Therapeutic Drug Monitoring of Isavuconazole: Lessons Learnt from a Real-life Setting in a Tertiary Care Center in India.

Introduction: Isavuconazole is an emerging therapeutic option for invasive infections caused by molds, especially aspergillosis and mucormycosis. Isavuconazole has predictable pharmacokinetics and good bioavailability. These attributes have led to some doubts regarding the need for therapeutic drug monitoring (TDM). There are no data from India regarding TDM for isavuconazole. Methods: A retrospective analysis of 50 patients who received oral isavuconazole for therapeutic purposes. Plasma isavuconazole levels were measured using a reversed phase high-performance liquid chromatography (HPLC) and UV detector with acetonitrile (ACN) as protein precipitating solvent. Results: Of the 50 cases, 5 (10.0%) patients had subtherapeutic levels, while 45 (90.0%) had therapeutic levels. Higher body weight and solid organ transplantation (SOT) were significantly associated with subtherapeutic levels of isavuconazole (p-value < 0.05 for all). Receipt of a SOT was the only independent and statistically significant factor which was associated with subtherapeutic levels of isavuconazole (p-value < 0.05). Conclusion: Our study reemphasizes the need of TDM for isavuconazole and adds to the growing evidence for the need to obtain drug levels. Factors associated with subtherapeutic levels of isavuconazole need to be assessed in larger studies to help identify those patients who are at risk of having subtherapeutic drug levels. How to cite this article: Prayag PS, Soman RN, Panchakshari SP, Ajapuje PS, Mahale NP, Dhupad S, et al. Therapeutic Drug Monitoring of Isavuconazole: Lessons Learnt from a Real-life Setting in a Tertiary Care Center in India. Indian J Crit Care Med 2023;27(4):260-264.

Factors associated with subtherapeutic levels of oral posaconazole tablet: a detailed analysis from a tertiary care center in India.

OBJECTIVES: Posaconazole is a broad-spectrum triazole antifungal, with activity against various clinically important fungi. The delayed release (DR) tablet of posaconazole has been shown to have a superior pharmacokinetic profile in comparison with the oral suspension. METHODS: We retrospectively analyzed the factors associated with posaconazole levels <1.25 µg/ml in 164 patients receiving the DR tablet for therapeutic purposes. RESULTS: Of the 164 patients, 53 (32.3%) showed subtherapeutic trough levels of posaconazole. The use of proton pump inhibitors (95% CI 1.41-3.91; P-value = 0.028) and the presence of diarrhea (95% CI 1.95-6.93; P-value = 0.001) were significantly associated with subtherapeutic levels. A total of 13 of the 21 patients receiving posaconazole tablets through a nasogastric tube had therapeutic levels. CONCLUSION: This is the largest study from India that analyzed factors associated with subtherapeutic levels of the DR tablet of posaconazole. These findings reinforce the importance of therapeutic drug monitoring. Unlike in previous studies, obesity and hypoalbuminemia were not found to be significant factors in our settings. The use of proton pump inhibitors and diarrhea remained significant factors, as found in previous studies. Administering the DR tablet of posaconazole through a nasogastric tube may be a viable option.

Fruit and Vegetable Consumption and Their Association With the Indicators of Iron and Inflammation Status Among Adolescent Girls.

BACKGROUND: The objective of this study was to identify an association among dietary components, iron, and inflammatory status among adolescent girls. METHOD: Dietary information for 85 adolescent girls was collected through food frequency questionnaires. Biomarkers of iron and inflammatory status were analyzed. RESULTS: We found that 28.2% of adolescent girls had anemia and 65.9% girls were iron-deficient. Girls who did not consume guava had 3.8-fold (95% confidence interval =1.1-9.4; p = 0.020) increased the risk of having low serum iron levels. Girls who consumed amaranth had significantly (p = 0.024) higher serum hepcidin levels (n = 44; 129.7 ± 81.40 pg/mL vs n = 41; 94.6 ± 55.8 pg/mL) as well as ferritin levels (n = 44; 19.7 ± 16.4 µg/L vs n = 41; 14.0 ± 10.2 µg/L). Overall consumption of fruits and green leafy vegetables among girls significantly affects their iron status. CONCLUSIONS: Regular consumption of vitamin C-rich fruits and green leafy vegetable intake are imperative for improvement of iron status among adolescent girls.

Association of metabolic syndrome with severity of coronary artery disease.

BACKGROUND: South Asians are more prone to develop metabolic syndrome (MetS). The additive predictive value of components of MetS for cardiovascular diseases is still debated. We undertook this study to evaluate the association of MetS and its components with severity of coronary artery disease (CAD). MATERIALS AND METHODS: Three hundred patients with known coronary disease above the age of 25 years were included in this study. Blood samples were collected for biochemical markers. Patients were stratified into subjects with and without MetS (International Diabetes Federation, IDF, criteria) and severity of CAD (number of vessel involved). RESULTS: Mean age of the patient in the study was 60.9 ± 12.4 years (male, M: 72%; female, F: 28%). MetS was present in 64% patients. Patients with MetS had more severe CAD compared to those without MetS. Triple vessel disease (TVD) was present in 62.5% of patients with MetS compared to 34.3% among without MetS (P < 0.0001). The percent number of patients with TVD showed increasing trend with increasing number of components of MetS (0-0%; 1-20%; 2-27.5%; 3-47.8%; 4-72.6%; 5-78.3%; Chi square for trend < 0.0001). Inflammatory markers [interleukin (IL) 6: 77.67 ± 79.48 vs. 41.21 ± 60.72 pg/ml, P < 0.0001; tumor nuclear factor (TNF)-α: 28.0 ± 47.49 vs 20.43 ± 24.5 pg/ml, P < 0.0001; high sensitive C-reactive protein (hsCRP): 14.30 ± 9.91 vs. 7.02 ± 7.18 mg/L, P < 0.0001], insulin resistance [homeostatic model analysis insulin resistance (HOMA-IR): 22.33 ± 23.37 vs. 10.86 ± 13.90, P < 0.0001] were higher and insulin sensitivity [quantitative insulin check index (QUICKI): 0.26 ± 0.03 vs. 0.30 ± 0.04, P < 0.0001] was significantly lower in subjects with MetS compared to subjects without MetS. Among lipids, total cholesterol were comparable but triglyceride (175 ± 42 vs. 179 ± 48 vs. 180 ± 47 mg/dl, P < 0.0001) was high and high-density lipoprotein (HDL; 44.72 ± 7.63 vs. 39.96 ± 8.70 vs. 36.05 ± 8.84, P < 0.0001) was low in subjects with TVD compared to others. Similarly, percentage of patients with diabetes (7.5% vs. 26.3% vs. 63.7%, P < 0.0001) and hypertension (34.3% vs. 56.6% vs. 77.7%, P < 0.0001) were higher in subjects with TVD compared to others. CONCLUSIONS: There is a strong correlation of MetS and its components with severity of CAD.

Study of pattern of dyslipidemia and its correlation with cardiovascular risk factors in patients with proven coronary artery disease.

INTRODUCTION: Dyslipidemia is a primary, widely established as an independent major risk factor for coronary artery disease (CAD). Asians differs in prevalence of various lipid abnormalities than non-Asians. Hence, this study was conducted with objective to evaluate the lipid abnormalities and there correlation with traditional and non-traditional risk factors in known subjects with CAD. MATERIALS AND METHODS: We studied the pattern and association of dyslipidemia with cardiovascular risk factors in 300 (Male: 216; Female: 84, age: 60.9 ± 12.4 years, range: 25-92 years) angiographically proved CAD patients. All patients were evaluated for anthropometry and cardiovascular risk factors and blood samples were collected for biochemical and inflammatory markers. RESULTS: Hypercholesterolemia, hypertriglyceridemia and low high density lipoprotein (HDL) was present in 23.3%, 63.0% and 54.6% in the total study population respectively. A total of 41.3% had atherogenic dyslipidemia (raised triglycerides [TG] and low HDL). Percentage of patients with type-2 diabetes mellitus and hypertension were higher in subjects with atherogenic dyslipidemia. Insulin sensitivity was low; insulin and insulin resistance (IR) along with inflammatory markers were high in subjects with atherogenic dyslipidemia. Patients with atherogenic dyslipidemia had significantly lower serum vitamin B12 levels and higher homocysteine (Hcy) levels. Hypertriglyceridemia was positively correlated with insulin, homeostasis model assessment of IR, Hcy, interleukin-6, Tumor necrosis factor-alpha, highly sensitive C-reactive protein and negatively with vitamin B12 and quantitative insulin check index and an opposite correlation of all quoted parameters was observed with low HDL. The correlation of traditional and non-traditional risk factors was stronger with low HDL and high TG compared with hypercholesterolemia. CONCLUSIONS: Hypertriglyceridemia and low HDL cholesterol is common in patients with CAD compared with hypercholesterolemia. This suggests that different preventive strategy is required in Indian patients with CAD.

Association of homocysteine with global DNA methylation in vegetarian Indian pregnant women and neonatal birth anthropometrics.

OBJECTIVE: The present study was designed to evaluate if plasma maternal folate, vitamin B-12 and homocysteine levels had an effect on maternal global DNA methylation and neonatal anthropometrics in Indian pregnant women. METHODS: A total of 49 participants having completed ≥36 weeks of pregnancy were enrolled in the study. Estimation of folate was by Ion capture assay, vitamin B-12 by microparticle enzyme immunoassay, total homocysteine by fluorescence polarization immunoassay and global DNA methylation using Cayman's DNA methylation enzyme immunoassay (EIA) kit. RESULTS: Folate and vitamin B-12 were inversely correlated to homocysteine in pregnant women consuming vegetarian and non-vegetarian diet. No difference in global DNA methylation was found between the vegetarian and non-vegetarian pregnant women. Folate and vitamin B-12 did not show association with global DNA methylation, however plasma total homocysteine of the vegetarian group showed significant correlation to global DNA methylation (r(2 )= 0.49, p = 0.011). Plasma total homocysteine was inversely related to tricep skinfold (r(2 )= -0.484, p = 0.01) and chest circumference (r(2 )= -0.104, p = 0.04) of neonates in vegetarian group. CONCLUSION: Moderate vitamin B-12 deficiency in vegetarian pregnant women might be the cause of hyperhomocystinemia, hypermethylation when compared to vitamin B-12 sufficient non-vegetarian group.

Differences in traditional and non-traditional risk factors with special reference to nutritional factors in patients with coronary artery disease with or without diabetes mellitus.

INTRODUCTION: There is an increase in awareness about the role of nutritional factors in chronic non-communicable diseases. We therefore conducted this study with an aim to assess the relationship between nutritional factor (vitamin B12 and homocysteine [Hcy]) and its association with insulin resistance and inflammatory markers, and differences in traditional and non-traditional risk factors among diabetics and non-diabetics in known cases of coronary artery disease (CAD). MATERIALS AND METHODS: Three hundred consecutive patients with known coronary disease on coronary angiography, who were >25 years old were included in this study. All cases were interviewed using a questionnaire. Blood samples were analyzed for insulin, vitamin B12, Hcy and inflammatory markers (highly sensitive C-reactive protein [hsCRP], interleukin-6 [IL-6], Tumor necrosis factor-alfa [TNF-α]). Insulin resistance was calculated with homeostasis model assessment of insulin resistance (HOMA-IR). RESULTS: Mean age of the patients was 60.95 ± 12.3 years. Body mass index and waist hip ratio were comparable in both groups. Triglyceride, very low-density lipoprotein and HbA1C were significantly higher and high-density lipoprotein (HDL) was significantly lower in patients with diabetes. Patients with diabetes had significantly high levels of IL-6, hsCRP and TNF-α compared with non-diabetic patients. Insulin resistance was twofold higher in diabetic patients. Serum vitamin B12 levels were significantly lower and Hcy was significantly higher in the diabetic group compared with the non-diabetic patients. HbA1C, HOMA-IR and Hcy levels were positively correlated with inflammatory markers in the total study population and in the non-diabetic patients; but, in diabetic patients, HbA1C and Hcy showed this relation. CONCLUSIONS: Vitamin B12 deficiency is common in the diabetic population. Hcy levels were higher in diabetics compared with non-diabetics, and were related to glycemic level and insulin resistance in diabetic patients. Patients with diabetes had higher traditional risk factors than patients without diabetes in known patients with CAD. Glycemic status was associated with insulin resistance and inflammatory markers.

Vitamin B12 deficiency and hyperhomocysteinemia as correlates of cardiovascular risk factors in Indian subjects with coronary artery disease.

BACKGROUND AND PURPOSE: Folate and vitamin B12 are essential components in the metabolism of homocysteine (Hcy). Hyperhomocysteinemia has been implicated in endothelial dysfunction and cardiovascular disease. However, the association of Hcy, vitamin B12, and folic acid with cardiovascular risk factors in patients with coronary artery disease (CAD) has not been studied in Indian patients. This study was conducted with the aim to evaluate the relationship of vitamin B12, folic acid, and Hcy levels with cardiovascular risk factors in subjects with known CAD. METHODS AND SUBJECTS: Three hundred patients (216 men; 84 women; aged 25-92 years) who had CAD on angiography were included in this study consecutively. All patients were evaluated for anthropometry and cardiovascular risk factors, and blood samples were collected for biochemical, nutritional, and inflammatory markers. RESULTS: Percentage of vitamin B12 and folate deficiency was 86.7% and 2.7%, respectively. Hyperhomocysteinemia was present in 95.3% patients. Vitamin B12 levels were significantly lower and Hcy levels were significantly higher in subjects with dyslipidemia, DM, and/or hypertension. Serum vitamin B12 was inversely associated with triglyceride and very low-density lipoprotein (VLDL) and positively with high-density lipoprotein (HDL). Hcy was positively associated with triglyceride and VLDL and negatively with HDL. Vitamin B12 was inversely correlated with inflammatory markers (high-sensitivity C-reactive protein and interleukin-6) directly related to insulin resistance whereas Hcy showed the opposite pattern. CONCLUSIONS: Serum vitamin B12 deficiency and hyperhomocysteinemia are related with cardiovascular risk factors in Indian patients with CAD.

Conventional and novel cardiovascular risk factors and markers of vascular damage in rural and urban Indian men.

BACKGROUND: India is undergoing rapid epidemiological and nutritional transition largely as a consequence of rapid urbanisation. We investigated conventional and novel cardiovascular risk factors in rural and urban Indian men and studied their association with markers of vascular damage. METHODS: We randomly selected and studied 149 rural, 142 urban slum residents and 150 urban middle class middle aged Indian men. We measured conventional (obesity, blood pressure, lipids, smoking habits) and novel (proinflammatory and prothrombotic factors) cardiovascular risk factors and markers of vascular damage (carotid intima media thickness (IMT), von Willebrand Factor (vWF), e-selectin). RESULTS: There was a progressive increase in most of the conventional cardiovascular (CV) risk factors from rural to slum to urban middle class men. Plasminogen activator inhibitor-1 (PAI-1), platelet count, total homocysteine and C-reactive protein showed similar patterns. Carotid IMT was similar in the three groups; vWF was highest in rural and e-selectin in slum men. Adjusting for location, age explained 17%, obesity 3% and conventional risk factors 1% of the variance in carotid IMT, whilst novel cardiovascular risk factors were without any significant impact. CONCLUSIONS: Urbanisation increases obesity related as well as prothrombotic and proinflammatory CV risk factors in Indian men, but appears not to impact on IMT.

Is hypomagnesaemia a coronary risk factor among Indians with coronary artery disease?

INTRODUCTION: Magnesium is an essential element that has numerous biological functions in the cardiovascular system. Hence, three hundred patients with known cardiovascular disease above the age of 25 years were studied to evaluate association between dietary and serum magnesium with cardiovascular risk factors. MATERIALS AND METHODS: Patients were divided into three groups according to serum magnesium levels; ≤1.6 (Group 1), >1.6-2.6 (Group 2) and: >2.6 mg/dl (Group 3), and into two groups according to dietary magnesium intake; ≤350 mg/day (Group 1) and >350 mg/day (Group 2), respectively. RESULTS: Mean age of patients was 60.97 ± 12.5 years. Total cholesterol, triglycerides, VLDL, and LDL were significantly higher and HDL cholesterol significantly lower in group 1 when compared with group 2 and group 3. Diabetes, dyslipidemia, and hypertension were negatively correlated with serum magnesium levels; which were maintained even after adjustment with age, sex, and anthropometric parameters in multiple regression analysis. Similar observations were observed in dietary magnesium intake except LDL and total cholesterol. Dietary magnesium was positively correlated with serum magnesium. CONCLUSIONS: Hypomagnesaemia and low dietary intake of magnesium are strongly related to cardiovascular risk factors among known subjects with coronary artery disease. Hence, magnesium supplementation may help in reducing cardiovascular disease.

Association of constitutional type of Ayurveda with cardiovascular risk factors, inflammatory markers and insulin resistance.

CONTEXT: Ayurveda propounds that diseases manifest from imbalance of doshas. There, have been attempts to indicate biochemical basis of constitutional types described in Ayurveda. AIMS: The study was intended to assess the association of constitutional types (Prakriti) with cardiovascular risk factors, inflammatory markers and insulin resistance in subjects with coronary artery disease (CAD). SETTINGS AND DESIGN: Hospital based cross sectional study. MATERIALS AND METHODS: Three hundred patients with CAD >25 years were studied. Assessment of Prakriti was done by using Ayusoft software. Biochemical parameters, inflammatory markers (hsCRP, TNF-alpha and IL-6) and insulin resistance (HOMA-IR) were measured. STATISTICAL ANALYSIS: Was done using EPI INFO, version 3.5.3. RESULTS: Mean age of patients was 60.97±12.5 years. Triglyceride, VLDL and LDL was significantly higher (P<0.0001, P<0.0001 and 0.0355, respectively) and HDL cholesterol (P<0.0001) significantly lower in vatta kapha (VK) Prakriti when compared with other constitution type. VK Prakriti was correlated with diabetes mellitus (r=0.169, P=0.003), hypertension (r=0.211, P≤0.0001) and dyslipidemia (r=0.541, P≤0.0001). Inflammatory markers; IL6, TNF alpha, hsCRP and HOMA IR was highest in VK Prakriti. Inflammatory markers were correlated positively with both VK and Kapha group. CONCLUSIONS: There is strong relation of risk factors (diabetes, hypertension, dyslipidemia), insulin resistance, and inflammatory markers with Vata Kapha and Kapha Prakriti.

Increases in plasma holotranscobalamin can be used to assess vitamin B-12 absorption in individuals with low plasma vitamin B-12.

Low plasma concentrations of vitamin B-12 are common in Indians, possibly due to low dietary intakes of animal-source foods. Whether malabsorption of the vitamin contributes to this has not been investigated. A rise in the plasma holotranscobalamin (holo-TC) concentration after a standard dose of oral vitamin B-12 has been proposed as a measure of gastrointestinal absorption in people with normal plasma vitamin B-12 concentrations. We studied 313 individuals (children and parents, 109 families) in the Pune Maternal Nutrition Study. They received 3 doses of 10 microg (n = 191) or 2 microg (n = 122) of cyanocobalamin at 6-h intervals. A rise in plasma holo-TC of > or =15% and >15 pmol/L above baseline was considered normal vitamin B-12 absorption. The baseline plasma vitamin B-12 concentration was <150 pmol/L in 48% of participants; holo-TC was <35 pmol/L in 98% and total homocysteine was high in 50% of participants (>10 micromol/L in children and >15 micromol/L in adults). In the 10 microg group, the plasma holo-TC concentration increased by 4.8-fold from (mean +/- SD) 9.3 +/- 7.0 pmol/L to 53.8 +/- 25.9 pmol/L and in the 2 microg group by 2.2-fold from 11.1 +/- 8.5 pmol/L to 35.7 +/- 19.3 pmol/L. Only 10% of the participants, mostly fathers, had an increase less than the suggested cut-points. Our results suggest that an increase in plasma holo-TC may be used to assess vitamin B-12 absorption in individuals with low vitamin B-12 status. Because malabsorption is unlikely to be a major reason for the low plasma vitamin B-12 concentrations in this population, increasing dietary vitamin B-12 should improve their status.

Determinants of incident hyperglycemia 6 years after delivery in young rural Indian mothers: the Pune Maternal Nutrition Study (PMNS).

OBJECTIVE: To study determinants of incident hyperglycemia in rural Indian mothers 6 years after delivery. RESEARCH DESIGN AND METHODS: The Pune Maternal Nutrition Study collected information in six villages near Pune on prepregnant characteristics and nutrition, physical activity, and glucose tolerance during pregnancy. An oral glucose tolerance test (OGTT) was repeated 6 years after delivery. RESULTS: A total of 597 mothers had an OGTT at 28 weeks' gestation; 3 had gestational diabetes (by World Health Organization 1999 criteria). Six years later, 42 of 509 originally normal glucose-tolerant mothers were hyperglycemic (8 diabetic, 20 with impaired glucose tolerance, and 14 with impaired fasting glucose). The hyperglycemic women had shorter legs and thicker skinfolds before pregnancy (P < 0.01, both), were less active and more hyperglycemic (2-h plasma glucose 4.8 vs. 4.4 mmol/l, P < 0.001) during pregnancy, and gained more weight during follow-up (6.0 vs. 2.7 kg, P < 0.001). Multivariate analysis revealed that total leukocyte count and blood pressure during pregnancy were additional independent predictors of 2-h glucose concentration at follow-up. CONCLUSIONS: Our results suggest that compromised linear growth, adiposity, inflammation, and less physical activity predispose to hyperglycemia in young rural Indian women. International cut points of diabetes risk factors are largely irrelevant in these women.

Oral vitamin B12 supplementation reduces plasma total homocysteine concentration in women in India.

People in India have a high prevalence of low vitamin B12 status and high plasma total homocysteine (tHcy) concentrations. In a proof of principle trial, we studied the effect of oral vitamin B12 (500 microg) and/or 100 g cooked green leafy vegetables (GLV) every alternate day in a 2x2 factorial design over a 6-week period. Forty-two non-pregnant vegetarian women (age 20-50 years) were randomly allocated to four study groups. Clinical measurements were made at the beginning and at the end of the study, and blood samples were collected before, and 2 and 6 weeks after commencement of intervention. Forty women completed the trial. Twenty-six women had low vitamin B12 status (<150 pmol/L) and 24 had hyperhomocysteinemia (>15 micromol/L). GLV supplementation did not alter plasma folate or tHcy. Vitamin B12 supplementation increased plasma vitamin B12 concentration (125 to 215 pmol/L, p <0.05) and reduced tHcy concentration (18.0 to 13.0 micromol/L, p <0.05) within first 2 weeks, both of which remained stable for the next 4 weeks. Plasma vitamin B12 and tHcy concentrations did not change in those who did not receive vitamin B12, and there was no change in plasma folate concentration in any of the groups. Blood haemoglobin concentration increased marginally within first two weeks in those women who received vitamin B12 (by 3 g/L, p <0.05) and the number of women with macrocytosis decreased from 2 to zero. There was no change in vibration sensory threshold during the period of the study. High-dose per oral vitamin B12 supplementation significantly reduced plasma tHcy within 2 weeks but did not achieve normal plasma tHcy concentration even after 6 weeks. People in India have a high prevalence of low vitamin B12 status and high plasma total homocysteine (tHcy) concentrations.

Maternal total homocysteine concentration and neonatal size in India.

The smallness of Indian babies is ascribed to small maternal size and their chronic under nutrition. Micronutrient nutrition of the mother may be particularly important. We investigated the relationship between maternal circulating concentrations of total homocysteine (tHcy), vitamin B12 and folate and offspring size at birth. Mothers of full term small for gestation age babies (SGA, gestation and sex specific birth weight <10th centile, N = 30) and mothers of appropriate for gestational age babies (AGA, >10th centile, N = 50) were compared for their body size, plasma tHcy, vitamin B12 and red cell folate concentration at 28 week gestation. Mothers of SGA babies were lighter and shorter than those of AGA babies (P <0.05, both) and had higher plasma tHcy concentration (P<0.01). Total homocysteine concentrations were inversely related to plasma vitamin B12 and red cell folate concentrations (r = approximately -0.5, P <0.01, both). Seventy percent of the women had a low vitamin B12 status (plasma vitamin B12 <150 pmol/L) but none were folate deficient (red cell folate <283 nmol/L). Higher maternal plasma tHcy concentration was significantly associated with lower offspring birth weight (r = -0.28, P<0.05 adjusting for maternal height, weight, gestation at delivery and the baby's gender), this effect was reduced by adjustment for red cell folate concentration. We conclude that maternal vitamin B12 deficiency reflected in plasma tHcy concentration contributes to small size of Indian babies.