Predicting COVID 19-Associated Pulmonary Aspergillosis Risk in Low- and Middle-Income Countries: A Matched Case-Control Study.

Background: Coronavirus disease 2019 (COVID-19)-associated pulmonary aspergillosis (CAPA) is a life-threatening fungal infection. Studies focusing on CAPA in low- and middle-income countries are limited. Methods: This retrospective matched case-control study was conducted at a tertiary care center in South India. Cases of CAPA were classified using the 2020 European Confederation of Medical Mycology/International Society for Human and Animal Mycology consensus criteria. A total of 95 cases were matched 1:1 with COVID-19 patients without CAPA. Matching was done based on age and period of admission. Inverse probability weighting was used to account for imbalances in COVID-19 severity and intensive care unit (ICU) admission. Data on demographics, clinical details, microbiologic and radiologic data, and treatment outcomes were collected. A predictive score for CAPA was developed from baseline risk factors. Results: The predictive score identified lymphopenia, European Organisation for Research and Treatment of Cancer risk factors, and broad-spectrum antibiotic use as the main risk factors for CAPA. Positivity for bacterial pathogens in blood or bronchoalveolar lavage samples reduced the risk of CAPA. The predictive model performed well in cross-validation, with an area under the curve value of 82%. CAPA diagnosis significantly increased mortality and shift to ICU. Conclusions: The predictive model derived from the current study offers a valuable tool for clinicians, especially in high-endemic low- and middle-income countries, for the early identification and treatment of CAPA. With further validation, this risk score could improve patient outcomes.

Characterization and predictive risk scoring of long COVID in a south indian cohort after breakthrough COVID infection; a prospective single centre study.

BACKGROUND: With the World Health Organization (WHO) declaring an end to the COVID-19 pandemic, the focus has shifted to understanding and managing long-term post-infectious complications. "Long COVID," characterized by persistent or new onset symptoms extending beyond the initial phase of infection, is one such complication. This study aims to describe the incidence, clinical features and risk profile of long COVID among individuals in a South Indian cohort who experienced post-ChAdOx1 n-Cov-2 vaccine breakthrough infections. METHODS: A single-centre hospital-based prospective observational study was conducted from October to December 2021. The study population comprised adult patients (> 18 years) with a confirmed COVID-19 diagnosis who had received at least a single dose of vaccination. Data was collected using a specially tailored questionnaire at week 2, week 6, and week 12 post-negative COVID-19 test. A propensity score based predictive scoring system was developed to assess the risk of long COVID. RESULTS: Among the 414 patients followed up in the study, 164 (39.6%) reported long COVID symptoms persisting beyond 6 week's post-infection. The presence of long COVID was significantly higher among patients above 65 years of age, and those with comorbidities such as Type II Diabetes Mellitus, hypertension, dyslipidemia, coronary artery disease, asthma, and cancer. Using backwards selection, a reduced model was developed, identifying age (OR 1.053, 95% CI 0.097-1.07, p < 0.001), hypertension (OR 2.59, 95% CI 1.46-4.59, p = 0.001), and bronchial asthma (OR 3.7176, 95% CI 1.24-11.12, p = 0.018) as significant predictors of long COVID incidence. A significant positive correlation was observed between the symptomatic burden and the number of individual comorbidities. CONCLUSIONS: The significant presence of long COVID at 12 weeks among non-hospitalised patients underscores the importance of post-recovery follow-up to assess for the presence of long COVID. The predictive risk score proposed in this study may help identify individuals at risk of developing long COVID. Further research is needed to understand the impact of long COVID on patients' quality of life and the potential role of tailored rehabilitation programs in improving patient outcomes.

A survey of patient and public perceptions and awareness of SARS-CoV-2-related risks among participants in India and South Africa.

A cross-sectional survey among participants in India and South Africa to explore perceptions and awareness of SARS-CoV-2-related risks. Main outcome measures-proportion of participants aware of SARS-CoV-2, and their perception of infection risks as it related to their views and perceptions on vaccination, i.e., using COVID-19 vaccine uptake as proxy for awareness level. Self-administered questionnaires were used to collect data via web- and paper-based surveys over three months. Pearson's Chi-squared test assessed relationships between variables; a p-value less than 0.05 was considered significant. There were 844 respondents (India: n = 660, South Africa: n = 184; response rate 87.6%), with a 61.1% vs 38.3% female to male ratio. Post-high-school or university education was the lowest qualification reported by most respondents in India (77.3%) and South Africa (79.3%). Sources of pandemic information were usually media and journal publications (73.2%), social media (64.6%), family and friends (47.7%) and government websites (46.2%). Most respondents correctly identified infection prevention measures (such as physical distancing, mask use), with 90.0% reporting improved hand hygiene practices since the pandemic. Hesitancy or refusal to accept the SARS-CoV-2 vaccine was reported among 17.9% and 50.9% of respondents in India and South Africa, respectively; reasons cited included rushed vaccine development and the futility of vaccines for what respondents considered a self-limiting flu-like illness. In South Africa, vaccine acceptance was associated with improved hand hygiene practices since the pandemic and flu vaccination in the preceding year. No relationship was noted between awareness and practice of infection prevention measures (such as hand hygiene) and socio-demographic factors such as employment status or availability of amenities. Pandemic response and infection prevention and control measures through vaccination campaigns should consider robust public engagement and contextually-fit communication strategies with multimodal, participatory online and offline initiatives to address public concerns, specifically towards vaccines developed for this pandemic and general vaccine hesitancy.

Incidence and Characterization of Post-COVID-19 Symptoms in Hospitalized COVID-19 Survivors to Recognize Syndemic Connotations in India: Single-Center Prospective Observational Cohort Study.

BACKGROUND: Long COVID, or post-COVID-19 syndrome, is the persistence of signs and symptoms that develop during or after COVID-19 infection for more than 12 weeks and are not explained by an alternative diagnosis. In spite of health care recouping to prepandemic states, the post-COVID-19 state tends to be less recognized from low- and middle-income country settings and holistic therapeutic protocols do not exist. Owing to the syndemic nature of COVID-19, it is important to characterize post-COVID-19 syndrome. OBJECTIVE: We aimed to determine the incidence of post-COVID-19 symptoms in a cohort of inpatients who recovered from COVID-19 from February to July 2021 at a tertiary-care center in South India. In addition, we aimed at comparing the prevalence of post-COVID-19 manifestations in intensive care unit (ICU) and non-ICU patients, assessing the persistence, severity, and characteristics of post-COVID-19 manifestations, and elucidating the risk factors associated with the presence of post-COVID-19 manifestations. METHODS: A total of 120 adult patients admitted with COVID-19 in the specified time frame were recruited into the study after providing informed written consent. The cohort included 50 patients requiring intensive care and 70 patients without intensive care. The follow-up was conducted on the second and sixth weeks after discharge with a structured questionnaire. The questionnaire was filled in by the patient/family member of the patient during their visit to the hospital for follow-up at 2 weeks and through telephone follow-up at 6 weeks. RESULTS: The mean age of the cohort was 55 years and 55% were men. Only 5% of the cohort had taken the first dose of COVID-19 vaccination. Among the 120 patients, 58.3% had mild COVID-19 and 41.7% had moderate to severe COVID-19 infection. In addition, 60.8% (n=73) of patients had at least one persistent symptom at the sixth week of discharge and 50 (41.7%) patients required intensive care during their inpatient stay. The presence of persistent symptoms at 6 weeks was not associated with severity of illness, age, or requirement for intensive care. Fatigue was the most common reported persistent symptom with a prevalence of 55.8%, followed by dyspnea (20%) and weight loss (16.7%). Female sex (odds ratio [OR] 2.4, 95% CI 1.03-5.58; P=.04) and steroid administration during hospital stay (OR 4.43, 95% CI 1.9-10.28; P=.001) were found to be significant risk factors for the presence of post-COVID-19 symptoms at 6 weeks as revealed by logistic regression analysis. CONCLUSIONS: Overall, 60.8% of inpatients treated for COVID-19 had post-COVID-19 symptoms at 6 weeks postdischarge from the hospital. The incidence of post-COVID-19 syndrome in the cohort did not significantly differ across the mild, moderate, and severe COVID-19 severity categories. Female sex and steroid administration during the hospital stay were identified as predictors of the persistence of post-COVID-19 symptoms at 6 weeks.

Survey of healthcare worker perceptions of changes in infection control and antimicrobial stewardship practices in India and South Africa during the COVID-19 pandemic.

Objective: To identify perceptions and awareness of changes in infection prevention and control (IPC) and antimicrobial stewardship (AMS) practices among healthcare workers (HCWs) during the COVID-19 pandemic in India and South Africa (SA). Method: A self-administered online survey which included participant demographics, knowledge and sources of COVID-19 infection, perceived risks and barriers, and self-efficacy. Data were analysed using descriptive statistics. Results: The study received 321 responses (response rate: 89.2%); 131/321 (40.8%) from India and 190/321 (59.2%) from SA; male to female response rate was 3:2, with majority of respondents aged 40-49 (89/321, 27.7%) and 30-39 (87/321, 27.1%) years. Doctors comprised 47.9% (57/119) of respondents in India and 74.6% (135/181) in SA. Majority of respondents in India (93/119, 78.2%) and SA (132/181, 72.9%) were from the private and public sectors, respectively, with more respondents in SA (123/174, 70.7%) than in India (38/104, 36.5%) involved in antimicrobial prescribing.Respondents reported increased IPC practices since the pandemic and noted a need for more training on case management, antibiotic and personal protective equipment (PPE) use. While they noted increased antibiotic prescribing since the pandemic, they did not generally associate their practice with such an increase. A willingness to be vaccinated, when vaccination becomes available, was expressed by 203/258 (78.7%) respondents. Conclusions: HCWs reported improved IPC practices and changes in antibiotic prescribing during the COVID-19 pandemic. Targeted education on correct use of PPE was an identified gap. Although HCWs expressed concerns about antimicrobial resistance, their self-perceived antibiotic prescribing practices seemed unchanged. Additional studies in other settings could explore how our findings fit other contexts.

An evaluation of the implementation of interventions to reduce postoperative infections and optimise antibiotic use across the surgical pathway in India: a mixed-methods exploratory study protocol.

INTRODUCTION: Postoperative infections represent a significant burden of disease, demanding antibiotic prescriptions, and are contributing to antimicrobial resistance. The burden of infection as a surgical complication is greater in low- and middle-income countries (LMICs). We report the protocol of a pilot study for the co-design, implementation and evaluation of two infection prevention and control (IPC) and antimicrobial stewardship (AMS) interventions across the surgical pathway in a teaching hospital in India. METHODS AND ANALYSIS: The two interventions developed following in-depth qualitative enquiry are (i) surveillance and feedback of postoperative infections to optimise the use of antibiotics in two surgical departments (gastrointestinal and cardiovascular and thoracic surgery) and (ii) raising awareness amongst patients, carers and members of public about IPC and AMS. We will conduct a prospective study, formatively evaluating the implementation process of delivering the two co-designed interventions using implementation science frameworks. The study will systematically assess the context of intervention delivery, so that implementation support for the interventions may be adapted to the needs of stakeholders throughout the study. Analysis of implementation logs and interviews with stakeholders upon completion of the implementation period, will offer insights into the perceived acceptability, appropriateness, feasibility and sustainability of the interventions and their implementation support. Implementation costs will be captured descriptively. Feasibility of clinical data collection to investigate effectiveness of interventions will also be assessed for a future larger study. Thematic framework analysis and descriptive statistics will be used to report the qualitative and quantitative data, respectively. STRENGTHS AND LIMITATIONS OF THIS STUDY: • The paired interventions have been co-designed from their inception with involvement of stakeholders at different stages in the surgical pathway. • Simultaneous evaluation of implementation and clinical outcomes will inform the development of a future larger study to enable/assess the scalability of interventions • The study offers a novel combination of implementation theory-informed, stakeholder-driven and clinically relevant evaluation, carried out in the context of a middle-income country hospital. • The project may not be applicable to every low-resource setting and surgical context due to differences in healthcare systems and cultures. However, the application of implementation science concepts may facilitate transferability and adaptation to other settings.

Epidemiology of Community-Acquired Sepsis: Data from an E-Sepsis Registry of a Tertiary Care Center in South India.

The study aims to characterize community-acquired sepsis patients admitted to our 1300-bedded tertiary care hospital in South India from the Surviving Sepsis Campaign (SSC) guideline-compliant e-sepsis registry stratified by focus of infection. The prospective observational study recruited 1009 adult sepsis patients presenting to the emergency department at the center based on Sepsis-2 criteria for a period of three years. Of the patients, 41% were between 61 and 80 years with a mean age of 57.37 ± 13.5%. A total of 13.5% (136) was under septic shock and in-hospital mortality for the study cohort was 25%. The 3 h and 6 h bundle compliance rates observed were 37% and 49%, respectively, without significant survival benefits. Predictors of mortality among patients with bloodstream infections were septic shock (p = 0.01, OR 2.4, 95% CI 1.23-4.79) and neutrophil-to-lymphocyte ratio (p = 0.008, OR 1.01, 95% CI 1.009-1.066). The presence of Acinetobacter (p = 0.005, OR 4.07, 95% CI 1.37-12.09), Candida non-albicans (p = 0.001, OR16.02, 95% CI 3.0-84.2) and septic shock (p = 0.071, OR 2.5, 95% CI 0.97-6.6) were significant predictors of mortality in patients with community-acquired pneumonia. The registry has proven to be a key data source detailing regional microbial etiology and clinical outcomes of adult sepsis patients, enabling comprehensive evaluation of regional community-acquired sepsis to tailor institutional sepsis treatment protocols.

Adverse events associated with Covishield vaccination among healthcare workers in a tertiary hospital in South India.

Background: Vaccination is the most important prophylactic measure taken to curb COVID-19 pandemics. This study was undertaken to throw light on the safety of Covishield vaccine among health care workers (HCWs) and to assess the co-variates associated with incidence of adverse events. Methods: This prospective observational study was conducted in a tertiary care center in South India as part of the HCW vaccination drive. All consenting HCWs who received the first dose of Covishield vaccine and developed ADRs were included in this study. After vaccination, all beneficiaries were monitored for AEFI for a period of half an hour and later followed up through telephone and google survey forms on day 2 and day 7 of vaccination. The data was subsequently collated into spreadsheet format and analyzed. Results: The study included 1264 consenting healthcare workers who were predominantly youth, aged 15-24 years (n = 583, 46 %) and with a female preponderance of 76 % (n = 960). Past history of COVID-19 infections was reported among 4.6 % (58) of the study population. Postvaccination symptoms were majorly reported during the first (40 %) and second day (44 %) after vaccination with a high prevalence of both local (n = 1083, 85 %) and systemic symptoms (n = 1065, 84 %). The mean duration of symptoms was observed to be 1.4 ± 0.81 days post vaccination. Symptoms were observed significantly high among females (76.7 %, p = 0.013). The prevalence of systemic (88 % vs 80 %) (p < 0.001) and allergic symptoms (7 % vs 3 %; p = 0.03) were observed to be significantly high among respondents with <25 years of age. The systemic and allergic symptoms following vaccination were reported to be low among healthcare workers who had a previous history of COVID-19 infection. Conclusion: COVID vaccination has been observed to be safe and well tolerated with more systemic symptoms reported among younger age group and females.

A quality improvement initiative to improve the appropriateness of candidemia management by the implementation of a comprehensive candidemia care bundle at a tertiary care hospital in South India: Results of a quasi-experimental study.

ABSTRACT: Management of candidemia in developing countries like India encounters laxity in appropriate clinical management and challenges in terms of healthcare capacity, despite its association with high morbidity and mortality. Our study aims to evaluate the impact of a comprehensive candidemia care bundle implementation on appropriateness of therapy and major clinical outcomes.The single-center, quasi-experimental study conducted at a south Indian tertiary care center included adult patients diagnosed with candidemia. Following a retrospective review of candidemia patients of the pre-implementation period (January 2013-December 2015), the hospital antifungal stewardship team instituted a clinical pharmacist driven comprehensive candidemia care bundle for candidemia patients during the post-implementation period (October 2017-2019) and its impact on appropriateness of antifungal prescriptions and inpatient mortality was evaluated.The study included 175 patients with candidemia, comprising of 103 patients in the pre-implementation period and 72 patients in the post-implementation period. Appropriateness of antifungal prescriptions rose to 65% during post-implementation period from 30% observed in pre-implementation phase (P = .0005). The inhospital mortality rate reduced from 40% in the pre-implementation phase to 36% in the post-implementation phase, recording a 10% reduction over 2 years post-implementation (P = .26). No significant difference was observed in terms length of stay (P = .17).Our study demonstrates the successful implementation of an antifungal stewardship led comprehensive care bundle in a low middle income countries setting. The results of our study will have profound implications in improving the appropriateness of management of candidemia and feasibility of scaling up to wider settings could be explored.

A Machine Learning Understanding of Sepsis.

Sepsis is a serious cause of morbidity and mortality and yet its pathophysiology remains elusive. Recently, medical and technological advances have helped redefine the criteria for sepsis incidence, which is otherwise poorly understood. With the recording of clinical parameters and outcomes of patients, enabling technologies, such as machine learning, open avenues for early prognostic systems for sepsis. In this work, we propose a two-phase approach towards prognostic scoring by predicting two outcomes in sepsis patients - Sepsis Severity and Comorbidity Severity. We train and evaluate multiple machine learning models on a dataset of 80 parameters collected from 800 patients at Amrita Institute of Medical Sciences, Kerala, India. We present an analysis of these results and harmonize consistencies and/or contradictions between elements of human knowledge and that of the model, using local interpretable model-agnostic explanations and other methods.

Evaluating the measures taken to contain a Candida auris outbreak in a tertiary care hospital in South India: an outbreak investigational study.

BACKGROUND: Candida auris infections are an emerging global threat with poor clinical outcome, high mortality rate, high transmission rate and outbreak potential. The objective of this work is to describe a multidisciplinary approach towards the investigation and containment of a Candida auris outbreak and the preventive measures adopted in a resource limited setting. METHODS: This outbreak investigational study was conducted at a 1300-bedded tertiary care academic hospital in South India. The study included 15 adult inpatients with laboratory confirmed Candida auris isolates. The outbreak cluster was identified in adult patients admitted from September 2017 to 2019. The system response consisted of a critical alert system for laboratory confirmed Candida auris infection and multidisciplinary 'Candida auris care team' for patient management. The team implemented stringent Infection Prevention and Control (IPC) measures including patient cohorting, standardized therapy and decolonization, staff training, prospective surveillance and introduction of Candida auris specific care bundle. RESULTS: Two outbreak clusters were identified; first cluster occurring between October and November 2017 and the second cluster in May 2018. The cohorts consisted of 7 and 8 Candida auris positive patients in the first and second waves of the outbreak respectively with a total survival rate of 93% (14/15). Deployment of containment measures led to gradual decline in the incidence of adult Candida auris positive cases and prevented further cluster formation. CONCLUSIONS: The sustained implementation of guideline and evidence-based IPC measures and training of healthcare workers for improving awareness on systematically following standardized protocols of Candida auris related IPC practices successfully contained Candida auris outbreaks at our hospital. This demonstrates the feasibility of establishing a multidisciplinary model and bundling of practices for preventing Candida auris outbreaks in a Low- and Middle-income country.

Antimicrobial Stewardship and Its Impact on the Changing Epidemiology of Polymyxin Use in a South Indian Healthcare Setting.

Polymyxins being last resort drugs to treat infections triggered by multidrug-resistant pathogens necessitates the implementation of antimicrobial stewardship program (ASP) initiatives to support its rational prescription across healthcare settings. Our study aims to describe the change in the epidemiology of polymyxins and patient outcomes following the implementation of ASP at our institution. The antimicrobial stewardship program initiated in February 2016 at our 1300 bed tertiary care center involved post-prescriptive audits tracking polymyxin consumption and evaluating prescription appropriateness in terms of the right indication, right frequency, right drug, right duration of therapy and administration of the right loading dose (LD) and maintenance dose (MD). Among the 2442 polymyxin prescriptions tracked over the entire study period ranging from February 2016 to January 2020, the number of prescriptions dropped from 772 prescriptions in the pre-implementation period to an average of 417 per year during the post-implementation period, recording a 45% reduction. The quarterly patient survival rates had a significant positive correlation with the quarterly prescription appropriateness rates (r = 0.4774, p = 0.02), right loading dose (r = 0.5228, p = 0.015) and right duration (r = 0.4361, p = 0.04). Our study on the epidemiology of polymyxin use demonstrated favorable effects on the appropriateness of prescriptions and mortality benefits after successful implementation of antimicrobial stewardship in a real-world setting.

A road-map for addressing antimicrobial resistance in low- and middle-income countries: lessons learnt from the public private participation and co-designed antimicrobial stewardship programme in the State of Kerala, India.

BACKGROUND: The global concern over antimicrobial resistance (AMR) is gathering pace. Low- and middle-income countries (LMICs) are at the epicentre of this growing public health threat and governmental and healthcare organizations are at different stages of implementing action plans to tackle AMR. The South Indian state of Kerala was one of the first in India to implement strategies and prioritize activities to address this public health threat. STRATEGIES: Through a committed and collaborative effort from all healthcare related disciplines and its professional societies from both public and private sector, the Kerala Public Private Partnership (PPP) has been able to deliver a state-wide strategy to tackle AMR A multilevel strategic leadership model and a multilevel implementation approach that included developing state-wide antibiotic clinical guidelines, a revision of post-graduate and undergraduate medical curriculum, and a training program covering all general practitioners within the state the PPP proved to be a successful model for ensuring state-wide implementation of an AMR action plan. Collaborative work of multi-professional groups ensured co-design and development of disease based clinical treatment guidelines and state-wide infection prevention policy. Knowledge exchange though international and national platforms in the form of workshops for sharing of best practices is critical to success. Capacity building at both public and private institutions included addressing practical and local solutions to the barriers e.g. good antibiotic prescription practices from primary to tertiary care facility and infection prevention at all levels. CONCLUSION: Through 7 years of stakeholder engagement, lobbying with government, and driving change through co-development and implementation, the PPP successfully delivered an antimicrobial stewardship plan across the state. The roadmap for the implementation of the Kerala PPP strategic AMR plan can provide learning for other states and countries aiming to implement action plans for AMR.

Vitamin C Therapy for Routine Care in Septic Shock (ViCTOR) Trial: Effect of Intravenous Vitamin C, Thiamine, and Hydrocortisone Administration on Inpatient Mortality among Patients with Septic Shock.

BACKGROUND: Sepsis remains a leading cause of death worldwide despite advances in management strategies. Preclinical and observational studies have found mortality benefit with high-dose vitamin C in sepsis. Our study aims to prospectively evaluate the effect of intravenous hydrocortisone, vitamin C [ascorbic acid (AA)], and thiamine (HAT) administration in reducing inpatient all-cause mortality among patients with septic shock. MATERIALS AND METHODS: Our single-center, prospective, open-label, randomized controlled trial recruited patients with admitting diagnosis of septic shock and assigned eligible patients (1:1) into either intervention (HAT) or control group (routine). The HAT group received intravenous combination of vitamin C (1.5 g every 6 hours), thiamine (200 mg every 12 hours), and hydrocortisone (50 mg every 6 hours) within 6 hours of onset of septic shock admission. The treatment was continued for at least 4 days, in addition to the routine standard of care provided to the control group. Thiamine and hydrocortisone use in control arm was not restricted. Vitamin C levels were estimated at baseline and at the end of the 4 days of treatment for both groups. The primary outcome evaluated was mortality during inpatient stay. RESULTS: Among 90 patients enrolled, 88 patients completed the study protocol. The baseline characteristics between the HAT (n = 45) and the routine (n = 43) groups were comparable. The all-cause mortality in the HAT cohort was 57% (26/45) compared to 53% (23/43) in the routine care group (p = 0.4, OR 1.19, 95% CI 0.51-2.76). The time to reversal of septic shock was significantly lower in the HAT (34.58 ± 22.63 hours) in comparison to the routine care (45.42 ± 24.4 hours) (p = 0.03, mean difference -10.84, 95% CI -20.8 to -0.87). No significant difference was observed between the HAT and the routine care with respect to changes in sequential organ failure assessment (SOFA) scores at 72 hours (2.23 ± 2.4 vs 1.38 ± 3.1), the use of mechanical ventilation (48% vs 46%), and mean Vasoactive Inotropic Score (7.77 ± 12.12 vs 8.86 ± 12.5). CONCLUSION: Intravenous administration of vitamin C, thiamine, and hydrocortisone did not significantly improve the inpatient all-cause mortality among patients with septic shock. CLINICAL SIGNIFICANCE: HAT protocol does not reduce hospital mortality but decreases time to shock reversal in septic shock. HOW TO CITE THIS ARTICLE: Mohamed ZU, Prasannan P, Moni M, Edathadathil F, Prasanna P, Menon A, et al. Vitamin C Therapy for Routine Care in Septic Shock (ViCTOR) Trial: Effect of Intravenous Vitamin C, Thiamine, and Hydrocortisone Administration on Inpatient Mortality among Patients with Septic Shock. Indian J Crit Care Med 2020;24(8):653-661.

Clinical efficacy and pharmacokinetics of colistimethate sodium and colistin in critically ill patients in an Indian hospital with high endemic rates of multidrug-resistant Gram-negative bacterial infections: A prospective observational study.

BACKGROUND: Safe and effective use of colistin requires robust pharmacokinetic (PK) and pharmacodynamic (PD) data to guide dosing. AIM: To evaluate the pharmacokinetics of colistimethate sodium and colistin in critically ill patients and correlate with clinical efficacy and renal function. MATERIALS AND METHODS: Twenty critically ill adult patients with colistin-susceptible multidrug-resistant (MDR) infections and normal renal function treated with intravenous colistimethate sodium - at a 9 million units (270 mg CBA) loading dose followed by maintenance (MD) of 3 million units t.i.d, 24 hours later - were evaluated for clinical cure (CC) at the end of therapy. Patient characteristics and plasma colistin levels at 0, 0.5, 1, 2, 4, 8 and 12 hours after the loading dose and at 1, 2 and 8 hours after the eighth and ninth infusion of MD were evaluated. Colistimethate sodium and colistin levels were measured by high-performance liquid chromatography and tandem mass spectrometry (HPLC-MS/MS). RESULTS: Among the 20 patients who were evaluated, 60% had pneumonia. Predominant pathogens were Klebsiella pneumoniae and Acinetobacter spp. Clinical cure was 50% (10/20). Mean peak loading dose concentrations were 3 ± 1.1 mg/L (1.75-5.14) and 2.37 ± 1.2 mg/L (1.52-5.54) for 'cure' and 'failure' groups, respectively (p = 0.13), while mean steady-state (Cssavg) concentrations were 2.25 ± 1.3 mg/L and 1.78 ± 1.1 mg/L in 'cure' and 'failure' groups, respectively (p = 0.19). Nephrotoxicity was 5% on day 7 of therapy. However, bacteriological cure could not be correlated with PK/PD. CONCLUSIONS: Subtherapeutic Cssavg with clinical failure and lower efficacy without significant nephrotoxicity highlights the need for therapeutic drug monitoring to guide colistin dosing.

Efficacy & safety of Carica papaya leaf extract (CPLE) in severe thrombocytopenia (≤30,000/µl) in adult dengue - Results of a pilot study.

Severe thrombocytopenia in dengue often prompts platelet transfusion primarily to reduce bleeding risk. In India, about 11-43% of dengue patients report receiving platelet transfusions which is considered scarce and expensive especially in resource limited settings. Herein, we evaluated the efficacy and safety of Carica papaya leaf extract (CPLE) in the management of severe thrombocytopenia (≤30,000/µL) in dengue infection. 51 laboratory confirmed adult dengue patients with platelet counts ≤30,000/µL were randomly assigned to either treatment (n = 26) or placebo (n = 24) group. By day 3, CPLE treated patients reported significantly (p = 0.007) increased platelet counts (482%± 284) compared to placebo (331%±370) group. In the treatment group, fewer patients received platelet transfusions (1/26 v/s 2/24) and their median time for platelets to recover to ≥ 50,000/µL was 2 days (IQR 2-3) compared to 3 days (IQR 2-4) in placebo. Overall, CPLE was safe and well tolerated with no significant decrease in mean hospitalization days. Plasma cytokine profiling revealed that by day 3, mean percent increase in TNFα and IFNγ levels in treatment group was less compared to that observed in placebos; (TNFα: 58.6% v/s 127.5%; p = 0.25 and IFNγ: 1.93% v/s 62.6% for; p = 0.12). While a mean percent increase in IL-6 levels occurred in placebos (15.92%±29.93%) by day 3, a decrease was noted in CPLE group (12.95%±21.75%; p = 0.0232). Inversely, CPLE treated patients reported a mean percent increase compared to placebo by day 3 (143% ±115.7% v/s 12.03%± 48.4%; p = 0.006). Further, by day 3, a faster clearance kinetics of viral NS1 antigenemia occurred-mean NS1 titers in treatment group decreased to 97.3% compared to 88% in placebos (p = 0.023). This study demonstrates safety and efficacy of CPLE in increasing platelet counts in severe thrombocytopenia in dengue infections. A possible immunomodulatory and antiviral activity may be attributed to CPLE treatment. These findings merit validation in larger prospective studies. Trial registration Name of the registry: Clinical Trials Registry-India (CTRI) Registration No.: CTRI-REF/2017/02/013314.

Waiting for Godot: A cross sectional survey based analysis of the hydroxychloroquine prophylaxis strategy against COVID-19 in India.

Background: India currently has the second largest burden of infections due to COVID-19. Health Care Worker (HCW) shortages are endemic to Indian healthcare. It should therefore be a huge priority to protect this precious resource as a critical component of the systemic response to this pandemic. Advisories from the Indian Council of Medical Research (ICMR) have focused on using hydroxychloroquine prophylaxis against COVID-19 in at risk HCW. This prophylaxis strategy has no evidence. In further jeopardy there appear to insubstantial attempts to build this evidence as well. In this connection, we commissioned a survey within our Institution to estimate the penetration of hydroxychloroquine (HCQ) use and use this to statistically model the impact of current ongoing studies in India. We also briefly review the literature on HCQ prophylaxis for COVID-19. Design and methods: A structured survey designed using RedCAP application was disseminated among healthcare professionals employed at an academic referral tertiary care centre via online social media platforms. The survey was kept open for the entire month of June 2020. The survey was additionally used to statistically model the size of studies required to comprehensively address the efficacy of HCQ in this setting. Results: 522 responses were received, of which 4 were incomplete. The ICMR strategy of 4 or more doses of HCQ was complete only in 15% of HCW in our survey. The majority of respondents were doctors (238, 46%). Amongst all category of responders, only 12% (n=63) received the full course. A majority of those who initiated the chemoprophylaxis with HCQ turned out to be medical professionals (59/63) with neither nurse nor other categories of healthcare workers accessing the medication. The respondents of our institutional survey did not report any life-threatening side effects. Presuming efficacy as per ICMR modelling for new registry trial on the lines of the published case control study, equal allocation between cases and controls and assuming a RR of 1.3.6, the power of such a study would be very low for n=2000 for event rates from 2.5-12.5%. Conclusion: We report the low penetration of HCQ chemoprophylaxis among the healthcare workers of our institution. We highlight the inherent drawbacks in the study design of current national COVID related trial based on the statistical modelling of our survey results and published literature, and thereby emphasis the need of evidence-based strategies contributing to research policy at national level.

Implementation and Impact of an Antimicrobial Stewardship Program at a Tertiary Care Center in South India.

BACKGROUND: Antimicrobial resistance is a major public health threat internationally but, particularly in India. A primary contributing factor to this rise in resistance includes unregulated access to antimicrobials. Implementing antimicrobial stewardship programs (ASPs) in the acute hospital setting will help curb inappropriate antibiotic use in India. Currently, ASPs are rare in India but are gaining momentum. This study describes ASP implementation in a large, academic, private, tertiary care center in India. METHODS: An ASP was established in February 2016 consisting of an administrative champion, hospitalist, microbiologist, intensivist, and pharmacists. Antimicrobial stewardship program interventions included postprescriptive audit and establishment of institutional guidelines. The ASP tracked appropriate drug selection including loading dose, maintenance dose, frequency, route, duration of therapy, de-escalation, and compliance with ASP recommendations. Defined daily dose (DDD) of drugs and cost of antimicrobials were compared between the pre-implementation phase (February 2015-January 2016) and post-implementation phase (February 2016-January 2017). RESULTS: Of 48 555 patients admitted during the post-implementation phase, 1020 received 1326 prescriptions for restricted antibiotics. Antibiotic therapy was appropriate in 56% (742) of the total patient prescriptions. A total of 2776 instances of "inappropriate" antimicrobial prescriptions were intervened upon by the ASP. Duration (806, 29%) was the most common reason for inappropriate therapy. Compliance with ASP recommendations was 54% (318). For all major restricted drugs, the DDD/1000 patient days declined, and there was a significant reduction in mean monthly cost by 14.4% in the post-implementation phase. CONCLUSIONS: Implementation of a multidisciplinary antibiotic stewardship program in this academic, large, Indian hospital demonstrated feasibility and economic benefits.

Myocardial injury after noncardiac surgery-incidence and predictors from a prospective observational cohort study at an Indian tertiary care centre.

Asymptomatic myocardial injury following noncardiac surgery (MINS) is an independent predictor of 30-day mortality and may go unrecognized based on standard diagnostic definition for myocardial infarction (MI). Given lack of published research on MINS in India, our study aims to determine incidence of MINS in patients undergoing noncardiac surgery at our tertiary care hospital, and evaluate the clinical characteristics including 30-day outcome.The prospective observational study included patients >65 years or >45 years with either hypertension (HTN), diabetes mellitus (DM), coronary artery disease (CAD), cerebrovascular accident (CVA), or peripheral arterial disease undergoing noncardiac surgery. MINS was peak troponin level of ≥0.03 ng/dL at 12-hour or 24-hour postoperative. All patients were followed for 30 days postoperatively. Predictors of MINS and mortality were analyzed using multivariate logistic regression. Patients categorized based on peak troponin cut-off values determined by receiver operating characteristic curve were analyzed by Kaplan-Meir test to compare the survival of patients between the groups.Among 1075 patients screened during 34-month period, the incidence of MINS was 17.5% (188/1075). Patients with DM, CAD, or who underwent peripheral nerve block anaesthesia were 1.5 (P < .01), 2 (P < .001), and 12 (P < .001) times, respectively, more likely to develop MINS than others. Patients with heart rates ≥96 bpm before induction of anesthesia were significantly associated with MINS (P = .005) and mortality (P = .02). The 30-day mortality in MINS cohort was 11.7% (22/188, 95% CI 7.5%-17.2%) vs 2.5% (23/887, 95% CI 1.7%-3.9%) in patients without MINS (P < .001). ECG changes (P = .002), peak troponin values >1 ng/mL (P = .01) were significantly associated with mortality. A peak troponin cut-off of >0.152 ng/mL predicted mortality among MINS patients at 72% sensitivity and 58% specificity. Lack of antithrombotic therapy following MINS was independent predictor of mortality (P < .001), with decreased mortality in patients who took post-op ASA (Aspirin) or Clopidogrel. Mortality among MINS patients with post-op ASA intake is 6.7% vs 12.1% among MINS patients without post-op ASA intake. Mortality among MINS patients with post-op Clopidogrel intake is 10.5% vs 11.8% among MINS patients without post-op Clopidogrel intake.A higher (17.5%, 95% CI 15-19%) incidence of MINS was observed in our patient cohort with significant association with 30-day mortality. Serial postoperative monitoring of troponin following noncardiac surgery as standard of care, would identify "at risk" patients translating to improved outcomes.

Identification of prolargin expression in articular cartilage and its significance in rheumatoid arthritis pathology.

Qualitative 2D gel-electrophoresis (2DE) protein profiling for osteoarthritis (OA) and rheumatoid arthritis (RA) is challenging because of selective protein loss due to discrepancies in protein precipitation methodologies. Thus, we aimed at developing qualitative protein representation from OA/RA articular cartilage without protein precipitation towards identification of clinically relevant proteins. Chondroitinase digested human articular cartilages from RA patients were subjected to protein extraction using guanidinium hydrochloride (GuHCl) or 8 M urea with 10 or 2% ASB-14-4 or 0.45 M urea with 2% ASB-14-4 with cetylpyridinium chloride (CPC). The GuHCl extract is further protein precipitated with acetone or ammonium acetate-methanol or centricon-fractionated using 100 kDa cut filters and protein precipitated using ethanol. Processed extracts were subjected to 2DE to identify protein profiles. Poor proteins representations were observed in 2D gels with protein precipitated samples compared to qualitative protein representations seen in 2D gels of 0.45 M urea and 2%ASB-14-4 extraction procedure reproducibly. The strategy circumventing protein precipitation generated qualitative 2D gels. RA vs OA gel comparison showed elevated prolargin levels in RA with biglycan levels remaining unaltered. Up regulation of prolargin in RA suggests the likelihood of an adaptive mechanism to control the increased osteoclastogenesis in RA and may have therapeutic value in controlling the disease.