Economic burden of beta-thalassaemia major receiving hypertransfusion therapy at a public hospital in Mumbai.

Background Treating beta-thalassaemia major may entail high costs with considerable out-of-pocket expenditure. Therefore, determination and valuation of the economic costs of a common haemoglobinopathy such as beta-thalassaemia major in India may provide insights to evolve policies for reduction or elimination of the disease. We estimated economic burden of beta-thalassaemia major in Mumbai in terms of cost to the family and the healthcare system. Methods This single-centre, prospective, cross-sectional, non-interventional study included children <12 years of age treated at the thalassaemia day care centre of a public hospital in Mumbai. The demographic data and treatment-related information was recorded. Cost of illness was studied from a societal perspective by the prevalence-based approach. Direct (medical and non-medical), indirect (loss of wages and loss of school days) and intangible costs (closed-ended iterative bidding) were calculated for each patient by interview. Results The total annual cost of treating 130 children with beta-thalassaemia major in Mumbai was ₹86 72 412 (US$ 127 535) or ₹66 710 (US$ 981) per patient per year and ₹12 82 30 412 (US$ 1 885 741) including intangible costs. Direct costs contributed to 94% of the cost of illness with chelation therapy (23%) and blood investigations (21%) being major contributors. Direct and indirect costs correlated significantly with duration of blood transfusion (p<0.05 and p=0.006, respectively), whereas indirect costs correlated with socioeconomic status (rho=0.25). Conclusion The majority (94%) of costs incurred by families for treatment of beta-thalassaemia major are direct costs, especially expenses for chelation and blood investigations. Even at subsidized rates, financial burden to the families from lower socioeconomic strata is likely to be considerable as these are out-of-pocket expenses. In consideration of the economic impact of treating beta-thalassaemia major in individual families, the healthcare system and society, it is prudent to promote and pursue long-term and short-term measures with urgent emphasis on prevention as a public health activity at the national level in India.

Evaluation of satisfaction and reasons for participation in a Covid-19 vaccine clinical trial: A single-centre, observational study.

Background In May 2020, WHO recognized the role of extensive immunization for interrupting the transmission of the SARS-CoV-2 virus. The development of such vaccines in clinical trials relies upon participants who are expected to be vested in the research process. Assessment of participant factors such as motivation and satisfaction are hence important to gauge perspective and ensure successful conduct and completion of these trials. Methods We administered a validated three-domain questionnaire to and documented the binary categorical responses (yes/no) of participants (after informed consent) who had taken both doses of COVOVAX™ in a phase 3 trial at our institute. Association of the dependent variables (participant responses) with the independent variables (participant demographics and socioeconomic strata) was computed using Chi-square test at 5% significance. In case of a significant association, Bonferroni post-hoc test was applied for multiple comparisons. Results Of the 78 participants who were administered the questionnaire, two-thirds were highly satisfied with their experience at our site. Gaining access to a new vaccine was a primary motivation overall (74%) and also in graduates (p=0.03) and middle-class population (p=0.002), whereas the lower-middle class population (p<0.0001) and those educated till secondary school (p=0.003) took part due to the long wait for government-approved vaccines. Conclusion Participants in a Covid-19 vaccine trial at Mumbai were largely satisfied with the care given to them though altruism did not feature as a primary reason for participation.

Evaluation of Allergic Reactions following COVID - 19 Vaccination in Patients with Documented Allergies.

BACKGROUND AND RATIONALE: The government guidance regarding COVID-19 vaccination lists food allergy, drug allergy and history of anaphylaxis as contraindications for receiving vaccination. This study was planned to evaluate such patients listed in the database of an allergy center and who took any COVID-19 vaccine. METHODS: Data on n=255 patients was mined. Inclusions were those over 18 years, any allergic diathesis and receipt of at least one dose of any COVID-19 vaccine. Age, gender, nature of allergy and type of COVID vaccine taken along with outcome of interest [occurrence or otherwise of all allergic reaction post vaccination] was collated. RESULTS: Data of 227 patients were finally analysed. Eighty one took the first dose and 33 took both doses. None with food and/or drug allergy and/or a history of anaphylaxis developed any adverse event (AE) post vaccination. Three AEs were seen in those with other allergic diathesis. Two AEs [One to COVAXIN™ and one to COVISHIELD™] were only generalized itching that were self-limiting. A female patient had itching with palmar erythema [post COVISHIELD™] which subsided after a week's treatment with an antihistamine. She had a history of allergy to radiocontrast media containing polyethylene glycol/PEG] indicating possible allergy to polysorbate 80 [PEG related compound contained in COVISHIELD™]. CONCLUSION: No patient fitting contraindications for COVID-19 vaccination laid down by the Indian government developed any allergic reaction post vaccination. The guidelines for vaccination may be revisited to make them more inclusive with appropriate training of the vaccination centre staff.

An Introduction to Statistics - Data Types, Distributions and Summarizing Data.

The purpose of research is to gather data, which can then be used to inform decision-making. Data can be of various types and an understanding of this is crucial for its proper analysis and interpretation. In this article, we look at various types and distributions of data, and methods to summarize this data. HOW TO CITE THIS ARTICLE: Ranganathan P, Gogtay NJ, An Introduction to Statistics - Data Types, Distributions and Summarizing Data. Indian J Crit Care Med 2019;23(Suppl 2):S169-S170.

Steady-state Pharmacokinetics of Vancomycin in Children Admitted to Pediatric Intensive Care Unit of a Tertiary Referral Center.

AIMS AND OBJECTIVES: Vancomycin is a drug of choice for various gram-positive bacterial (GPB) infections and is largely prescribed to pediatric intensive care unit (PICU) patients. Despite the different pathophysiology of these patients, limited data are available on pharmacokinetics of vancomycin. There are lack of data for critically ill Indian children; hence, study was conducted to assess the steady-state pharmacokinetics in children admitted to PICU. MATERIALS AND METHODS: Twelve subjects (seven males, five females) aged 1-12 years were enrolled. Vancomycin (dose of 20 mg/kg per 8 hours) was infused for over 1 hour and steady-state pharmacokinetics was performed on day 3. Vancomycin concentrations were measured by the validated liquid chromatography mass spectrometry method. Pharmacokinetic parameters were calculated using Winnonlin (Version 6.3; Pharsight, St. Louis, MO). RESULTS: The steady-state mean C ssmax was 40.94 µg/mL (±15.07), and mean AUC0-8 hours was 124.15 µg/mL (±51.27). The mean t 1/2 was 4.82 hours (±2.71), Vd was 12.48 L (±4.43), and Cl was 2.08 mL/minute (±0.89). The mean AUC0-24 among 12 subjects was 372.44 µg/mL (±153.82). Among 35 measured trough concentrations, 23 (65.71%) were below, 11 (31.43%) were within, and 1 (2.86%) was above the recommended range. CONCLUSION: The pharmacokinetic parameters of vancomycin were comparable with previously reported studies. However, recommended trough levels (10-20 µg/mL) were not achievable with current recommended dosing of 60 mg/kg/day. HOW TO CITE THIS ARTICLE: Mali NB, Tullu MS, Wandalkar PP, Deshpande SP, Ingale VC, Deshmukh CT, et al. Steady-state Pharmacokinetics of Vancomycin in Children Admitted to Pediatric Intensive Care Unit of a Tertiary Referral Center. IJCCM 2019;23(11):497-502.

Single-dose and Steady-state Pharmacokinetics of Vancomycin in Critically Ill Patients Admitted to Medical Intensive Care Unit of India.

RATIONALE: Vancomycin remains the standard of care for gram-positive bacterial infections, though there are significant developments in newer antibacterial agents. Efficacy can be improved by linking pharmacokinetic with pharmacodynamic principles, thus leading to optimum antibiotic exposure. There is scarcity of pharmacokinetic data in Indian intensive care unit (ICU) population. MATERIALS AND METHODS: Fifteen subjects with suspected or proven gram-positive bacterial infection of either gender between 18 years and 65 years of age were enrolled. Vancomycin at the dose of 1 g every 12 hours was administered over 1-hour period and pharmacokinetic assessments performed on blood samples collected on days 1 and 3. Vancomycin concentrations were measured on validated liquid chromatography mass spectrometry method. Pharmacokinetic parameters were calculated using Winnonlin (Version 6.3; Pharsight, St. Louis, MO). RESULTS: The mean C max, elimination half-life, AUC0-12hours, volume of distribution, and clearance of single dose were 36.46 µg/mL (±14.87), 3.98 hours (±1.31), 113.51 µg/mL (±49.51), 52.01 L (±31.31), and 8.90 mL/minute (±3.29), respectively, and at steady state were 40.87 µg/mL (±19.29), 6.27 hours (±3.39), 147.94 µg/mL (±72.89), 56.39 L (±42.13), and 6.98 mL/minute (±4.48), respectively. The elimination half-life increased almost two-fold at steady state. The steady state mean AUC0-24 was 295.89 µg/mL (±153.82). Out of 45 trough levels, 32 (71.11%) concentrations were below recommended range. CONCLUSION: Recommended AUC0-24hours and trough concentrations were not achieved in majority of patients with current dosing, suggesting reevaluation of current vancomycin dosing. Individualized treatment based on close monitoring of vancomycin serum concentrations in critically ill patients is imperative. HOW TO CITE THIS ARTICLE: Mali NB, Deshpande SP, Wandalkar PP, Gupta VA, Karnik ND, Gogtay NJ, et al. Single-dose and Steady-state Pharmacokinetics of Vancomycin in Critically Ill Patients Admitted to Medical Intensive Care Unit of India. IJCCM 2019;23(11):513-517.

Comparison of a Novel Human Rabies Monoclonal Antibody to Human Rabies Immunoglobulin for Postexposure Prophylaxis: A Phase 2/3, Randomized, Single-Blind, Noninferiority, Controlled Study.

Background: Lack of access to rabies immunoglobulin (RIG) contributes to high rabies mortality. A recombinant human monoclonal antibody (SII RMAb) was tested in a postexposure prophylaxis (PEP) regimen in comparison with a human RIG (HRIG)-containing PEP regimen. Methods: This was a phase 2/3, randomized, single-blind, noninferiority study conducted in 200 participants with World Health Organization category III suspected rabies exposures. Participants received either SII RMAb or HRIG (1:1 ratio) in wounds and, if required, intramuscularly on day 0, along with 5 doses of rabies vaccine intramuscualarly on days 0, 3, 7, 14 and 28. The primary endpoint was the ratio of the day 14 geometric mean concentration (GMC) of rabies virus neutralizing activity (RVNA) as measured by rapid fluorescent focus inhibition test for SII RMAb recipients relative to HRIG recipients. Results: One hundred ninety-nine participants received SII RMAb (n = 101) or HRIG (n = 98) and at least 1 dose of vaccine. The day 14 GMC ratio of RVNA for the SII RMAb group relative to the HRIG group was 4.23 (96.9018% confidence interval [CI], 2.59-6.94) with a GMC of of 24.90 IU/mL (95% CI, 18.94-32.74) for SII RMAb recipients and 5.88 IU/mL (95% CI, 4.11-8.41) for HRIG recipients. The majority of local injection site and systemic adverse reactions reported from both groups were mild to moderate in severity. Conclusions: A PEP regimen containing SII RMAb was safe and demonstrated noninferiority to HRIG PEP in RVNA production. The novel monoclonal potentially offers a safe and potent alternative for the passive component of PEP and could significantly improve the management of bites from suspected rabid animals. Clincical Trials Registration: CTRI/2012/05/002709.

An assessment of the compliance of randomized controlled trials published in two high impact journals with the CONSORT statement.

Background: The Consolidated Standards of Reporting Trials (CONSORT) statement has been developed to improve the quality of reporting of clinical trials. There is possibly suboptimal adherence to the CONSORT statement in published trials. We evaluated the compliance of randomized controlled trials ( RCTs) published in the Journal of the American Medical Association (JAMA) and British Medical Journal (BMJ) in 2013 to the CONSORT statement 2010. Methods: A PubMed search for RCTs published in JAMA and BMJ for 2013 was done. Scores were assigned to each subitem of CONSORT by one of four authors and disputes were resolved by mutual consensus. The total score for each RCT was calculated and converted to a percentage total score (PTS). Scores were expressed as median (range). The median scores between journals and types of RCTs were compared using the Mann-Whitney U test. Results: There were 97 RCTs (69 in JAMA and 28 in the BMJ) comprising parallel (75), cluster (14) and non-inferiority (8) design studies. The overall median (range) of PTS of all RCTs was 82% (59.4%-97.1 %). JAMA had an overall median (range) PTS of 81.6% (59.4%-97.1 %) and the BMJ 84% (65.2%-92.2%). The difference was not statistically significant (p=0.25). Between trial designs, the highest PTS was seen with parallel (which included parallel, crossover and factorial designs) with a median (range) of 85.1% (68.4%-90.2%) followed by cluster randomized trials 82.8% (65.2%-92.2%) and non-inferiority trials 78.6% (72.7%-85.7%). There was no significant difference between the three trial designs (p=0.48). Conclusion: A wide range in PTS (59.4%-97.1 %) even in high impact journals indicates poor compliance of reported trials with CONSORT.

A Prospective Antibacterial Utilization Study in Pediatric Intensive Care Unit of a Tertiary Referral Center.

PURPOSE: Antibacterials are commonly prescribed to Pediatric Intensive Care Unit (PICU) patients. However, inappropriate antibacterial prescriptions lead to increases in antibacterial resistance, treatment cost, duration of treatment, and poor clinical outcome. The antibacterial utilization study assesses the prescription patterns and if necessary recommends the interventions to improve antibacterial prescriptions. Hence, the present prospective groundwork was conducted. MATERIALS AND METHODS: The study was conducted over the period of 6 months (April 18 to October 20, 2014). The demographics and drug use details were captured daily from patients admitted to PICU to assess World Health Organization indicators. RESULTS: A total of 200 patients enrolled, among them 119 males and 81 females. There were 12.46 (±6.16) drugs prescribed per patient, of which 2.38 (±1.48) were antibacterials. Among the total drug prescribed, 18.49% were antibacterials and 97% patients received at least one antibacterial. Ceftriaxone (49.48%) was the most commonly prescribed antibacterial, while imipenem (2.58%) and colistin (2.06%) use was very low. A total of 80.95% antibacterials were prescribed by generic name, 94.88% were administered intravenously, and 80.76% were prescribed from hospital pharmacy. The average length of PICU stay was 6.15 days (±6.20), the average length of antibacterial treatment was 6.08 days (±6.27), and the average length of empirical antibacterial treatment was 5.50 days (±5.40). The cost of antibacterial therapy per patient was Indian rupees 824.64 (±235.35). In 27 patients, bacterial culture test was positive and of whom 21 received antibacterials as per sensitivity pattern. CONCLUSIONS: The use of antibacterials was not indiscriminately high but more prescriptions per sensitivity pattern are required.

A Multicentric, Prospective, Observational Antibacterial Utilization Study in Indian Tertiary Referral Centers.

RATIONALE: Antibacterials are largely prescribed to the intensive care unit (ICU) patients due to high prevalence of infections. However, appropriate use of antibacterials is imperative; since the misuse of antibacterials increases antibacterial resistance and ultimately, it has negative impact on health care and economic system. Hence, continuous antibacterials prescription assessments are very important to judge and improve prescription patterns. The present work was carried out at public and private hospitals to assess the differences in antibacterial prescribing pattern. METHODS: The present study was conducted at three public and two private hospitals over the period of 14 months. Demographic and drug use details were captured daily from patients admitted to medical ICUs to assess the World Health Organization indicators. RESULTS: A total of 700 patients were enrolled across the five centers (140 per center), among them 424 were male and 276 were female. Average number of drugs and antibacterials prescribed at public hospitals are significantly higher than the private hospital. However, percentage of antibacterial agents prescribed at public hospitals was significantly lower than the private hospitals (P = 0.0381). Private hospitals had significantly lower percentage of antibacterial agents prescribed by generic name (P < 0.0001). Differences in change of antibacterial agents required were not statistically significantly different (P = 0.1888); however, significant difference was observed in percentage of patients who received antibacterial treatment as per sensitivity pattern (P = 0.0385) between public and private hospitals. Significantly higher mortality was observed in public hospitals compared to private hospitals (<0.0001). CONCLUSIONS: More generic prescriptions and more number of prescriptions as per the sensitivity pattern are required at each public and private hospital.

An audit of colistin use in neonatal sepsis from a tertiary care centre of a resource-limited country.

BACKGROUND & OBJECTIVES: Sepsis due to multidrug-resistant Gram-negative pathogens is a challenge for clinicians and microbiologists and has led to use of parenteral colistin. There is a paucity of data regarding safety and efficacy of intravenous colistin use in neonates. The objective of this retrospective analysis was to study the efficacy and safety of intravenous colistin in the treatment of neonatal sepsis. METHODS: An audit of the data from neonates, admitted to a neonatal intensive care unit of a tertiary care hospital during January 2012 to December 2012, and who received intravenous colistin was carried out. RESULTS: Sixty two neonates received intravenous colistin (52 preterm and 10 term) for the treatment of pneumonia, bloodstream infections and meningitis. The isolated pathogens in decreasing order of frequency were Acinetobacter baumannii, Klebsiella pneumonia and Pseudomonas aeruginosa. Of the total 62 neonates, 41 (66.12%) survived and 21 (33.87%) died. Significantly higher mortality was observed in neonates with lower body weights (P < 0.05). A significant association of mortality was found in those with sepsis due to Klebsiella species. Only one of seven with this infection survived as against 15 of the 23 who grew other organisms [P = 0.03; crude odds ratio = 11.25 (1.2, 110.5)]. None of the neonates developed neurotoxicity or nephrotoxicity. INTERPRETATION & CONCLUSIONS: This retrospective study in neonates with sepsis showed that intravenous colistin was safe and effective in the treatment of neonatal sepsis. Further, well-controlled, prospective clinical trials need to be done to corroborate these findings.

Writing an Abstract for a Research Manuscript: Providing an Honest, Succinct and Complete Summary.

is a vital part of a research paper. Besides the title, it is the most widely read section of an article. The first impressions created by the abstract on editors and reviewers can have a great influence on the fate of the article. After its publication, a reader might decide to give the article a miss, if he finds the information provided in the abstract uninteresting, irrelevant or uninspiring. An abstract should, therefore, be packed with all important relevant information about the study, so that reviewers and readers understand the rationale of the study, are assured of adequacy of the methodology employed, are informed about the important findings and appreciate the reasonable conclusions stated in the abstract. Brevity, self-sufficiency, providing complete and accurate information in an unbiased manner are some of the important characteristics of a good abstract.

Use of computerized tests to evaluate psychomotor performance in children with specific learning disabilities in comparison to normal children.

BACKGROUND & OBJECTIVES: Children with specific learning disabilities (SpLD) have an unexplained difficulty in acquiring basic academic skills resulting in a significant discrepancy between their academic potential and achievements. This study was undertaken to compare the performance on a battery of six psychomotor tests of children with SpLD and those without any learning disabilities (controls) using computerized tests. METHODS: In this study, 25 children with SpLD and 25 controls (matched for age, socio-economic status and medium of instruction) were given three training sessions over one week. Then children were asked to perform on the six computerized psychomotor tests. RESULTS were compared between the two groups. RESULTS: Children with SpLD fared significantly worse on finger tapping test, choice reaction test, digit picture substitution test and card sorting test compared to the controls ( p <0.05). INTERPRETATION & CONCLUSIONS: Children with SpLD have impairment of psychomotor skills like attention, sensory-motor coordination and executive functioning. Further research is needed to evaluate if the remedial education plan results in improvement in psychomotor performance of children with SpLD on these selected tests.

Economic Burden of Gaucher Disease at a Tertiary Care Public Hospital in Mumbai.

OBJECTIVES: To estimate the economic burden of patients diagnosed with Gaucher disease at a public hospital from a societal perspective. METHODS: Data from 30 Gaucher patients visiting the Genetic Clinic of the Department of Pediatrics at the study site in Mumbai was analyzed between January 2019 and January 2021. A cost of illness analysis was undertaken to estimate direct, indirect and intangible costs. Costs in treated and treatment naive groups were compared. RESULTS: The total cost (direct and indirect) for 30 patients was ₹25,45,74,743/- (3440199.2 USD). Majority of this cost (99.8%) was due to direct costs of which medications [Enzyme replacement therapy (ERT) and Substrate reduction therapy (SRT)] constituted 98.8%. The notional cost was ₹1,43,94,695. Total costs of 14 treated patients were ₹25,29,67,279 and 16 treatment naive patients were ₹16,15,064 with a ratio of 157:1. Direct costs and cost of school absenteeism were significantly higher in the treated subgroup. Overall, direct, total costs and costs of school absenteeism were significantly associated with age and disease duration. CONCLUSIONS: The economic burden of Gaucher disease is a staggering amount. This is an underestimate, as the expenses are highly subsidized in a public health facility. The highest contributor to cost component was direct costs, especially medication costs. Against the backdrop of the National Policy for Rare Diseases, resource allocation towards Gaucher disease should consider short term measures for judicious funding or reimbursement of disease-specific therapy and long-term cost-effective measures for promoting preventive strategies as the most practically feasible solution to reduce this economic burden.

Low-dose emicizumab prophylaxis in patients with severe hemophilia A: a retrospective study bringing new hope for our patients.

BACKGROUND: Low-dose emicizumab can potentially offer a cost-effective treatment option in persons with hemophilia A, especially in developing countries. OBJECTIVES: To compare the efficacy and safety of low-dose emicizumab with those on low-dose factor (F)VIII prophylaxis via chart review. METHODS: After ethics approval, chart data of 2 groups of patients were reviewed: group 1 (low-dose emicizumab, n = 10; 3 mg/kg monthly without a loading dose) and group 2 (low-dose FVIII prophylaxis, n = 10; 10-20 IU/kg of FVIII concentrates twice a week). Outcomes were target joints, annual bleeding rate, annual joint bleeding rate, Hemophilia Joint Health Score, nonactivated thromboelastometry-rotational thromboelastometry clotting time, plasma emicizumab levels, and direct costs of treatment. RESULTS: All outcome measures were significantly better in the low-dose emicizumab group than in the low-dose FVIII prophylaxis group. For nonactivated thromboelastometry-rotational thromboelastometry, median values after 6 months in the low-dose emicizumab group were comparable with values seen in patients with mild hemophilia, while the values in the low-dose FVIII prophylaxis group were similar to those of patients with moderate hemophilia. The direct cost of low-dose emicizumab was found to be approximately US $6000 and that for low-dose recombinant FVIII prophylaxis used in our study was US $6282 (the cost may range from US $3432 to $7920 depending on the type of factor) when compared to approximately US $15 000 for standard-dose emicizumab. CONCLUSION: Low-dose emicizumab offers a cost-effective treatment option and can improve access in developing countries. These findings need to be confirmed in a larger and better-controlled study.

Seropersistence of SII-ChAdOx1 nCoV-19 (COVID-19 vaccine): 6-month follow-up of a randomized, controlled, observer-blind, phase 2/3 immuno-bridging study in Indian adults.

AZD1222 (ChAdOx1 nCoV-19) is a replication-deficient adenoviral vectored coronavirus disease-19 (COVID-19) vaccine that is manufactured as SII-ChAdOx1 nCoV-19 by the Serum Institute of India Pvt Ltd following technology transfer from Oxford University/AstraZeneca. The non-inferiority of SII-ChAdOx1 nCoV-19 with AZD1222 was previously demonstrated in an observer-blind, phase 2/3 immuno-bridging study (trial registration: CTRI/2020/08/027170). In this analysis of immunogenicity and safety data 6 months post first vaccination (Day 180), 1,601 participants were randomized 3:1 to SII-ChAdOx1 nCoV-19 or AZD1222 (immunogenicity/reactogenicity cohort n = 401) and 3:1 to SII-ChAdOx1 nCoV-19 or placebo (safety cohort n = 1,200). Immunogenicity was measured by anti-severe acute respiratory syndrome coronavirus 2 spike (anti-S) binding immunoglobulin G and neutralizing antibody (nAb) titers. A decline in anti-S titers was observed in both vaccine groups, albeit with a greater decline in SII-ChAdOx1 nCoV-19 vaccinees (geometric mean titer [GMT] ratio [95% confidence interval (CI) of SII-ChAdOx1 nCoV-19 to AZD1222]: 0.60 [0.41-0.87]). Consistent similar decreases in nAb titers were observed between vaccine groups (GMT ratio [95% CI]: 0.88 [0.44-1.73]). No cases of severe COVID-19 were reported following vaccination, while one case was observed in the placebo group. No causally related serious adverse events were reported through 180 days. No thromboembolic or autoimmune adverse events of special interest were reported. Collectively, these data illustrate that SII-ChAdOx1 nCoV-19 maintained a high level of immunogenicity 6 months post-vaccination. SII-ChAdOx1 nCoV-19 was safe and well tolerated.

An audit of therapeutic drug monitoring services of anticonvulsants at a tertiary care hospital in India.

BACKGROUND: Therapeutic drug monitoring (TDM) is an important adjunct to the treatment of epilepsy. However, few studies have actually correlated plasma levels of antiepileptic drugs (AEDs) with treatment response. The present audit aimed to study (i) the association between seizure control and number of AEDs, plasma AED concentration, and concomitant use of antitubercular drugs; (ii) the pattern of indications for TDM requisitions; and (iii) the association between referral for toxicity and plasma AED concentration. METHODS: This observational and retrospective study was carried out to analyze the TDM data of patients referred between January 2008 and December 2011. As per the International League Against Epilepsy Task Force 2009, patients were categorized into responders and nonresponders. Plasma AED levels were interpreted as below, within, and above the reference range. RESULTS: Of 3206 TDM requisitions, 67% were monotherapy and 33% were 2 or more AEDs. Only 8% were responders as against 92% nonresponders. Of 95 patients on concomitant antituberculosis treatment, 72 were nonresponders, with odds ratio (95% confidence interval) 3.71 [2.19 to 6.23]. Breakthrough seizure (37%) was the most common indication followed by suspected toxicity and routine monitoring in 22% each and suspected nonadherence in 11% of the total requests. In 52% of patients, plasma levels were below the reference range, and they were equally distributed amongst responders and nonresponders. Among patients referred for suspected phenytoin toxicity, only 59% (50.6 to 67.8) had plasma concentrations above the reference range. CONCLUSIONS: TDM continues to remain an important tool to support dose individualization when the patient is receiving multiple AEDs or other drugs such as antitubercular medicines, to assess compliance, and to monitor and treat toxicity.

Pharmacokinetics of colistin in critically ill patients with multidrug-resistant Gram-negative bacilli infection.

PURPOSE: Colistin, which had not been used widely because of nephrotoxicity and neurotoxicity, has gained clinical importance in recent times due to the resurgence of multidrug-resistant Gram-negative bacilli. Very few studies, especially pharmacokinetic studies, have been performed with intravenous colistimethate sodium, and none in India. The aim of our study was to study the single-dose and steady-state pharmacokinetics of colistin in patients with multidrug-resistant Gram-negative bacilli infections. METHOD: This was a prospective open-label pharmacokinetic study done in an intensive care unit in a tertiary care hospital on 15 critically ill patients with proven multidrug-resistant Gram-negative bacilli infection. Colistimethate sodium was injected as intermittent intravenous infusions in accordance with the recommendations on the package insert. For patients weighing ≥ 60 kg with a normal renal function or with a creatinine clearance (CL(CR)) of between 20 and 50 ml/min, the drug was administered at 2 million international units (MIU) every 8 h; for those with a CL(CR) of 10-20 ml/min, the dose was 2 MIU every 12 h. Those patients who weighed <60 kg were administered 50,000 IU/kg/day in three divided doses at 8-h intervals. Both single-dose and steady-state pharmacokinetics of colistin were determined and correlated with clinical outcomes. RESULTS: A wide inter-individual variation was observed in pharmacokinetic parameters. The median (range) of the maximum plasma drug concentration/minimum inhibitory concentration (C(max)/MIC) ratio for Acinetobacter spp. was 13.4 (1.3-40.3) following the administration of a single dose of colistimethate sodium and 26.3 (0.9-64.9) at steady-state. For Pseudomonas spp., these values were 3.18 (1.6-23.1) following the single dose and 3.82 (2.3-10.9) at steady-state. For those patients whose cultures grew Acinetobacter spp., an optimum value of the C(max)/MIC ratio of >8 was achieved in seven of nine patients after the single dose and in seven of eight patients at steady-state. For those patients whose cultures grew Pseudomonas spp, only one patient after the single dose and one patient at steady-state achieved a C(max)/MIC ratio of >8. A significant association was noted between dose and survival, and a trend was observed with patients weighing ≤ 60 kg (who received 50,000 IU/kg/day instead of 6 MIU/day for those >60 kg) having an increased mortality. CONCLUSION: The pharmacokinetic parameters of colistin were comparable to those reported in previous studies in critically ill patients. However, the recommended dose may be inadequate to maintain the C(max)/MIC ratio to an optimal level-at least in patients infected with Pseudomonas spp. The dose recommendation should be based only on creatinine clearance and not body weight.