaxis and treatment respectively)], and correlate levels with treatment efficacy and safety. Results VOR/POS TDM was performed mostly among patients with hematological malignancy or solid-organ transplant (146/174, 83.9%). Less than half (32/70, 45.7%) of patients on VOR achieved target—18 (25.7%) were < 2 mg/L while 20 (28.5%) had levels > 5.5 mg/L. Doses required to achieve TDM target ranged from 1.9–11.4 mg/kg/day. Drug interactions, critically ill state and change in drug formulation were major causes of intra-patient variability. One-fifth (n = 14) experienced transaminitis; corresponding VOR trough levels were 0.5–> 7.5 mg/L. Neurotoxicity was also seen in 3 (4.3%) patients—all 3 had VOR trough ≥ 6.7 mg/L and saw symptom resolution upon dose reduction. There appears to be no association between the achievement of TDM targets and response rates. Majority (81/104, 77.9%) of patients on POS achieved TDM targets. Patients prescribed POS tablet were significantly more likely to attain targets compared with suspension 600 mg/day [19/26 (73.0%) vs. 27/62 (43.5%), P < 0.05] and 800 mg/day [17/26 (65.3%) vs. 4/16 (25.0%), P < 0.05)]. Of 23 with sub-therapeutic levels, 19 (82.6%) responded to dose increase and/or change in acid-reducing agents. Breakthrough infection occurred despite troughs ≥ 0.7 mg/L [5/42 (11.9%) vs. 2/40 (5.0%) when < 0.7 mg/L (P = 0.3)]. Treatment failure was observed in 2 patients (troughs > 1.0 mg/L). Conclusion VOR/POS TDM should be implemented in Southeast Asians due to significant unpredictability in dose exposure and potential to avoid need for switch to alternative anti-fungals due to intolerability. Higher POS trough cutoff may be required for effective anti-fungal prophylaxis. Disclosures All authors: No reported disclosures.

scholarly journals Invasive infections with Purpureocillium lilacinum: clinical characteristics and outcome of 101 cases from FungiScope® and the literature

2021 ◽  
Author(s):  
Rosanne Sprute ◽  
Jon Salmanton-García ◽  
Ertan Sal ◽  
Xhorxha Malaj ◽  
Zdeněk Ráčil ◽  
...  
Keyword(s):  
Amphotericin B ◽  
Organ Transplant ◽  
Solid Organ ◽  
Intrinsic Resistance ◽  
Breakthrough Infection ◽  
Purpureocillium Lilacinum ◽  
Invasive Infections ◽  
Oncological Diseases ◽  
Overall Mortality

Abstract Objectives To provide a basis for clinical management decisions in Purpureocillium lilacinum infection. Methods Unpublished cases of invasive P. lilacinum infection from the FungiScope® registry and all cases reported in the literature were analysed. Results We identified 101 cases with invasive P. lilacinum infection. Main predisposing factors were haematological and oncological diseases in 31 cases (30.7%), steroid treatment in 27 cases (26.7%), solid organ transplant in 26 cases (25.7%), and diabetes mellitus in 19 cases (18.8%). The most prevalent infection sites were skin (n = 37/101, 36.6%) and lungs (n = 26/101, 25.7%). Dissemination occurred in 22 cases (21.8%). Pain and fever were the most frequent symptoms (n = 40/101, 39.6% and n = 34/101, 33.7%, respectively). Diagnosis was established by culture in 98 cases (97.0%). P. lilacinum caused breakthrough infection in 10 patients (9.9%). Clinical isolates were frequently resistant to amphotericin B, whereas posaconazole and voriconazole showed good in vitro activity. Susceptibility to echinocandins varied considerably. Systemic antifungal treatment was administered in 90 patients (89.1%). Frequently employed antifungals were voriconazole in 51 (56.7%) and itraconazole in 26 patients (28.9%). Amphotericin B treatment was significantly associated with high mortality rates (n = 13/33, 39.4%, P = &lt;0.001). Overall mortality was 21.8% (n = 22/101) and death was attributed to P. lilacinum infection in 45.5% (n = 10/22). Conclusions P. lilacinum mainly presents as soft-tissue, pulmonary or disseminated infection in immunocompromised patients. Owing to intrinsic resistance, accurate species identification and susceptibility testing are vital. Outcome is better in patients treated with triazoles compared with amphotericin B formulations.

scholarly journals 1538. Who Will Benefit From Therapeutic Drug Monitoring of Ganciclovir?

2019 ◽  
Vol 6 (Supplement_2) ◽  
pp. S560-S561
Author(s):  
Anne-Grete Martson ◽  
Marieke G G Sturkenboom ◽  
Stefan P Berger ◽  
Kevin Damman ◽  
Erik A M Verschuuren ◽  
...  
Keyword(s):  
Renal Function ◽  
Therapeutic Drug Monitoring ◽  
Observational Study ◽  
Drug Monitoring ◽  
Drug Formulation ◽  
Therapeutic Window ◽  
Therapeutic Drug ◽  
Solid Organ ◽  
Cell Transplant ◽  
Specific Patient

Abstract Background Oral valganciclovir and intravenous ganciclovir are used for prophylaxis, treatment, and pre-emptive treatment of cytomegalovirus and human herpesvirus 6. It is important to estimate the exposure to these antivirals, as deviating levels can cause adverse events or induce acquired drug resistance, which can both lead to treatment failure. Therapeutic drug monitoring (TDM) is a good tool to estimate drug exposure in these patients. With this observational study we aimed to evaluate which patients would benefit most from TDM. Methods An observational study was performed in adult solid-organ and stem cell transplant recipients on routine (val)ganciclovir (dosed according to renal function, weight and indication). As valganciclovir is a prodrug of ganciclovir, only the latter was measured. Ganciclovir trough (Ctrough) and peak (Cpeak) concentrations were measured with a validated LC-MS/MS assay. The target concentrations defined for the study were 1–2 mg/L and 2–4 mg/L for prophylaxis and treatment, respectively, and over 5 mg/L toxic. Results From June 2018 to April 2019, 66 patients were included. Within this timeframe, 236 Ctrough and 52 Cpeak were measured with median of 4 samples per patient. The median Ctrough was 1.1 mg/L and 2.3 mg/L for prophylaxis and treatment, respectively. Over 50% of the concentrations were out of the therapeutic window. The median creatinine for all measurements was 100 µmol/L. Observational analysis showed patients with kidney failure and on continuous renal replacement therapy (CVVH) had more concentrations measured out of the predefined range (Figures 1 and 2). For one individual with augmented renal clearance we observed significantly lower concentrations during routine dosing. 6 toxic concentrations were measured (5 subjects); creatinine concentrations ranged 71–527 µmol/L in these individuals. A preliminary linear-mixed model analysis did not show drug formulation, age or gender as a significant predictor for ganciclovir concentrations. Conclusion We believe that patients with decreased renal function, on CVVH or showing changes in renal function might benefit from TDM to guide therapy. TDM of ganciclovir for patients without renal failure remains debatable. Further studies with specific patient groups are needed to confirm these results. Disclosures All authors: No reported disclosures.

scholarly journals Effects of Isavuconazole on the Plasma Concentrations of Tacrolimus among Solid-Organ Transplant Patients

2017 ◽  
Vol 61 (9) ◽  
Author(s):  
Ryan M. Rivosecchi ◽  
Cornelius J. Clancy ◽  
Ryan K. Shields ◽  
Christopher R. Ensor ◽  
Michael A. Shullo ◽  
...  
Keyword(s):  
Plasma Concentrations ◽  
Organ Transplant ◽  
Tacrolimus Concentration ◽  
Therapeutic Drug ◽  
Solid Organ ◽  
Transplant Recipients ◽  
Dose Ratio ◽  
Transplant Patients ◽  
Daily Dose ◽  
Liver Transplant Recipients

ABSTRACT We evaluated the interaction between isavuconazole and tacrolimus among 55 organ transplant recipients. After isavuconazole discontinuation, the tacrolimus concentration/dose ratio normalized by weight (C/D) was reduced by 16%. Liver transplant recipients experienced the largest C/D reduction. A 1.3-fold decrease in tacrolimus daily dose was required to maintain desired tacrolimus levels. There was considerable interpatient variability in the magnitude of the drug interaction. Tacrolimus doses should not be adjusted uniformly but, rather, be guided by therapeutic drug monitoring.

Inhibitors of Calcineurin

2003 ◽  
Vol 16 (6) ◽  
pp. 414-433
Author(s):  
Curtis D. Holt ◽  
Gordon Ingle ◽  
Theodore M. Sievers
Keyword(s):  
Adverse Effects ◽  
Drug Interactions ◽  
Immunosuppressive Agents ◽  
Organ Transplant ◽  
Solid Organ Transplant ◽  
Therapeutic Drug ◽  
Solid Organ ◽  
Transplant Recipients ◽  
Organ Transplant Recipients ◽  
Solid Organ Transplant Recipients

Before the early 1980s, patient and allograft survival for solid organ transplant recipients was dismal. By 1983, the first calcineurin blocker, cyclosporine (Sandimmun), had been introduced, and outcomes were dramatically improved. However, cyclosporine macroemulsion had suboptimal pharmacokinetics, significant drug interactions, and several adverse effects, including nephrotoxicity, neurotoxicity, hyperlipidemia, and hypertension. Recent advances with cyclosporine include the introduction of modified dosage formulations: Neoral, a microemulsion, and several generic microemulsion products. The potent second-generation calcineurin blocker tacrolimus (Prograf) was introduced in 1994 and has become the drug of choice for several types of transplant recipients. Although tacrolimus has improved pharmacokinetics and therapeutic drugmonitoring parameters, it has adverse effects such as nephrotoxicity, neurotoxicity, and diabetes. Thus, current immunosuppressive regimens implementing calcineurin blockers often involve additional immunosuppressive agents to “spare” the use of these agents, minimizing their adverse effects. This article reviews the mechanisms of action, pharmacokinetics, clinical use, therapeutic drug monitoring, drug interactions, adverse effects, and dosing of cyclosporine and tacrolimus in solid organ transplant recipients.

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