COVID-19 complicating pregnancy: A retrospective study of nine intensive care unit patients.

Background: With the emergence of the coronavirus 2019 (COVID-19) pandemic, it was essential to determine the impact of this disease on pregnant women and neonatal outcomes. In this study, we present a series of nine cases of pregnant women with COVID-19 disease requiring intensive care unit (ICU) admission. Methods: We retrospectively collected clinical data of pregnant women with COVID-19 disease admitted to ICU between September 2020 and September 2021. Results: Most common presenting symptom was cough. Two patients had no respiratory symptoms at presentation. Five of the nine patients required invasive mechanical ventilation. Seven patients required caesarean section, four of whom delivered preterm. There were no maternal or neonatal deaths. Conclusions: Although maternal and neonatal outcomes reported in our study are encouraging, it is imperative to emphasize the importance of an individualized, multidisciplinary approach, and good healthcare infrastructure for optimal management of this group of patients.

A Dose-Finding Study to Guide Use of Verapamil as an Adjunctive Therapy in Tuberculosis.

Induction of mycobacterial efflux pumps is a cause of Mycobacterium tuberculosis (Mtb) drug tolerance, a barrier to shortening antitubercular treatment. Verapamil inhibits Mtb efflux pumps that mediate tolerance to rifampin, a cornerstone of tuberculosis (TB) treatment. Verapamil's mycobacterial efflux pump inhibition also limits Mtb growth in macrophages in the absence of antibiotic treatment. These findings suggest that verapamil could be used as an adjunctive therapy for TB treatment shortening. However, verapamil is rapidly and substantially metabolized when co-administered with rifampin. We determined in a dose-escalation clinical trial of persons with pulmonary TB that rifampin-induced clearance of verapamil can be countered without toxicity by the administration of larger than usual doses of verapamil. An oral dosage of 360 mg sustained-release (SR) verapamil given every 12 hours concomitantly with rifampin achieved median verapamil exposures of 903.1 ng.h/mL (area under the curve (AUC)0-12 h ) in the 18 participants receiving this highest studied verapamil dose; these AUC findings are similar to those in persons receiving daily doses of 240 mg verapamil SR but not rifampin. Moreover, norverapamil:verapamil, R:S verapamil, and R:S norverapamil AUC ratios were all significantly greater than those of historical controls receiving SR verapamil in the absence of rifampin. Thus, rifampin administration favors the less-cardioactive verapamil metabolites and enantiomers that retain similar Mtb efflux inhibitory activity to verapamil, increasing overall benefit. Finally, rifampin exposures were 50% greater after verapamil administration, which may also be advantageous. Our findings suggest that a higher dosage of verapamil can be safely used as adjunctive treatment in rifampin-containing treatment regimens.

Extracorporeal membrane oxygenation in COVID-19- Associated acute respiratory distress syndrome - Outcome and experience in a tertiary care intensive care unit - A retrospective study.

Background: Extracorporeal membrane oxygenation (ECMO) has been used in patients with severe acute respiratory distress syndrome (ARDS) due to coronavirus disease 2019 (COVID-19) who fail conventional treatment. Methods: A retrospective observational study was designed in patients who underwent ECMO for severe COVID-19 ARDS in a tertiary care centre from September 2020 to July 2021. The primary outcome was to assess factors influencing clinical outcomes and survival to hospital discharge. Secondary outcomes were to assess the clinical profile and pre-ECMO features, ECMO characteristics and complications. Collected data were entered in Excel software and analysed using R software version 4.0.2 (R foundation for statistical computing, Vienna, Austria). Results: A total of 19 patients underwent ECMO. Ten patients survived and discharge. Survivors had a longer median (interquartile range [IQR]) duration (days) on ECMO, that is, 25 (7-50), compared to non-survivors, that is, 12 (1-34) (P = 0.133). We also noted that patients who survived had a longer median (IQR) duration (days) of intensive care unit (ICU) stay, that is, 41.5 (30-70), compared to non-survivors, that is, 9 (2-40) (P = 0.001). Conclusion: In our study, 52.3% of patients survived and discharge, and with ECMO outcomes for COVID-19 ARDS were at par with ECMO outcomes for non-COVID-19 ARDS despite requiring ECMO for longer duration and increased ICU length of stay.

Innovations with Validation: An Ingenious Way Forward?

How to cite this article: Ajith Kumar AK, Nikhil N. Innovations with Validation: An Ingenious Way Forward? Indian J Crit Care Med 2023;27(6):377-378.

In-vivo studies on Transitmycin, a potent Mycobacterium tuberculosis inhibitor.

This study involves the in-vitro and in-vivo anti-TB potency and in-vivo safety of Transitmycin (TR) (PubChem CID:90659753)- identified to be a novel secondary metabolite derived from Streptomyces sp (R2). TR was tested in-vitro against drug resistant TB clinical isolates (n = 49). 94% of DR-TB strains (n = 49) were inhibited by TR at 10µg ml-1. In-vivo safety and efficacy studies showed that 0.005mg kg-1 of TR is toxic to mice, rats and guinea pigs, while 0.001mg kg-1 is safe, infection load did not reduce. TR is a potent DNA intercalator and also targets RecA and methionine aminopeptidases of Mycobacterium. Analogue 47 of TR was designed using in-silico based molecule detoxification approaches and SAR analysis. The multiple targeting nature of the TR brightens the chances of the analogues of TR to be a potent TB therapeutic molecule even though the parental compound is toxic. Analog 47 of TR is proposed to have non-DNA intercalating property and lesser in-vivo toxicity with high functional potency. This study attempts to develop a novel anti-TB molecule from microbial sources. Though the parental compound is toxic, its analogs are designed to be safe through in-silico approaches. However, further laboratory validations on this claim need to be carried out before labelling it as a promising anti-TB molecule.

Pharmacokinetics of rifampicin, isoniazid & pyrazinamide during daily & intermittent dosing: A preliminary study.

Background & objectives: The National Tuberculosis (TB) Control Programme has transitioned from thrice-weekly to daily drug treatment regimens in India. This preliminary study was conceived to compare the pharmacokinetics of rifampicin (RMP), isoniazid (INH) and pyrazinamide (PZA) in TB patients being treated with daily and thrice weekly anti-TB treatment (ATT). Methods: This prospective observational study was undertaken in 49 newly diagnosed adult TB patients receiving either daily ATT (n=22) or thrice-weekly ATT (n=27). Plasma RMP, INH and PZA were estimated by high-performance liquid chromatography. Results: The peak concentration (Cmax) of RMP was significantly higher (RMP: 8.5 µg/ml vs. 5.5 µg/ml; P=0.003) and Cmax of INH was significantly lower (INH: 4.8 µg/ml vs. 10.9 µg/ml; P<0.001) in case of daily dosing compared to thrice-weekly ATT. Cmax of drugs and doses was significantly correlated. A higher proportion of patients had subtherapeutic RMP Cmax (8.0 µg/ml) during thrice-weekly compared to daily ATT (78% vs. 36%; P=0.004). Multiple linear regression analysis showed that Cmax of RMP was significantly influenced by the dosing rhythm, pulmonary TB and Cmax of INH and PZA by the mg/kg doses. Interpretation & conclusions: RMP concentrations were higher and INH concentrations were lower during daily ATT, suggesting that INH doses may need to be increased in case of a daily regimen. Larger studies are, however, required using higher INH doses when monitoring for adverse drug reactions and treatment outcomes.

Is Anxiety a Rising Concern during COVID-19 Pandemic among Healthcare Workers?

How to cite this article: Murthy PR, Venkatesha Gupta KV, Ajith Kumar AK. Is Anxiety a Rising Concern during COVID-19 Pandemic among Healthcare Workers? Indian J Crit Care Med 2020;24(5):369-370.

Wild-Type MIC Distribution for Re-evaluating the Critical Concentration of Anti-TB Drugs and Pharmacodynamics Among Tuberculosis Patients From South India.

The World Health Organization (WHO) has developed specific guidelines for critical concentrations (CCs) of antibiotics used for tuberculosis (TB) treatment, which is universally followed for drug susceptibility testing (DST) of clinical specimens. However, the CC of drugs can differ significantly among the mycobacterial species based on the population, geographic location, and the prevalence of the infecting strain in a particular area. The association between CC and the minimal inhibitory concentration (MIC) of anti-TB drugs is poorly understood. In this study, we assessed the MICs of anti-TB drugs, including isoniazid (INH), rifampicin (RMP), moxifloxacin (MXF), ethambutol (ETH), and p-aminosalicylic acid (PAS) on drug-sensitive Mtb isolates from pulmonary TB patients in South India. The MIC assays performed using solid- and liquid-growth media showed changes in the CC of a few of the tested antibiotics compared with the WHO-recommended levels. Our observation suggests that the WHO guidelines could potentially lead to overdiagnosis of drug-resistant cases, which can result in inappropriate therapeutic decisions. To evaluate the correlation between drug-resistance and CC, we performed the whole-genome sequencing for 16 mycobacterial isolates, including two wild-type and 14 resistant isolates. Our results showed that two of the isolates belonged to the W-Beijing lineage, while the rest were of the East-African-Indian type. We identified a total of 74 mutations, including five novel mutations, which are known to be associated with resistance to anti-TB drugs in these isolates. In our previous study, we determined the serum levels of INH and RMP among the same patients recruited in the current study and estimated the MICs of the corresponding infected isolates in these cases. Using these data and the CCs for INH and RMP from the present study, we performed pharmacodynamics (PD) evaluation. The results show that the PD of RMP was subtherapeutic. Together, these observations emphasize the need for optimizing the drug dosage based on the PD of large-scale studies conducted in different geographical settings.

Association of Maternal History of Neonatal Death With Subsequent Neonatal Death in India.

Importance: Among the United Nations' Sustainable Development Goals is to reduce the neonatal mortality rate to 12 per 1000 live births by 2030. Identifying high-risk pregnancies can help achieve this target in low-resource countries, such as India, which accounts for one-fourth of global neonatal deaths. Objective: To analyze the association of maternal history of neonatal death with subsequent neonatal mortality. Design, Setting, and Participants: This cross-sectional study included a nationally representative sample of singleton live births from multiparous women. Data were obtained from the 2016 National Family Health Survey in India. Data were analyzed from November 2018 to January 2020. Exposures: Maternal history of neonatal death and a comprehensive set of covariates, including socioeconomic environment, maternal anthropometry, and pregnancy care. Main Outcomes and Measures: Subsequent neonatal mortality. Population-attributable risk associated with history of neonatal death was calculated, and sensitivity analyses were performed. Results: The overall study population consisted of 127 336 singleton live births from multiparous women aged 15 to 49 (mean [SD] age, 28.8 [5.2] years) years when the survey was undertaken. In our analytic sample, 11 101 (8.7%) mothers had a history of neonatal death, and 506 of 2224 total neonatal deaths (22.8%) were attributed to women with history of neonatal death. The prevalence of history of neonatal death differed by selected covariates and across states or union territories. Maternal history of neonatal death was associated with significantly higher odds of neonatal mortality (adjusted odds ratio, 2.23; 95% CI, 1.96-2.55), and this remained consistent across different subgroups. The population-attributable risk associated with maternal history of neonatal death was 11.8%. Stronger associations were found for maternal history of multiple neonatal deaths (adjusted odds ratio, 3.50; 95% CI, 2.78-4.41) and in respect to the risk of mortality in early neonatal period (ie, 0-2 completed days) (adjusted odds ratio, 2.45; 95% CI, 2.09-2.86). Conclusions and Relevance: These findings suggest that maternal history of neonatal death is a potentially useful risk factor to identify women and neonates who may need extended and enhanced pregnancy care.

Adrenomedullin in Sepsis: Finally, a Friend or an Enemy?

Adrenomedullin (ADM) is a 52 amino acid containing free circulating vasoactive peptide hormone found to be active in various pathophysiological states including sepsis. High ADM levels at admission have been correlated with vasopressor requirements, organ dysfunction, and mortality in sepsis patients. ADM stimulation results in vasodilation and loss of vascular resistance in humans resulting in hypotension with the potential for negative impact in septic shock. However, in vitro human and animal experiments have shown that ADM decreases hyperpermeability and capillary leak, thus having an endothelial barrier stabilizing effect during septic shock. Adrenomedullin thus appears to be a double-edged weapon. This editorial critically reviews the article by Daga et al. who evaluated serum ADM as a prognostic marker to review the gender-related difference in mortality pattern, and also the correlation of ADM level to APACHE II and SOFA scores. The role of adrenomedullin in sepsis and the potential developments in the future have been discussed concisely. How to cite this article: Ajith Kumar AK. Adrenomedullin in Sepsis: Finally, a Friend or an Enemy? Indian J Crit Care Med 2020;24(12):1151-1153.

Differential Culturability of Mycobacterium tuberculosis in Culture-Negative Sputum of Patients With Pulmonary Tuberculosis and in a Simulated Model of Dormancy.

Tuberculosis (TB) remains a leading killer among infectious diseases of humans worldwide. Delayed diagnosis is a crucial problem in global TB control programs. Bacteriological methods currently used to diagnose TB in endemic countries take up to 8 weeks, which poses a significant delay in starting antibiotic therapy. The presence of a heterogeneous population of Mycobacterium tuberculosis, the causative agent of TB, is among the reasons for delayed diagnosis by bacteriological methods. Previously, it has been shown that mycobacterial resuscitation-promoting factors (RPFs), a family of proteins secreted by actively growing bacteria into the media, are capable of activating the growth of dormant bacteria, thus enhancing the detection of bacilli in the sputum of confirmed TB cases. However, the variability in bacterial resuscitation by RPF in the sputum of suspected pulmonary TB cases that showed differential smear and/or culture positivity during diagnosis has not been fully explored. Here, we report the presence of non-replicating bacteria in the sputum of suspected TB cases that show differential growth response to RPF treatment. Using crude and recombinant RPF treatment, we show improved sensitivity and reduced time to detect bacilli in the sputum samples of smear-positive/culture-negative or smear-negative/culture-negative cases. We also report the phenotypic heterogeneity in the RPF responsiveness among Mtb strains using an in vitro dormancy model. Our findings have implications for improving the bacteriological diagnostic modalities currently used to diagnose TB in endemic countries.

Pharmacokinetics of rifabutin during atazanavir/ritonavir co-administration in HIV-infected TB patients.

BACKGROUND & OBJECTIVE: Rifabutin (RBT) is the rifamycin that is recommended to treat tuberculosis (TB) in HIV-infected individuals during combination antiretroviral therapy (ART) containing HIV protease inhibitors (PIs). We studied the pharmacokinetics of rifabutin at doses of 300 mg thrice weekly and 150 mg daily during concomitant atazanavir/ritonavir (ATZ/r) administration in adult HIV-infected TB patients treated in the Revised National TB Control Programme (RNTCP) in India. METHODS: This was a multi-centric study conducted in 45 adult HIV-infected TB patients, who were being treated for TB with a RBT-containing regimen and an antiretroviral treatment regimen with ATZ/r, at doses of 300 mg thrice-weekly (n = 36) or 150 mg daily (n = 9). Serial blood draws at pre-dosing and at 1, 2, 4, 6, 8, 12 and 24 hours after drug administration were done. Plasma RBT was estimated by high pressure liquid chromatography (HPLC). RESULTS: The peak concentration (Cmax) of both doses were within the therapeutic range (0.45-0.90 µg/ml) of RBT. Proportion of patients having Cmax above or below the therapeutic range and trough concentration (Cmin) below the minimum inhibitory concentration of RBT did not significantly differ between the two doses. TB treatment outcomes were also similar at both doses. CONCLUSIONS: This is the first and only study from India reporting on the pharmacokinetics of RBT at 300 mg thrice weekly and 150 mg daily doses. Both doses yielded similar plasma RBT concentrations, outcomes and were well tolerated. RBT can be administered at either doses during ATZ/r co-administration in HIV-infected patients with TB.

A cross-sectional study on the role of stress in hyperglycemia and the effect of Mahatiktaka Kashaya (an Ayurvedic formulation) in its management.

BACKGROUND: Stress is a potential contributer to chronic hyperglycemia. Pitta Prakriti (body constitution) individuals are more prone to stress and the prevalence of type 2 diabetes in stressed out individuals is much more. Aim of study was to evaluate the role of stress in hyperglycemia in individuals of Pitta predominant constitution and to assess the effectiveness of Mahatiktaka Kashaya in stress-induced hyperglycemia. METHODOLOGY: A cross-sectional study was carried out in 100 Pitta predominant patients having fasting blood sugar level greater than 140 mg/dl, to find the association of stress and hyperglycemia, using International Stress Management Association questionnaire followed by open lebelled clinical trial with Mahatiktaka Kashaya (Decoction). Trial drug was administered at a dose of 15 ml twice daily for 14 days. Assessment was done before and after the treatment. OBSERVATION AND ANALYSIS: 80% of Pitta predominant individuals have reported stress-associated hyperglycemia. Overall effect of Mahatiktaka Kashaya in major domains of Stress Assessment Questionnaire, i.e., symptoms, stability and strategies was significant. Furthermore, the trial drug showed significant improvement in biochemical parameters of diabetes. CONCLUSION: The study concludes that there is significant association between stress and hyperglycemia in the individuals of Pitta constitution. Mahatiktaka Kashaya is found to be highly significant in stress-associated hyperglycemia in the above said group.

Intrapatient variability in plasma rifampicin & isoniazid in tuberculosis patients.

Background & objectives: Large variability in anti-tuberculosis (TB) drug concentrations between patients is known to exist. However, limited information is available on intrapatient drug levels during the course of anti-TB treatment (ATT). This study was conducted to evaluate intrapatient variability in plasma rifampicin (RMP) and isoniazid (INH) concentrations during ATT at start of the treatment, at the end of intensive phase (IP) of ATT and at the end of ATT in adult TB patients being treated in the Revised National TB Control Programme (RNTCP). Methods: Adult TB patients (n=485), receiving thrice-weekly ATT in the RNTCP, were studied. Two-hour post-dosing concentrations of RMP and INH were determined at month 1, end of IP and end of ATT, after directly observed drug administration. Drug concentrations were estimated by high-performance liquid chromatography. Results: The median (inter-quartile range) RMP concentrations during the first month, at end of IP and end of ATT were 2.1 (0.4-5.0), 2.4 (0.6-5.5) and 2.2 (0.5-5.3) µg/ml, respectively. The corresponding INH concentrations were 7.1 (4.2-9.9), 7.2 (3.9-10.9) and 6.7 (3.9-9.5) µg/ml. None of the differences in drug concentrations obtained at different time points during ATT were significant. RMP and INH concentrations at different time points were significantly correlated. Age and body mass index caused significant variability in drug concentrations. Interpretation & conclusions: Plasma RMP and INH estimations in adult TB patients at two hours after drug administration remained unaltered during ATT. Clinicians can consider testing drug concentrations at any time point during ATT. These findings may assume significance in the context of therapeutic drug monitoring of anti-TB drug concentrations.

Pharmacokinetic study of isoniazid and pyrazinamide in children: impact of age and nutritional status.

OBJECTIVES: To evaluate pharmacokinetics of first-line antitubercular drugs, isoniazid (INH) and pyrazinamide (PZA), with revised WHO dosages and to assess its adequacy in relation to age and nutritional status. DESIGN: Observational study. SETTING: This study was conducted at Sarojini Naidu Medical College, Agra, and National Institute for Research in Tuberculosis, Chennai. PATIENTS: 40 subjects diagnosed with tuberculosis were registered in the study and started on daily first-line antitubercular regimen based on the revised WHO guidelines. INTERVENTIONS: Blood samples were collected at 0, 2, 4, 6 and 8 hours from these subjects after 15 days of treatment for drug estimations. MAIN OUTCOME MEASURE: The measurement of drug concentrations (maximum peak concentration (Cmax) and area under the time -concentration curve (AUC0-8 hours)) for INH and PZA. Appropriate statistical methods were used to evaluate the impact of age and nutritional status on pharmacokinetic variables. RESULTS: For INH, the difference in drug exposures in children <3 years (Cmax 3.18 µg/mL and AUC0-8 hours15.76 µg/mL hour) and children >3 years (Cmax3.05 µg/mL and AUC0-8 hours 14.37 µg/mL hour) was not significant (P=0.94, P=0.81, respectively). The drug levels in children with low body mass index (BMI) (Cmax3.08 µg/mL; AUC0-8 hours14.81 µg/mL hour) were also comparable with their normal counterparts (Cmax3.09 µg/mL, P=0.99; AUC0-8 hours 14.69 µg/mL hour, P=0.82). PZA drug exposures obtained in children less than 3 years (Cmax29.22 µg/mL, AUC0-8 hours 155.45 µg/mL hour) were significantly lower compared with drug levels in children above 3 years (Cmax 37.12 µg/mL, P=0.03; AUC 202.63 µg/mL hour, P value=0.01). Children with low BMI had significantly lower drug concentrations (Cmax 31.90 µg/mL, AUC0-8 hours167.64 µg/mL hour) when compared with normal counterparts (Cmax 37.60 µg/mL, P=0.02; AUC0-8 hours 208.77 µg/mL hour, P=0.01). CONCLUSIONS: The revised WHO drug dosages were found to be adequate for INH with respect to age and nutritional status, whereas PZA showed significantly lower drug levels in children <3 years and in malnourished children.

A selective and sensitive high performance liquid chromatography assay for the determination of cycloserine in human plasma.

BACKGROUND: Cycloserine (CYC) is a second line antitubercular drug that is used for the treatment of multidrug resistant tuberculosis (MDR-TB) along with other antitubercular agents and is often used in developing countries. Monitoring CYC levels in plasma could be useful in the clinical management of patients with MDR-TB. A high performance liquid chromatography method for the determination of CYC in human plasma was developed. METHODS: The method involved extraction of the sample using solid phase extraction cartridges and analysis of the extracted sample using a reverse phase T3 column (150mm) and detection at 240nm with Photo Diode Array (PDA) detector. The chromatogram was run for 15min at a flow rate of 0.4ml/min at 30°C. RESULTS AND CONCLUSION: The assay was specific for CYC and linear from 5.0 to 50.0µg/ml. The relative standard deviations of within- and between-day assays were less than 10%. Recovery of CYC ranged from 102% to 109%. The interference of other second line anti-TB drugs in the assay of CYC was ruled out. The assay spans the concentration range of clinical interest. The specificity and sensitivity of this assay makes it highly suitable for pharmacokinetic studies.

Suboptimal Antituberculosis Drug Concentrations and Outcomes in Small and HIV-Coinfected Children in India: Recommendations for Dose Modifications.

This work aimed to evaluate the once-daily antituberculosis treatment as recommended by the new Indian pediatric guidelines. Isoniazid, rifampin, and pyrazinamide concentration-time profiles and treatment outcome were obtained from 161 Indian children with drug-sensitive tuberculosis undergoing thrice-weekly dosing as per previous Indian pediatric guidelines. The exposure-response relationships were established using a population pharmacokinetic-pharmacodynamic approach. Rifampin exposure was identified as the unique predictor of treatment outcome. Consequently, children with low body weight (4-7 kg) and/or HIV infection, who displayed the lowest rifampin exposure, were associated with the highest probability of unfavorable treatment (therapy failure, death) outcome (Punfavorable ). Model-based simulation of optimized (Punfavorable ≤ 5%) rifampin once-daily doses were suggested per treatment weight band and HIV coinfection status (33% and 190% dose increase, respectively, from the new Indian guidelines). The established dose-exposure-response relationship could be pivotal in the development of future pediatric tuberculosis treatment guidelines.

N-acetyltransferase gene polymorphisms & plasma isoniazid concentrations in patients with tuberculosis.

BACKGROUND & OBJECTIVES: Variations in the N-acetyltransferase (NAT2) gene among different populations could affect the metabolism and disposition of isoniazid (INH). This study was performed to genotype NAT2 gene polymorphisms in tuberculosis (TB) patients from Chennai, India, and compare plasma INH concentrations among the different genotypes. METHODS: Adult patients with TB treated in the Revised National TB Control Programme (RNTCP) in Chennai, Tamil Nadu, were genotyped for NAT2 gene polymorphism, and two-hour post-dosing INH concentrations were compared between the different genotypes. Plasma INH was determined by high-performance liquid chromatography. Genotyping of the NAT2 gene polymorphism was performed by real-time polymerase chain reaction method. RESULTS: Among the 326 patients genotyped, there were 189 (58%), 114 (35%) and 23 (7%) slow, intermediate and fast acetylators, respectively. The median two-hour INH concentrations in slow, intermediate and fast acetylators were 10.2, 8.1 and 4.1 µg/ml, respectively. The differences in INH concentrations among the three genotypes were significant (P<0.001). INTERPRETATION & CONCLUSIONS: Genotyping of TB patients from south India for NAT2 gene polymorphism revealed that 58 per cent of the study population comprised slow acetylators. Two-hour INH concentrations differed significantly among the three genotypes.