Indian consensus on the managemeNt of carbapenem-resistant enterobacterales infection in critically ill patients II (ICONIC II).

INTRODUCTION: The rising challenge of carbapenem-resistant Enterobacterales (CRE) infections in Indian healthcare settings calls for clear clinical guidance on the management of these infections. The Indian consensus on the management of CRE infection in critically ill patients (ICONIC-II) is a follow-up of the ICONIC-I study, which was undertaken in 2019. AREAS COVERED: A modified Delphi method was used to build expert consensus on CRE management in India, involving online surveys, face-to - face expert meetings, and a literature review. A panel of 12 experts was formed to develop potential clinical consensus statements (CCSs), which were rated through two survey rounds. The CCSs were finalized in a final face-to - face discussion. The finalized CCSs were categorized as consensus, near consensus, and no consensus. EXPERT OPINION: The outcomes included 46 CCSs (consensus: 40; near consensus: 3; and no consensus: 3). The expert panel discussed and achieved consensus on various strategies for managing CRE infections, emphasizing the significance of existing and emerging resistance mechanisms, prompt and tailored empiric therapy, and use of combination therapies. The consensus statements based on the collective expertise of the panel can potentially assist clinicians in the management of CRE infections that lack high-level evidence.

Detection of Wuchereria bancrofti DNA in wild caught vector and non-vector mosquitoes: implications for elimination of lymphatic filariasis.

BACKGROUND: Transmission Assessment Survey (TAS) is the WHO recommended method used for decision-making to stop or continue the MDA in lymphatic filariasis (LF) elimination programme. The WHO has also recommended Molecular Xenomonitoring (MX) of LF infection in vectors as an adjunct tool in settings under post-MDA or validation period. Screening of non-vectors by MX in post-MDA / validation settings could be useful to prevent a resurgence of LF infection, as there might be low abundance of vectors, especially in some seasons. In this study, we investigated the presence of LF infection in non-vectors in an area endemic for LF and has undergone many rounds of annual MDA with two drugs (Diethylcarbamazine and Albendazole, DA) and two rounds of triple drug regimens (Ivermectin + DA). METHODS AND RESULTS: Mosquitoes were collected from selected villages of Yadgir district in Karnataka state, India, during 2019. A total of 680 female mosquitoes were collected, identified morphologically by species and separated as pools. The female mosquitoes belonging to 3 species viz., Anopheles subpictus, Culex gelidus and Culex quinquefaciatus were separated, pooled, and the DNA extracted using less expensive method and followed by LDR based real-time PCR assay for detecting Wuchereria bancrofti infection in vector as well as non-vector mosquitoes. One pool out of 6 pools of An. subpictus, 2 pools out of 6 pools of Cx. gelidus, and 4 pools out of 8 pools of Cx. quinquefaciatus were found to be positive for W. bancrofti infection by RT-PCR. The infection rate in vectors and non-vectors was found to be 1.8% (95% CI: 0.5-4.2%) and 0.9% (95% CI: 0.2-2.3%), respectively. CONCLUSIONS: Our study showed that non-vectors also harbour W. bancrofti, thus opening an opportunity of using these mosquitoes as surrogate vectors for assessing risk of transmission to humans in LF endemic and post MDA areas.

Clinical utility of procalcitonin in implementation of procalcitonin-guided antibiotic stewardship in the South-East Asia and India: evidence and consensus-based recommendations.

INTRODUCTION: The South-East Asian (SEA) region and India are highly susceptible to antibiotic resistance, which is caused due to lack of antimicrobial stewardship (AMS) knowledge, uncontrolled use of antibiotics, and poor infection control. Nonadherence to national/local guidelines, developed to combat antimicrobial resistance, is a major concern. A virtual advisory board was conducted to understand the current AMS standards and challenges in its implementation in these regions. AREAS COVERED: Procalcitonin (PCT)-guided antibiotic use was discussed in various clinical conditions across initiation, management, and discontinuation stages. Most experts strongly recommended using PCT-driven antibiotic therapy among patients with lower respiratory tract infections, sepsis, and COVID-19. However, additional research is required to understand the optimal use of PCT in patients with organ transplantation and cancer patients with febrile neutropenia. Implementation of the solutions discussed in this review can help improve PCT utilization in guiding AMS in these regions and reducing challenges. EXPERT OPINION: Experts strongly support the inclusion of PCT in AMS. They believe that PCT in combination with other clinical data to guide antibiotic therapy may result in more personalized and precise targeted antibiotic treatment. The future of PCT in antibiotic treatment is promising and may result in effective utilization of this biomarker.

India-discovered levonadifloxacin & alalevonadifloxacin: A review on susceptibility testing methods, CLSI quality control and breakpoints along with a brief account of their emerging therapeutic profile as a novel standard-of-care.

BACKGROUND: Levonadifloxacin (intravenous) and alalevonadifloxacin (oral prodrug) are novel antibiotics based on benzoquinolizine subclass of fluoroquinolone, licensed for clinical use in India in 2019. The active moiety, levonadifloxacin, is a broad-spectrum antibiotic with a high potency against methicillin-resistant Staphylococcus. aureus, multi-drug resistant pneumococci and anaerobes. OBJECTIVE: This review, for the first time, critically analyses the antimicrobial susceptibility testing methods, Clinical Laboratory & Standards Institute (CLSI)-quality control of susceptibility testing and breakpoints of levonadifloxacin. Further, the genesis, discovery and developmental aspects as well as therapeutic profile of levonadifloxacin and alalevonadifloxacin are briefly described. CONTENTS: In order to aid the scientific and clinician communities with a single comprehensive overview on all the key aspects of levonadifloxacin and alalevonadifloxacin, the present article covers the reference MIC and disk diffusion methods for levonadifloxacin susceptibility testing that were approved by CLSI and the reference ranges for quality control strains published in the CLSI M100 document. The breakpoints of levonadifloxacin were derived in concordance to US FDA, European Committee on Antibiotic Susceptibility Testing (EUCAST) and CLSI approaches. Further, the article provides a brief account of challenges encountered during the discovery stages of levonadifloxacin and alalevonadifloxacin, activity spectrum and safety benefits accruing from structural novelty-linked mechanism of action. Further, the review also covers in vitro and in vivo activities, registrational clinical studies and patient-friendly features of levonadifloxacin/alalevonadifloxacin. Cumulatively, levonadifloxacin has a potential to offer a long awaited new standard-of-care treatment for the resistant Gram-positive bacterial infections.

The potential liver donor with tuberculosis: A fresh look at international recommendations based on a survey of practice in Indian liver transplant centres.

Background The western recommendations for the use of organs from liver donors with tuberculosis (TB) come from an environment where the burden of disease is low and cadaveric organ donation rates are high-in complete contrast to the Indian scenario, where these recommendations may be too restrictive. Methods A questionnaire relating to current practice on the use of organs from liver donors with TB was sent to all liver transplant centres in India. Results Responses were obtained from 94% of centres. Two-thirds accepted organs from deceased donors with TB in the elective setting, especially for recipients with a high MELD (Model for end-stage liver disease) score. The proportion rose by 1.5 times in the setting of acute liver failure. Two-thirds advised anti-TB treatment (ATT) for corresponding recipients, and the remaining advised isonicotinic acid hydrazide (INH) prophylaxis. Untreated living donors with TB were not accepted. Half the respondents accepted living donors after completion of ATT, and did not treat recipients postoperatively. The remainder accepted them after 8 weeks of treatment and advised INH prophylaxis or ATT for recipients. Conclusions That this practice has not impacted recipient outcomes suggests that the guidelines for management of liver donors and recipients may need to be altered for populations endemic for TB.

Early and Appropriate Use of Ceftazidime-Avibactam in the Management of Multidrug-Resistant Gram-Negative Bacterial Infections in the Indian Scenario.

The increasing prevalence of antibiotic-resistant pathogens exerts a substantial burden on the healthcare infrastructure worldwide. The World Health Organization (WHO) has declared that multidrug-resistant (MDR) Gram-negative pathogens, especially, carbapenem-resistant Enterobacterales (CRE), Acinetobacter baumannii, and Pseudomonas aeruginosa as the topmost priority while developing newer antimicrobials. The increasing prevalence of infectious diseases caused by MDR Gram-negative bacteria also poses a challenge when choosing the empiric antimicrobial therapy for seriously ill hospitalized patients. The infections caused by MDR Gram-negative organisms ultimately result in increased mortality, morbidity, prolonged hospital stay, and increased cost of management. To tackle these challenges, newer antimicrobials like ceftazidime-avibactam were explored. The article also discusses the in vitro activity and therapeutic efficacy of ceftazidime-avibactam along with its pharmacokinetic properties and the role it will play in the management of MDR Gram-negative organisms in the Indian setting. Several studies have highlighted the role of early and appropriate antibiotic use in the reduction of mortality in patients with Gram-negative infections. Timely initiation of appropriate antibiotic therapy for serious infections leads to favorable clinical outcomes. Early and appropriate use of ceftazidime-avibactam while treating MDR Gram-negative infections has been associated with improved clinical outcomes. The aim of this review is to highlight the efficacy of ceftazidime-avibactam in the treatment of MDR Gram-negative infections. We have also summarized the information on outcomes achieved by early and appropriate use of ceftazidime-avibactam.

Treatment of MRSA infections in India: Clinical insights from a Delphi analysis.

PURPOSE: International and Indian guidelines for the management of patients with methicillin-resistant Staphylococcus aureus (MRSA) infections are available, but the local guidelines are not MRSA-specific. This study aimed to provide clinical insights for the treatment of MRSA infections in India. METHODS: We used a three-step modified Delphi method to obtain insights. Ten experts comprising infectious disease specialists, microbiologists, pulmonologists, and critical care experts agreed to participate in the analysis. In round 1, a total of 161 statements were circulated to the panel and the experts were asked to 'agree' or 'disagree' by responding 'yes' or 'no' to each statement and provide comments. The same process was used for 73 statements in round 2. Direct interaction with the experts was carried out in round 3 wherein 35 statements were discussed. At least 80% of the experts had to agree for a statement to reach concordance. RESULTS: Eighty-eight statements in round 1, thirty-eight statements in round 2, and eight statements in round 3 reached concordance and were accepted without modification. The final document comprised 152 statements on the management of various syndromes associated with MRSA such as skin and soft tissue infections, bacteremia and endocarditis, pneumonia, bone and joint infections, and central nervous system infections. CONCLUSIONS: This analysis will assist clinicians in India to choose an appropriate course of action for MRSA infections.

Recommendations for Evaluation and Selection of Deceased Organ Donor: Position Statement of ISCCM.

There is a wide gap between patients who need transplants and the organs that are available in India. Extending the standard donation criterion is certainly important to address the scarcity of organs for transplantation. Intensivists play a major role in the success of deceased donor organ transplants. Recommendations for deceased donor organ evaluation are not discussed in most intensive care guidelines. The purpose of this position statement is to establish current evidence-based recommendations for multiprofessional critical care staff in the evaluation, assessment, and selection of potential organ donors. These recommendations will give "real-world" criteria that are acceptable in the Indian context. The aim of this set of recommendations is to both increase the number and enhance the quality of transplantable organs. How to cite this article: Zirpe KG, Tiwari AM, Pandit RA, Govil D, Mishra RC, Samavedam S, et al. Recommendations for Evaluation and Selection of Deceased Organ Donor: Position Statement of ISCCM. Indian J Crit Care Med 2022;26(S2):S43-S50.

Management of serious infections caused by metallo ß-lactamases with or without OXA-48-like expressing Enterobacterales with aztreonam and ceftazidime/avibactam combination: Dosing strategy for better clinical outcome.

Serious infections caused by MBLs with or without OXA-48-like expressing Enterobacterales remain challenging to treat. Since aztreonam is stable to MBLs, it can be combined with ceftazidime/avibactam to protect against concurrently expressed ESBLs and class C ß-lactamases in MBL pathogens. However, in the light of dose-limiting hepatotoxicity of aztreonam, short half life of avibactam, significant protein binding of aztreonam, appropriate dosing and method of administration to optimize PK/PD and toxicodynamics for this combination is being debated. Based on in-vitro PK/PD studies, simultaneous administration of 6/1.5 g of ceftazidime/avibactam and 8 g of aztreonam per day has been recently suggested.

Clinical practice guidelines 2019: Indian consensus-based recommendations on influenza vaccination in adults.

Influenza, a common cause of acute respiratory infections, is an important health problem worldwide, including in India. Influenza is associated with several complications; people with comorbidities and the elderly are at a higher risk for such complications. Moreover, the influenza virus constantly changes genetically, thereby worsening therapeutic outcomes. Vaccination is an effective measure for the prevention of influenza. Despite the availability of global guidelines on influenza vaccination in adults, country-specific guidelines based on regional variation in disease burden are required for better disease management in India. With this aim, the Indian Chest Society and National College of Chest Physicians of India jointly conducted an expert meeting in January 2019. The discussion was aimed at delineating evidence-based recommendations on adult influenza vaccination in India. The present article discusses expert recommendations on clinical practice guidelines to be followed in India for adult influenza vaccination, for better management of the disease burden.

Clinical practice guidelines 2019: Indian consensus-based recommendations on pneumococcal vaccination for adults.

Similar to the global scenario, pneumococcal diseases are a significant health concern in India. Pneumococcal diseases occur frequently among adults and are largely preventable through vaccines. Globally, several guidelines and recommendations are available for pneumococcal vaccination in adults. However, owing to wide variations in the disease burden, regulatory landscape, and health-care system in India, such global guidelines cannot be unconditionally implemented throughout the country. To address these gaps, the Indian Chest Society and National College of Chest Physicians of India jointly conducted an expert meeting in January 2019. The aim of the discussion was to lay down specific evidence-based recommendations on adult pneumococcal vaccination for the country, with a view to further ameliorate the disease burden in the country. This article presents an overview of the closed-door discussion by the expert members on clinical practice guidelines to be followed for adult pneumococcal vaccination in India.

A Comprehensive Review of Meningococcal Disease Burden in India.

INTRODUCTION: Meningococcal disease caused by Neisseria meningitidis has a high case fatality rate. Of 12 distinct serogroups, A, B, C, W-135 (W) and Y cause the majority of infections. The meningococcal disease burden and epidemiology in India are not reliably known. Hence, we performed a narrative review with a systematically conducted search to summarize information on meningococcal disease burden and epidemiology and vaccination recommendations for meningococcal disease in India. METHODS: A search of Medline and Embase databases was undertaken to identify relevant publications published in the last 25 years. RESULTS: Results from 32 original publications, 11 of which were case reports, suggest a significant burden of meningococcal disease and related complications. Meningococcal disease is increasingly reported among adolescents and adults, and large outbreaks have been reported in this population. Meningococcal disease in India is caused almost exclusively by serogroup A; serogroups B, C, W and Y have also been documented. Meningococcal disease burden data remain unreliable because of limited disease surveillance, insufficient laboratory capacity, misdiagnosis and prevalence of extensive antibiotic use in India. Lack of access to healthcare also increases under-reporting, thus bringing the reliability of the data into question. Conjugate meningococcal vaccines are being used for disease prevention by national governments and immunization programs globally. In India, meningococcal vaccination is recommended only for certain high-risk groups, during outbreaks and for international travelers such as Hajj pilgrims and students pursuing studies abroad. CONCLUSION: Meningococcal disease is prevalent in India but remains grossly underestimated and under-reported. Available literature largely presents outbreak data related to serogroup A disease; however, non-A serogroup disease cases have been reported. Reliable epidemiologic data are urgently needed to inform the true burden of endemic disease. Further research into the significance of meningococcal disease burden can be used to improve public health policy in India. Fig. 1 Plain language summary.

Susceptibility Pattern of Doxycycline in Comparison to Azithromycin, Cefuroxime and Amoxicillin against Common Isolates: A Retrospective Study Based on Diagnostic Laboratory Data.

INTRODUCTION: Doxycycline acts against a broad range of gram-positive, gramnegative and 'atypical' bacteria as well as some protozoan pathogens such as malaria. In this era of increasing multidrug-resistance, recycling of old antimicrobials should be considered and need more focus in this domain of research. We, therefore, aimed to assess the antimicrobial susceptibility patterns of commonly isolated pathogens against doxycycline, azithromycin, cefuroxime, and amoxicillin from common clinical specimens by using laboratory-based diagnostic data from western India. MATERIALS AND METHODS: The non-interventional retrospective study was conducted on secondary data extracted from multi-center diagnostic laboratory based in Mumbai, India. Susceptibility data of bacteria isolated from blood, urine, pus, and sputum were used in the study and culture positive samples were segregated. Antimicrobial susceptibility status of doxycycline was checked and compared with azithromycin, cefuroxime, and amoxicillin. Chi-square tests of significance were carried out to assess significant differences in susceptibility patterns. Association between variables was considered statistically significant if the p-value was <0.05. RESULTS: Percentage susceptibility of collective bacterial isolates was found to be highest for doxycycline in all four specimens (93.1%). Individual percentage susceptibility was observed to be highest for sputum isolates (97.5%) followed by blood (93.8%), pus (92.7%) and urine (70.0%). The activity of doxycycline was found to be 93.5% for the samples resistant to azithromycin. Doxycycline also showed good susceptibility for the isolates resistant to amoxicillin and cefuroxime which was 75.9% and 64.8%, respectively. CONCLUSION: Several bacterial isolates from all four sources were found to be susceptible to Doxycycline. It has an important role in the form of a better alternative of major antimicrobial agents like azithromycin, cefuroxime, and amoxicillin against gram-positive cocci. Doxycycline appeared to show better activity against isolates which were resistant to other three antimicrobials.

Procalcitonin (PCT)-guided antibiotic stewardship in Asia-Pacific countries: adaptation based on an expert consensus meeting.

Introduction Recently, an expert consensus on optimal use of procalcitonin (PCT)-guided antibiotic stewardship was published focusing mainly on Europe and the United States. However, for Asia-Pacific countries, recommendations may need adaptation due to differences in types of infections, available resources and standard of clinical care. Methods Practical experience with PCT-guided antibiotic stewardship was discussed among experts from different countries, reflecting on the applicability of the proposed Berlin consensus algorithms for Asia-Pacific. Using a Delphi process, the group reached consensus on two PCT algorithms for the critically ill and the non-critically ill patient populations. Results The group agreed that the existing evidence for PCT-guided antibiotic stewardship in patients with acute respiratory infections and sepsis is generally valid also for Asia-Pacific countries, in regard to proposed PCT cut-offs, emphasis on diagnosis, prognosis and antibiotic stewardship, overruling criteria and inevitable adaptations to clinical settings. However, the group noted an insufficient database on patients with tropical diseases currently limiting the clinical utility in these patients. Also, due to lower resource availabilities, biomarker levels may be measured less frequently and only when changes in treatment are highly likely. Conclusions Use of PCT to guide antibiotic stewardship in conjunction with continuous education and regular feedback to all stakeholders has high potential to improve the utilization of antibiotic treatment also in Asia-Pacific countries. However, there is need for adaptations of existing algorithms due to differences in types of infections and routine clinical care. Further research is needed to understand the optimal use of PCT in patients with tropical diseases.

Evaluation of long-lasting indoor residual spraying of deltamethrin 62.5 SC-PE against malaria vectors in India.

BACKGROUND: Deltamethrin 62.5 polymer-enhanced suspension concentrate (SC-PE) is one of the World Health Organization-approved insecticides for indoor residual spraying and was recommended to evaluate its residual activity for determination of appropriate spray cycles in different eco-epidemiologic settings. In the current study, efficacy of deltamethrin 62.5 SC-PE was evaluated against vectors of malaria and its impact on malaria incidence in a Plasmodium falciparum hyper-endemic area in Koraput district, Odisha State, India. METHODS: The trial had two comparable arms, arm 1 with residual spraying of deltamethrin 62.5 SC-PE and arm 2 with deltamethrin 2.5% WP (positive control). Comparative assessment of the impact of each intervention arm on entomological (density, parity, infection and human blood index), epidemiological (malaria incidence) parameters, residual efficacy and adverse effects were evaluated. RESULTS: Both the arms were comparable in terms of entomological and epidemiological parameters. While, deltamethrin 62.5 SC-PE was found to be effective for 150 days in mud and wood surfaces and 157 days in cement surfaces; deltamethrin 2.5% was effective only for 105 days on mud surfaces and 113 days on cement and wood surfaces. CONCLUSIONS: Deltamethrin 62.5 SC-PE had prolonged killing effectiveness up to 5 months. Hence, one round of IRS with deltamethrin 62.5 SC-PE would be sufficient to cover two existing malaria peak transmission seasons (July-August and October-November) in many parts of India.

Frequency and Clinical Significance of Localized Adverse Events following Mass Drug Administration for Lymphatic Filariasis in an Endemic Area in South India.

Fear of adverse events (AEs) negatively affects compliance to mass drug administration (MDA) for lymphatic filariasis (LF) elimination program. Systemic AEs are believed to occur because of killing of microfilariae, whereas localized soft tissue reactions might be due to the death of adult worms following therapy. Most AEs are mild and self-limited. However, localized AEs are sometimes more significant and of concern to participants. Here, we describe localized AEs that were noted during a large community study that evaluated the safety of a triple-drug regimen (ivermectin, diethylcarbamazine, and albendazole) for the treatment of LF in India. We have also discussed the importance of timely detection and careful management of AEs for preserving community confidence in MDA.

Colistin-sparing approaches with newer antimicrobials to treat carbapenem-resistant organisms: Current evidence and future prospects.

Antimicrobial resistance is on the rise across the globe. Increasing incidence of infections due to carbapenem resistance organisms is becoming difficult to treat, due to the limited availability of therapeutic agents. Very few agents such as colistin, fosfomycin, tigecycline and minocycline are widely used, despite its toxicity. However, with the availability of novel antimicrobials, beta-lactam/beta-lactamase inhibitor-based and non-beta-lactam-based agents could be of great relief. This review covers three important aspects which include (i) current management of carbapenem-resistant infections, (ii) determination of specific types of carbapenemases produced by multidrug-resistant and extensively drug-resistant Gram-negative pathogens and (iii) the currently available novel beta-lactam/beta-lactamase inhibitors and non-beta-lactam-based agents' laboratory findings, clinical outcome and implications.

Indian consensus on the management of CRE infection in critically ill patients (ICONIC) - India.

Background: The increasing burden of carbapenem-resistant Enterobacteriaceae (CRE) carriage and infection in different patient settings in India has created an acute need for guidance for clinicians regarding optimal strategies for the management of CRE infection in critically ill patients. Research design and methods: A multidisciplinary panel of 11 Indian experts in CRE infection assembled for comprehensive discussion and consensus development. The experts developed clinical statements through a systematic review of key literature. Main outcome measures: The panel voted anonymously on 60 clinically relevant questions, through a modified Delphi process. Results: Forty-six key clinical consensus statements (CCS) were proposed. The panel reached a consensus on several important issues, providing recommendations on surveillance, diagnosis, prevention, pharmacokinetic challenges, combination therapy, and cornerstone molecules in CRE infections. The panel also proposed a treatment algorithm for NDM-prevalent settings. Conclusion: These consensus statements may offer clinicians expert guidance on the management of CRE infections. There is a dearth of high-/moderate-level evidence on managing CRE infections; the recommendations presented herein are based on expert opinion.

An unusual cause of graft loss in pediatric liver transplant recipient-Fasciola hepatica.

Fascioliasis is caused by the trematode liver fluke Fasciola hepatica. Humans are accidental hosts getting infected after ingesting contaminated plants or water. 90 million people in 75 nations are at risk of infection with F hepatica. Immunosuppressed patients are higher risk of acquiring infection and may present with atypical manifestations. Patients can present with hepatic involvement, biliary features or a combination of both. Confirmation of the diagnosis is by demonstration of live parasites or eggs in bile or feces, serology (immunoelectrophoresis, indirect immunofluorescence, indirect hemagglutination), ELISA, typical imaging findings or a combination of any of the above. The drug of choice for treatment is triclabendazole. Fascioliasis should always be considered as a possibility in post-LT patients with findings of hepatobiliary disorder from endemic areas. Unfamiliarity with this infection in non-endemic areas often eludes prompt diagnosis thereby increasing the morbidity. We report the first case of fascioliasis in a pediatric liver transplant recipient leading to graft loss and mortality.