A significant proportion of patients with Rhino-orbito-cerebral mucormycosis (ROCM) develop oroantral fistulas. Due to the unclear efficacy of crushed delayed-release posaconazole tablets (DRPT) via ...nasogastric tube in this group of patients, clinicians often use inferior alternatives like posaconazole suspension. In this prospective study, we report good plasma concentrations (median, 2,639 ng/mL; interquartile range IQR, 1,690 to 3,575 ng/mL; and range, 1,004 to 4,835ng/mL) and complete cure and survival at 3 and 6 months in 19 such patients.
Ten years ago, a consensus report on the optimization of tacrolimus was published in this journal. In 2017, the Immunosuppressive Drugs Scientific Committee of the International Association of ...Therapeutic Drug Monitoring and Clinical Toxicity (IATDMCT) decided to issue an updated consensus report considering the most relevant advances in tacrolimus pharmacokinetics (PK), pharmacogenetics (PG), pharmacodynamics, and immunologic biomarkers, with the aim to provide analytical and drug-exposure recommendations to assist TDM professionals and clinicians to individualize tacrolimus TDM and treatment. The consensus is based on in-depth literature searches regarding each topic that is addressed in this document. Thirty-seven international experts in the field of TDM of tacrolimus as well as its PG and biomarkers contributed to the drafting of sections most relevant for their expertise. Whenever applicable, the quality of evidence and the strength of recommendations were graded according to a published grading guide. After iterated editing, the final version of the complete document was approved by all authors. For each category of solid organ and stem cell transplantation, the current state of PK monitoring is discussed and the specific targets of tacrolimus trough concentrations (predose sample C0) are presented for subgroups of patients along with the grading of these recommendations. In addition, tacrolimus area under the concentration-time curve determination is proposed as the best TDM option early after transplantation, at the time of immunosuppression minimization, for special populations, and specific clinical situations. For indications other than transplantation, the potentially effective tacrolimus concentrations in systemic treatment are discussed without formal grading. The importance of consistency, calibration, proficiency testing, and the requirement for standardization and need for traceability and reference materials is highlighted. The status for alternative approaches for tacrolimus TDM is presented including dried blood spots, volumetric absorptive microsampling, and the development of intracellular measurements of tacrolimus. The association between CYP3A5 genotype and tacrolimus dose requirement is consistent (Grading A I). So far, pharmacodynamic and immunologic biomarkers have not entered routine monitoring, but determination of residual nuclear factor of activated T cells-regulated gene expression supports the identification of renal transplant recipients at risk of rejection, infections, and malignancy (B II). In addition, monitoring intracellular T-cell IFN-g production can help to identify kidney and liver transplant recipients at high risk of acute rejection (B II) and select good candidates for immunosuppression minimization (B II). Although cell-free DNA seems a promising biomarker of acute donor injury and to assess the minimally effective C0 of tacrolimus, multicenter prospective interventional studies are required to better evaluate its clinical utility in solid organ transplantation. Population PK models including CYP3A5 and CYP3A4 genotypes will be considered to guide initial tacrolimus dosing. Future studies should investigate the clinical benefit of time-to-event models to better evaluate biomarkers as predictive of personal response, the risk of rejection, and graft outcome. The Expert Committee concludes that considerable advances in the different fields of tacrolimus monitoring have been achieved during this last decade. Continued efforts should focus on the opportunities to implement in clinical routine the combination of new standardized PK approaches with PG, and valid biomarkers to further personalize tacrolimus therapy and to improve long-term outcomes for treated patients.
The appropriate antibiotic treatment for severe scrub typhus, a neglected but widespread reemerging zoonotic infection, is unclear.
In this multicenter, double-blind, randomized, controlled trial, we ...compared the efficacy of intravenous doxycycline, azithromycin, or a combination of both in treating severe scrub typhus. Patients who were 15 years of age or older with severe scrub typhus with at least one organ involvement were enrolled. The patients were assigned to receive a 7-day course of intravenous doxycycline, azithromycin, or both (combination therapy). The primary outcome was a composite of death from any cause at day 28, persistent complications at day 7, and persistent fever at day 5.
Among 794 patients (median age, 48 years) who were included in the modified intention-to-treat analysis, complications included those that were respiratory (in 62%), hepatic (in 54%), cardiovascular (in 42%), renal (in 30%), and neurologic (in 20%). The use of combination therapy resulted in a lower incidence of the composite primary outcome than the use of doxycycline (33% and 47%, respectively), for a risk difference of -13.3 percentage points (95% confidence interval CI, -21.6 to -5.1; P = 0.002). The incidence with combination therapy was also lower than that with azithromycin (48%), for a risk difference of -14.8 percentage points (95% CI, -23.1 to -6.5; P<0.001). No significant difference was seen between the azithromycin and doxycycline groups (risk difference, 1.5 percentage points; 95% CI, -7.0 to 10.0; P = 0.73). The results in the per-protocol analysis were similar to those in the primary analysis. Adverse events and 28-day mortality were similar in the three groups.
Combination therapy with intravenous doxycycline and azithromycin was a better therapeutic option for the treatment of severe scrub typhus than monotherapy with either drug alone. (Funded by the India Alliance and Wellcome Trust; INTREST Clinical Trials Registry-India number, CTRI/2018/08/015159.).
To evaluate the efficacy and safety of short-course intravenous amphotericin B followed by sustained release posaconazole tablets for diabetes or COVID-19-associated rhino-orbito-cerebral ...mucormycosis.
This prospective, pragmatic study included adults with diabetes or COVID-19-associated rhino-orbito-cerebral mucormycosis. Patients received short (7–14 days) or long (15–28 days) intravenous antifungal therapy (short intravenous antifungal treatment SHIFT or long intravenous antifungal treatment LIFT, respectively) depending on the presence or absence of brain involvement. All patients received step-down posaconazole tablets, debridement, and glycemic control. The primary outcome was the treatment success at week 14, which was determined by assessing survival and the absence of disease progression through clinical evaluation and nasal endoscopy. Log-binomial regression analysis (risk ratio and 95% CI) was performed to assess factors associated with the primary outcome.
Intravenous therapy was administered to 251 participants: SHIFT, 205 (median duration, 13 days); LIFT, 46 (median duration, 22 days). Treatment success at 3 months was 88% (217/248; 95% CI, 83–91%): SHIFT group, 93% (189/203; 89–96%); LIFT group, 62% (28/45; 47–76%). All-cause mortality was 12% (30/251): SHIFT group, 6% (13/205); LIFT group, 37% (17/46). Age (aRR 95% CI: 1.02 1.00–1.05; p 0.027), diabetic ketoacidosis at presentation (2.32 1.20–4.46; p 0·012), glycated haemoglobin A1c (1.19 1.03–1.39; p 0.019), stroke (3.93 1.94–7.95; p 0·0001), and brain involvement (5.67 3.05–10.54; p < 0.0001) were independently associated with unsuccessful outcomes.
: Short intravenous amphotericin B with step-down posaconazole tablets should be further studied as primary treatment option for diabetes or COVID-19-associated mucormycosis in randomized controlled trials.
Suboptimal exposure to antituberculosis (anti-TB) drugs has been associated with unfavourable treatment outcomes. We aimed to investigate estimates and determinants of first-line anti-TB drug ...pharmacokinetics in children and adolescents at a global level.
We systematically searched MEDLINE, Embase and Web of Science (1990-2021) for pharmacokinetic studies of first-line anti-TB drugs in children and adolescents. Individual patient data were obtained from authors of eligible studies. Summary estimates of total/extrapolated area under the plasma concentration-time curve from 0 to 24 h post-dose (AUC
) and peak plasma concentration (
) were assessed with random-effects models, normalised with current World Health Organization-recommended paediatric doses. Determinants of AUC
and
were assessed with linear mixed-effects models.
Of 55 eligible studies, individual patient data were available for 39 (71%), including 1628 participants from 12 countries. Geometric means of steady-state AUC
were summarised for isoniazid (18.7 (95% CI 15.5-22.6) h·mg·L
), rifampicin (34.4 (95% CI 29.4-40.3) h·mg·L
), pyrazinamide (375.0 (95% CI 339.9-413.7) h·mg·L
) and ethambutol (8.0 (95% CI 6.4-10.0) h·mg·L
). Our multivariate models indicated that younger age (especially <2 years) and HIV-positive status were associated with lower AUC
for all first-line anti-TB drugs, while severe malnutrition was associated with lower AUC
for isoniazid and pyrazinamide.
-acetyltransferase 2 rapid acetylators had lower isoniazid AUC
and slow acetylators had higher isoniazid AUC
than intermediate acetylators. Determinants of
were generally similar to those for AUC
.
This study provides the most comprehensive estimates of plasma exposures to first-line anti-TB drugs in children and adolescents. Key determinants of drug exposures were identified. These may be relevant for population-specific dose adjustment or individualised therapeutic drug monitoring.
This study was a retrospective assessment of the therapeutic drug monitoring data collected for levetiracetam and lamotrigine from a clinical setting. The proportion of patients in relation to the ...therapeutic ranges for serum concentrations of lamotrigine and levetiracetam was estimated, and the influence of age and anticonvulsant comedications on their clearances were studied.
Information on levetiracetam (2011-2013) and lamotrigine (2008-2013) dose, trough concentration, age, sex, body weight, and anticonvulsant comedications prescribed was obtained from the therapeutic drug monitoring register and archived medical records. Patients were categorized into 4 groups based on anticonvulsant comedications and further divided into 3 subgroups based on age (a: <9 years; b: 9-17 years; c: ≥18 years). In each subgroup, the proportion of patients who achieved trough concentrations in the therapeutic range for levetiracetam and lamotrigine was computed. Apparent clearance (CL/F) was compared across subgroups by 1-way analysis of variance, and factors which significantly predicted CL/F were identified by stepwise multiple linear regression.
Overall, 348 (330 patients) and 706 (493 patients) samples for levetiracetam and lamotrigine were included in the analysis. Of these, 56.9% and 72.4% were within, 43.1% and 23.9% below, 0% and 3.7% above the therapeutic range for levetiracetam and lamotrigine, respectively. A significant difference in CL/F was noted across subgroups for levetiracetam (P < 0.001) and lamotrigine (P < 0.001). Age <9 years, age ≥18 years, and inducer comedications significantly predicted CL/F for levetiracetam. For lamotrigine, inhibitor comedications, age <9 years, inducer comedications, and age 9-17 years significantly predicted CL/F.
These findings emphasize the need to monitor relatively newer anticonvulsants, lamotrigine and levetiracetam, especially among children and when other anticonvulsant comedications are prescribed or discontinued in the treatment regimen.
Pharmacokinetics of meropenem differ widely in the critically ill population. It is imperative to maintain meropenem concentrations above the inhibitory concentrations for most of the interdose ...interval. A population pharmacokinetic/pharmacodynamic model was developed to determine the probability of target attainment for 3-hour and 30-minute infusion regimens in this population.
This study was performed in an intensive care setting among adult patients who were initiated on meropenem at a dose of 1000 mg. Multiple blood specimens were collected at predetermined time points during the interdose period, and meropenem concentrations were measured using high performance liquid chromatography. Using Pmetrics, a pharmacokinetic/pharmacodynamic model was developed and validated. Monte Carlo simulation was performed, and probability of target attainment (100% T > minimum inhibitory concentration (MIC), with a probability >0.9) for doubling MICs was determined for different regimens of meropenem.
A 2-compartment multiplicative gamma error model best described the population parameters from 34 patients. The pharmacokinetic parameters used in the final model were Ke (elimination rate constant from the central compartment), Vc (volume of distribution of central compartment), KCP and KPC (intercompartmental rate constants), and IC2 (the fitted amount of meropenem in the peripheral compartment). Inclusion of creatinine clearance (CLcreat) and body weight as covariates improved the model prediction (Ke = Ke0 × (Equation is included in full-text article.), Vc = Vc0 × Weight). The Ke and Vc geometric mean (range) of the individuals were 0.54 (0.01-2.61)/h and 9.36 (4.35-21.62) L, respectively. The probability of attaining the target, T > MIC of 100%, was higher for 3-hour infusion regimens compared with 30-minute infusion regimens for all ranges of CLcreat.
This study emphasizes that extended regimens of meropenem are preferable for treating infections caused by bacteria with higher MICs. The nonparametric analysis using body weight and CLcreat as covariate adequately predicted the pharmacokinetics of meropenem in critically ill patients with a wide range of renal function.
Mycophenolate mofetil (MMF) has variable pharmacokinetics. This study examines the pharmacokinetic and clinical correlations in proliferative lupus nephritis.
Thirty-four patients were started on ...MMF, and the area under the concentration-time curve (AUC) was measured by limited sampling strategies, and dosing was adjusted to achieve an AUC of 30-60 mg·h·L. Twenty-seven patients had at least 2 measurements, and renal response was assessed within 1 year.
About 61.8% of patients had mycophenolic acid (MPA) AUC <30 mg·h·L with an empiric starting dose of 30 mg/kg. About 79.4% of patients achieved renal response by 1 year, and the median time to renal response was 111 days. MMF dose per body weight had a weak correlation with the AUC and did not correlate with trough concentrations. The median dose was 1.5 g/d at entry and 2 g/d after dose modification during the induction phase. Trough concentrations had a weak correlation with AUC. Patients with serum albumin ≥35 g/L had a greater chance of having an AUC ≥30 mg·h·L. The between-patient coefficient of variability for dose-normalized AUC was 37.9% at entry and 31% within 1 year, whereas repeated measurements over time in an individual had a good intraclass correlation of 0.78. Infections occurred in 11.8% and toxicities in 5.9%. MPA exposure was not significantly associated with adverse events. Patients with an AUC ≥30 mg·h·L had greater renal response at 1 year.
Lupus nephritis patients induced with concentration-controlled MMF had excellent renal response and fewer adverse events with lower than usual dosing. MPA exposure had high interpatient variability, requiring measurements for personalized dosing, and fewer adverse events. Long-term cost reduction is achievable with lower doses and good renal response in the majority of patients.
Objectives: Carbamazepine (CBZ) is a commonly used anti-epileptic in rural hospitals in India. These hospitals lack the facilities to measure CBZ concentration; however, in larger hospitals this is ...performed using high performance liquid chromatography (HPLC). Dried blood spot (DBS) represents a feasible matrix for safe transportation by post/courier. This study was to determine whether the concentration of CBZ in serum can be predicted from that measured in DBS using an inexpensive HPLC method and inexpensive standard filter paper.
Methods: CBZ in serum and DBS from 80 epileptic patients were measured using a validated HPLC assay. The data was then randomly divided into two groups; simple Deming regression was performed with the first group and validation was performed using the second.
Results: There was a good correlation between the serum and DBS concentrations (r = 0.932) in the first group. The regression equation obtained was: predicted serum concentration = DBS concentration x 0.83 + 1.09. In the validation group, the correlation between the predicted and actual serum concentrations was also good (r = 0.958), and the mean difference between them was only 0.28 μg/ml (p = 0.8062). The imprecision and bias in both the groups were acceptable.
Conclusion: Using inexpensive materials, serum CBZ concentrations can be accurately predicted from DBS specimens. This method can be recommended for the therapeutic drug monitoring of CBZ in resource-limited settings.
Enteric-coated mycophenolate sodium (EC-MPS) is widely used in renal transplantation. With a delayed absorption profile, it has not been possible to develop limited sampling strategies to estimate ...area under the curve (mycophenolic acid MPA AUC₀₋₁₂), which have limited time points and are completed in 2 hours. We developed and validated simplified strategies to estimate MPA AUC₀₋₁₂ in an Indian renal transplant population prescribed EC-MPS together with prednisolone and tacrolimus. Intensive pharmacokinetic sampling (17 samples each) was performed in 18 patients to measure MPA AUC₀₋₁₂. The profiles at 1 month were used to develop the simplified strategies and those at 5.5 months used for validation. We followed two approaches. In one, the AUC was calculated using the trapezoidal rule with fewer time points followed by an extrapolation. In the second approach, by stepwise multiple regression analysis, models with different time points were identified and linear regression analysis performed. Using the trapezoidal rule, two equations were developed with six time points and sampling to 6 or 8 hours (8hrAUC₀₋₁₂exp) after the EC-MPS dose. On validation, the 8hrAUC(₀₋₁₂exp) compared with total measured AUC₀₋₁₂ had a coefficient of correlation (r²) of 0.872 with a bias and precision (95% confidence interval) of 0.54% (-6.07-7.15) and 9.73% (5.37-14.09), respectively. Second, limited sampling strategies were developed with four, five, six, seven, and eight time points and completion within 2 hours, 4 hours, 6 hours, and 8 hours after the EC-MPS dose. On validation, six, seven, and eight time point equations, all with sampling to 8 hours, had an acceptable r with the total measured MPA AUC₀₋₁₂ (0.817-0.927). In the six, seven, and eight time points, the bias (95% confidence interval) was 3.00% (-4.59 to 10.59), 0.29% (-5.4 to 5.97), and -0.72% (-5.34 to 3.89) and the precision (95% confidence interval) was 10.59% (5.06-16.13), 8.33% (4.55-12.1), and 6.92% (3.94-9.90), respectively. Of the eight simplified approaches, inclusion of seven or eight time points improved the accuracy of the predicted AUC compared with the actual and can be advocated based on the priority of the user.
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