Prevalence of co-existent COVID-19-associated pulmonary aspergillosis (CAPA) and its impact on early mortality in patients with COVID-19-associated pulmonary mucormycosis (CAPM).

BACKGROUND: Data on mixed mould infection with COVID-19-associated pulmonary aspergillosis (CAPA) and COVID-19-associated pulmonary mucormycosis (CAPM) are sparse. OBJECTIVES: To ascertain the prevalence of co-existent CAPA in CAPM (mixed mould infection) and whether mixed mould infection is associated with early mortality (≤7 days of diagnosis). METHODS: We retrospectively analysed the data collected from 25 centres across India on COVID-19-associated mucormycosis. We included only CAPM and excluded subjects with disseminated or rhino-orbital mucormycosis. We defined co-existent CAPA if a respiratory specimen showed septate hyphae on smear, histopathology or culture grew Aspergillus spp. We also compare the demography, predisposing factors, severity of COVID-19, and management of CAPM patients with and without CAPA. Using a case-control design, we assess whether mixed mould infection (primary exposure) were associated with early mortality in CAPM. RESULTS: We included 105 patients with CAPM. The prevalence of mixed mould infection was 20% (21/105). Patients with mixed mould infection experienced early mortality (9/21 [42.9%] vs. 15/84 [17.9%]; p = 0.02) and poorer survival at 6 weeks (7/21 [33.3] vs. 46/77 [59.7%]; p = 0.03) than CAPM alone. On imaging, consolidation was more commonly encountered with mixed mould infections than CAPM. Co-existent CAPA (odds ratio [95% confidence interval], 19.1 [2.62-139.1]) was independently associated with early mortality in CAPM after adjusting for hypoxemia during COVID-19 and other factors. CONCLUSION: Coinfection of CAPA and CAPM was not uncommon in our CAPM patients and portends a worse prognosis. Prospective studies from different countries are required to know the impact of mixed mould infection.

Salmonella Typhi acquires diverse plasmids from other Enterobacteriaceae to develop cephalosporin resistance.

BACKGROUND: Recent reports have established the emergence and dissemination of extensively drug resistant (XDR) H58 Salmonella Typhi clone in Pakistan. In India where typhoid fever is endemic, only sporadic cases of ceftriaxone resistant S. Typhi are reported. This study aimed at elucidating the phylogenetic evolutionary framework of ceftriaxone resistant S. Typhi isolates from India to predict their potential dissemination. METHODS: Five ceftriaxone resistant S. Typhi isolates from three tertiary care hospitals in India were sequenced on an Ion Torrent Personal Genome Machine (PGM). A core genome single-nucleotide-polymorphism (SNP) based phylogeny of the isolates in comparison to the global collection of MDR and XDR S. Typhi isolates was built. Two of five isolates were additionally sequenced using Oxford Nanopore MinION to completely characterize the plasmid and understand its transmission dynamics within Enterobacteriaceae. RESULTS: Comparative genomic analysis and detailed plasmid characterization indicate that while in Pakistan (4.3.1 lineage I) the XDR trait is associated with blaCTX-M-15 gene on IncY plasmid, in India (4.3.1 lineage II), the ceftriaxone resistance is due to short term persistence of resistance plasmids such as IncX3 (blaSHV-12) or IncN (blaTEM-1B + blaDHA-1). CONCLUSION: Considering the selection pressure exerted by the extensive use of ceftriaxone in India, there are potential risks for the occurrence of plasmid transmission events in the predominant H58 lineages. Therefore, continuous monitoring of S. Typhi lineages carrying plasmid-mediated cephalosporin resistant genes is vital not just for India but also globally.

Clinical Outcome of Patients on Ceftazidime-Avibactam and Combination Therapy in Carbapenem-resistant Enterobacteriaceae.

INTRODUCTION: Carbapenem-resistant Enterobacteriaceae (CRE) infections have a major effect on mortality as well as healthcare cost. Intensive care units (ICUs) in India, the epicenters for multidrug-resistant organisms, are facing a "postantibiotic era" because of very limited treatment options. A latest beta-lactam/beta-lactamase inhibitor ceftazidime-avibactam (CZA) new has a broad-spectrum antibacterial activity. CZA inhibits class-A and class-C beta-lactamases (as well Klebsiella pneumoniae carbapenemase (KPC)), along with some class-D carbapenems such as OXA-48-like enzymes that are seen in Enterobacteriaceae has recently become available. The current study aimed to assess and present the clinical response and patient outcome with infections due to CRE when treated with CZA alone or in combination with other drugs. MATERIALS AND METHODS: This retrospective study reviews the experience recorded and analyzed at two tertiary care centers including only adult patients with CRE infection who had received CZA alone or in combination with other antibiotics over a period between February 2019 and January 2020. RESULTS: In the period from February 2019 to January 2020, 119 culture-confirmed CRE isolates were tested for Xpert Carba-R. The predominant genetic mechanism was a combination of NDM+OXA-48 in 45/119 (37.81%). Total 40/57 patients received CZA+aztreonam alone or in combination with other drugs with an overall cure rate of 77.5% while the rest 17 received CZA alone in combination with the cure rate of 82.35%. 41/57 (71.92%) patients were in ICU. CONCLUSION: With overall mortality of 21%, these data suggest that CZA is a viable option for patients with CRE infections. To our knowledge, this is the first Indian study reporting CZA data in CRE infections. HOW TO CITE THIS ARTICLE: Nagvekar V, Shah A, Unadkat VP, Chavan A, Kohli R, Hodgar S, et al. Clinical Outcome of Patients on Ceftazidime-Avibactam and Combination Therapy in Carbapenem-resistant Enterobacteriaceae. Indian J Crit Care Med 2021;25(7):780-784.

Treatment challenges in the management of difficult-to-treat gram-positive infections: A consensus view apropos therapeutic role of novel anti-MRSA antibiotics, levonadifloxacin (IV) and alalevonadifloxacin (oral).

PURPOSE: Treatment of antibiotic-resistant Gram-positive infections (GPIs), including methicillin-resistant Staphylococcus aureus (MRSA) is becoming increasingly difficult, particularly in patients with multiple co-morbidities who require antibiotics with greater safety and a consistent pharmacokinetic/pharmacodynamic (PK/PD) profile. Such difficult-to-treat GPIs are often associated with poor outcomes, extended hospital stay and increased expenditure. This can be partly attributed to the limited safety and aberrant PK/PD profile of existing anti-MRSA antibiotics. In this context, intravenous levonadifloxacin and its oral prodrug alalevonadifloxacin are novel anti-MRSA antibiotics that have significant advantages over conventional anti-Gram-positive antibiotics. The purpose of this paper was to generate a consensus on the optimal use of levonadifloxacin and alalevonadifloxacin for tackling resistant Gram-positive infections in patients with multiple co-morbidities. METHOD: Using a modified Delphi approach that combines critical appraisal of evidence and expert opinion, therapeutic use of levonadifloxacin and alalevonadifloxacin in various clinical scenarios and specific unmet conditions was deliberated. Fifteen expert members from medicine, critical-care, emergency, microbiology, and intensive-care disciplines participated and voted on 11 pre-conceived statements. When there was at least 70 % agreement, a consensus was reached. RESULTS: Following the voting, agreements were reached on 10 out of the 11 statements. Broadly, a consensus was reached in defining the therapeutic role of levonadifloxacin and alalevonadifloxacin in the treatment of various clinical indications involving resistant Gram-positive pathogens, including MRSA, in patients with co-morbidities, such as co-existing or increased risk for kidney dysfunction or hepatic disease and/or immunosuppression; also, in therapeutically challenging conditions caused by Gram-positive bacteria such as bacteraemia, bone and joint infection, diabetic foot infection, febrile neutropenia, and hospital-acquired pneumonia. CONCLUSIONS: This consensus supports the therapeutic use of levonadifloxacin and alalevonadifloxacin in the treatment of antibiotic-resistant GPIs, including those caused by MRSA and certain polymicrobial infections, in patients with multiple co-morbidities requiring drug with adequate safety and consistent efficacy.

Risk factors, mortality, and predictors of survival in COVID-19-associated pulmonary mucormycosis: a multicentre retrospective study from India.

OBJECTIVES: To compare COVID-19-associated pulmonary mucormycosis (CAPM) with COVID-19-associated rhino-orbital mucormycosis (CAROM), ascertain factors associated with CAPM among patients with COVID-19, and identify factors associated with 12-week mortality in CAPM. METHODS: We performed a retrospective multicentre cohort study. All study participants had COVID-19. We enrolled CAPM, CAROM, and COVID-19 subjects without mucormycosis (controls; age-matched). We collected information on demography, predisposing factors, and details of COVID-19 illness. Univariable analysis was used to compare CAPM and CAROM. We used multivariable logistic regression to evaluate factors associated with CAPM (with hypoxemia during COVID-19 as the primary exposure) and at 12-week mortality. RESULTS: We included 1724 cases (CAPM [n = 122], CAROM [n = 1602]) and 3911 controls. Male sex, renal transplantation, multimorbidity, neutrophil-lymphocyte ratio, intensive care admission, and cumulative glucocorticoid dose for COVID-19 were significantly higher in CAPM than in CAROM. On multivariable analysis, COVID-19-related hypoxemia (aOR, 2.384; 95% CI, 1.209-4.700), male sex, rural residence, diabetes mellitus, serum C-reactive protein, glucocorticoid, and zinc use during COVID-19 were independently associated with CAPM. CAPM reported a higher 12-week mortality than CAROM (56 of the 107 [52.3%] vs. 413 of the 1356 [30.5%]; p = 0.0001). Hypoxemia during COVID-19 (aOR [95% CI], 3.70 [1.34-10.25]) and Aspergillus co-infection (aOR [95% CI], 5.40 [1.23-23.64]) were independently associated with mortality in CAPM, whereas surgery was associated with better survival. DISCUSSION: CAPM is a distinct entity with a higher mortality than CAROM. Hypoxemia during COVID-19 illness is associated with CAPM. COVID-19 hypoxemia and Aspergillus co-infection were associated with higher mortality in CAPM.

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.

Prescription-Event Monitoring Study on Safety and Efficacy of Levonadifloxacin (Oral and I.V.) in Management of Bacterial Infections: Findings of Real-World Observational Study.

Background: Levonadifloxacin is a novel broad-spectrum antibiotic belonging to the benzoquinolizine subclass of quinolones. It is available in intravenous as well as oral formulation for the treatment of infections caused by common Gram-positive bacterial pathogens including methicillin-resistant Staphylococcus aureus (MRSA). Patients and Methods: This study retrospectively assessed the real-world safety and efficacy of levonadifloxacin (oral and/or IV) in the treatment of 1229 patients across various clinical conditions. Study outcomes were clinical and microbiological success at the end of therapy. Results: The mean duration of levonadifloxacin therapy was 7.2 days, with a time to clinical improvement averaging at 4 days. Three hundred and three patients received oral therapy, 875 received IV, and 51 received a combination of IV followed by oral therapy. Patients were prescribed levonadifloxacin for skin and soft-tissue infections, diabetic foot infections, septicemia, catheter-related bloodstream infections, bone and joint infections, febrile neutropenia, and respiratory infections including COVID-19 pneumonia. High clinical success rates of 98.3%, 93.7%, and 96.1% with oral, IV, and IV followed by oral levonadifloxacin, respectively, were obtained. Only 11 mild adverse events were reported in 9 patients which included constipation, diarrhea, hyperglycemia, nausea, fatigue, and vomiting. Overall, 96.3% and 97.3% of investigators rated the efficacy and safety of levonadifloxacin as "good to excellent." Conclusions: An excellent safety and efficacy profile of levonadifloxacin was observed in this study making it a suitable treatment option for management of various bacterial infections, including those caused by resistant Gram-positive pathogens such as MRSA and quinolone-resistant S. aureus.

Prevalence of multidrug-resistant Gram-negative bacteria cases at admission in a multispeciality hospital.

OBJECTIVES: The prevalence of drug-resistant cases is increasing globally. The present study aimed to investigate the prevalence of cases of blood culture positive for multidrug-resistant Gram-negative bacteria (MDR-GNB) at the time of admission, i.e. within 24h of admission to hospital from primary or secondary care centres. METHODS: This record-based retrospective cross-sectional study was designed to analyze MDR-GNB-positive cases at Fortis Hospital, Mumbai, India. Fortis Hospital is a 500-bed referral tertiary care centre. An increase of MDR-GNB was seen from January 2012 to June 2014 in the hospital. A retrospective analysis of blood culture GNB-positive samples was performed to evaluate MDR-GNB-positive cases at admission. RESULTS: The total number of positive blood cultures in January to December 2012, January to December 2013 and January to June 2014 were 221, 236 and 116, respectively, with 77.83%, 79.66% and 69.83% GNB-positive. Total MDR-GNB-positive cases were 26.16%, 32.98% and 33.33%, respectively, and amongst these MDR-GNB, 22%, 32% and 37% where positive at time of admission to the hospital. The MDR-GNB were Escherichia coli, Klebsiella, Acinetobacter, Pseudomonas and Enterobacter. CONCLUSION: MDR-GNB blood cultures positive at admission rose from January 2012 to June 2014 and hence there is an urgent need for possible contact isolation of all patients coming from primary and secondary to tertiary health care centres which should be made compulsory until screening rules out MDR-GNB to prevent spread of MDR organisms in the hospital.

Towards adult vaccination in India: a narrative literature review.

Despite vast improvements in childhood vaccination coverage in India, adult vaccination coverage is negligible. Our aim was, therefore, to create awareness about the importance of adult immunization. Although the true burden of vaccine-preventable diseases (VPDs) among Indian adults is unknown, adults are particularly vulnerable during outbreaks, due to a lack of immunization, waning immunity, age-related factors (e.g. chronic conditions and immunosenescence), and epidemiological shift. There are no national adult immunization guidelines in India, and although several medical societies have published adult immunization guidelines, these vary, making it unclear who should receive which vaccines (based on age, underlying conditions, etc.). Other barriers to adult immunization include vaccine hesitancy, missed opportunities, and cost. Steps to improve adult vaccination could include: adoption of national guidelines, education of healthcare providers and the public, and promotion of life-course immunization. Improving adult vaccine coverage could help reduce the burden of VPDs, particularly among older adults.

Current Perspectives on Treatment of Gram-Positive Infections in India: What Is the Way Forward?

The emerging antimicrobial resistance leading to gram-positive infections (GPIs) is one of the major public health threats worldwide. GPIs caused by multidrug resistant bacteria can result in increased morbidity and mortality rates along with escalated treatment cost and hospitalisation stay. In India, GPIs, particularly methicillin-resistant Staphylococcus aureus (MRSA) prevalence among invasive S. aureus isolates, have been reported to increase exponentially from 29% in 2009 to 47% in 2014. Apart from MRSA, rising prevalence of vancomycin-resistant enterococci (VRE), which ranges from 1 to 9% in India, has raised concerns. Moreover, the overall mortality rate among patients with multidrug resistant GPIs in India is reported to be 10.8% and in ICU settings, the mortality rate is as high as 16%. Another challenge is the spectrum of adverse effects related to the safety and tolerability profile of the currently available drugs used against GPIs which further makes the management and treatment of these multidrug resistant organisms a complex task. Judicious prescription of antimicrobial agents, implementation of antibiotic stewardship programmes, and antibiotic policies in hospitals are essential to reduce the problem of drug-resistant infections in India. The most important step is development of newer antimicrobial agents with novel mechanisms of action and favourable pharmacokinetic profile. This review provides a synopsis about the current burden, treatment options, and the challenges faced by the clinicians in the management of GPIs such as MRSA, Quinolone-resistant Staphylococcus, VRE, and drug-resistant pneumococcus in India.

Fatal aspergillosis of the renal vasculature in a combined liver-kidney transplant recipient.

Invasive aspergillosis remains a problem in solid organs and haematopoietic stem cell transplants. We report a case of 12-year-old female with primary hyperoxaluria with regular haemodialysis for the end-stage renal disease. She underwent a combined liver and renal transplantation which got infected by aspergillosis. In this case study, it is speculated that the most likely source of Aspergillus was contaminated preservative solution (perfusate), resulting in infection within the donor kidney and subsequent systemic infection in the recipient. This case study calls for critical analysis and needs for the routine culture of the preservative solution before transplantation, to detect any fungal contamination and manage it prophylactically.

Mycobacterium abscessus causing native valve endocarditis due to peripherally inserted central catheter line.

Infections due to rapidly-growing mycobacteria (RGM) are increasing worldwide, especially in immunocompromised hosts. However, data on the clinical features of patients with RGM bacteremia are limited [1]. Data on the incidence of clinically significant non-tuberculous mycobacteria (NTM) infections from India are scarce as these are frequently under-diagnosed due to either under recognition by clinicians because of the nonspecific nature of their clinical manifestations, and/or the inadequacy of laboratory services [2].We present a case of Mycobacterium abscessus native tricuspid valve endocarditis in a patient who had a peripherally inserted central catheter line (PICC). Clinicians need to be aware of RGM as a cause of prolonged fever in patients who have chronic indwelling intravenous catheters [3].

High degree atrioventricular block with ventricular asystole in a case of dengue fever.

Cardiac rhythm abnormalities have been uncommonly observed in dengue fever and most of them have been reported in children. We discuss a 30-year-old female with dengue fever, who presented with repeated symptomatic episodes of high degree atrioventricular block with ventricular asystole, which responded to intravenous atropine and oral orciprenaline without recurrence on 6 months follow-up.