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.

Candida auris - Comparison of sensititre YeastOne and Vitek 2 AST systems for antifungal susceptibility testing - A single centre experience.

INTRODUCTION: Candida auris is emerging as an important cause of candidemia and deep seated candidal infection. We compared the susceptibility results of bloodstream Candida auris isolates by Vitek 2 with Sensititre YeastOne (SYO) method. METHODS: Forty-seven C. auris blood stream isolates were simultaneously tested for AFST by Vitek 2 and SYO. RESULTS: All strains were resistant to Fluconazole. 25.5% isolates showed pan-azole resistance. In comparison with SYO, lower MICs for voriconazole were noted with Vitek 2 (VME rate 76.1%). All strains were sensitive to anidulafungin and micafungin by SYO. For micafungin, Vitek 2 demonstrated higher MICs and an ME rate of 23.5%. Susceptibility interpretation of caspofungin by SYO was challenged by development of 'Eagle effect' resulting in sensitivity of 28.2%. We studied the evolution of caspofungin 'Eagle effect' with SYO by serial hourly MIC readings and noted that paradoxical growth commenced at 21 hrs of incubation. Compared to SYO, Vitek 2 showed higher resistance rate to Amphotericin B with ME rate of 25.6%. CONCLUSION: Laboratories using commercial AFST systems for Candida auris need to be aware of the possibility of ME and VME for amphotericin B and voriconazole respectively with Vitek 2 and 'Eagle effect' for caspofungin with SYO.

Fecal Microbiota Transplantation for Clostridium difficile-associated Diarrhea in Hematopoietic Stem Cell Transplant Recipients: A Single-center Experience from a Tertiary Center in India.

Objectives: Fecal microbiota transplantation (FMT) is an emerging option for recurrent or refractory Clostridium difficile-associated diarrhea (CDAD). We describe a single-center experience of FMT in hematopoietic stem cell transplant (HSCT) recipients with CDAD in India. Methods: A prospective observational study of HSCT recipients with CDAD who received FMT in our center. Results: A total of 13 patients were included. All the patients were allogenic HSCT recipients; FMT was performed in seven patients due to refractory CDAD, in five patients due to the presence of both CDAD and graft vs host disease (GVHD), and in 1 patient due to recurrent CDAD. The approach to FMT was colonoscopic in 10 (77%) patients. Only one patient reported bacteremia and one patient had candidemia, both of which were unrelated to FMT. Of the 10 patients who had complete resolution of CDAD, only one patient presented with a recurrence of CDAD within 8 weeks post-FMT. Conclusion: This is the first study from India using FMT as a therapeutic modality for CDAD in the setting of HSCT. Here we demonstrate that FMT in India is an effective option, especially when patients have refractory CDAD, recurrent CDAD, or both GVHD and CDAD. Further studies should explore the efficacy and feasibility of FMT in India. How to cite this article: Prayag PS, Patwardhan SA, Ajapuje PS, Melinkeri S, Gadhikar H, Palnitkar S, et al. Fecal Microbiota Transplantation for Clostridium difficile-associated Diarrhea in Hematopoietic Stem Cell Transplant Recipients: A Single-center Experience from a Tertiary Center in India. Indian J Crit Care Med 2024;28(2):106-110.

Ceftazidime-avibactam and aztreonam combination for Carbapenem-resistant Enterobacterales bloodstream infections with presumed Metallo-ß-lactamase production: a systematic review and meta-analysis.

INTRODUCTION: Carbapenem-resistant Enterobacterales (CRE) due to Metallo-ß-lactamase (MBL) production are treated with either polymyxins or the novel combination of ceftazidime-avibactam and aztreonam (AA). This study aims to evaluate the 30-day mortality of AA in patients with BSI caused by MBL-CRE infections. METHODOLOGY: In this systematic review and meta-analysis, all articles up to June 2023 were screened using search terms like 'CRE', 'MBL', 'AA' and 'polymyxins'. The risk ratio for AA vs polymyxins was pooled using a random-effect model, and the results were represented by a point estimate with a 95% confidence interval. RESULTS: After removing the duplicates, the titles and abstracts of 455 articles were screened, followed by a full-text screening of 50 articles. A total of 24 articles were included for systematic review, and four comparative studies were included in the meta-analysis. All four studies had a moderate or serious risk of bias. The pooled risk ratio for 30-day mortality for AA vs. polymyxins was 0.51 (95%CI: 0.34-0.76), p < 0.001. There was no significant heterogeneity. CONCLUSION: The meta-analysis from studies with a high risk of bias shows that AA is associated with lesser 30-day mortality when compared to polymyxins in patients with MBL-producing CRE BSI. Registration with PROSPERO- CRD42023433608.

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.

Enzyme Patterns and Factors Associated with Mortality among Patients with Carbapenem Resistant AcinetobacterBaumannii (CRAB) Bacteremia: Real World Evidence from a Tertiary Center in India.

Introduction: In the Indian setting, antimicrobial resistance in A. baumannii is a considerable problem, especially in intensive care units (ICUs). Due to the limited data, clinicians are left with very few choices except polymyxins for treating serious infections caused by A. baumannii. There is sparse data regarding the local mechanisms of resistance. Given the current therapeutic challenges, it is critical to know the local enzymatic patterns and antibiograms. Materials and methods: A retrospective analysis of 50 episodes of bacteremia caused by CRAB. We analyzed the enzyme patterns and the susceptibility rates to various antibiotics. Results: The resistance rates for amikacin, tigecycline, minocycline, and fluoroquinolones were 88, 82, 50, and 88% respectively. OXA-23 was the most commonly isolated enzyme (86% of the isolates produced OXA-23) followed by OXA-51 and NDM. The overall mortality was high (58%). On univariate analysis, pneumonia, and higher Pitt's bacteremia score were significantly associated with mortality (p = 0.04 and p = 0.001 respectively). Of the total patients who received combination therapy, a majority (58%) received polymyxin plus meropenem. Combination therapy using polymyxins as a backbone was not associated with reduced mortality (p = 0.1). Conclusion: A. baumannii is associated with significant morbidity and mortality, as shown in our study. The rates of resistance for aminoglycosides were very high, and minocycline showed better susceptibility rates in comparison with tigecycline. In our study, OXA-23 and NDM remained the most important enzymes. The routine use of the combination of polymyxin and meropenem may not offer a significant advantage over monotherapy. How to cite this article: Prayag PS, Patwardhan SA, Joshi RS, Panchakshari SP, Rane T, Prayag AP. Enzyme Patterns and Factors Associated with Mortality among Patients with Carbapenem Resistant Acinetobacter Baumannii (CRAB) Bacteremia: Real World Evidence from a Tertiary Center in India. Indian J Crit Care Med 2023;27(9):663-668.

Therapeutic Drug Monitoring of Isavuconazole: Lessons Learnt from a Real-life Setting in a Tertiary Care Center in India.

Introduction: Isavuconazole is an emerging therapeutic option for invasive infections caused by molds, especially aspergillosis and mucormycosis. Isavuconazole has predictable pharmacokinetics and good bioavailability. These attributes have led to some doubts regarding the need for therapeutic drug monitoring (TDM). There are no data from India regarding TDM for isavuconazole. Methods: A retrospective analysis of 50 patients who received oral isavuconazole for therapeutic purposes. Plasma isavuconazole levels were measured using a reversed phase high-performance liquid chromatography (HPLC) and UV detector with acetonitrile (ACN) as protein precipitating solvent. Results: Of the 50 cases, 5 (10.0%) patients had subtherapeutic levels, while 45 (90.0%) had therapeutic levels. Higher body weight and solid organ transplantation (SOT) were significantly associated with subtherapeutic levels of isavuconazole (p-value < 0.05 for all). Receipt of a SOT was the only independent and statistically significant factor which was associated with subtherapeutic levels of isavuconazole (p-value < 0.05). Conclusion: Our study reemphasizes the need of TDM for isavuconazole and adds to the growing evidence for the need to obtain drug levels. Factors associated with subtherapeutic levels of isavuconazole need to be assessed in larger studies to help identify those patients who are at risk of having subtherapeutic drug levels. How to cite this article: Prayag PS, Soman RN, Panchakshari SP, Ajapuje PS, Mahale NP, Dhupad S, et al. Therapeutic Drug Monitoring of Isavuconazole: Lessons Learnt from a Real-life Setting in a Tertiary Care Center in India. Indian J Crit Care Med 2023;27(4):260-264.

Author Reply: Therapeutic Drug Monitoring of Isavuconazole: Lessons Learnt from a Real-life Setting in a Tertiary Care Center in India.

How to cite this article: Prayag PS. Author Reply: Therapeutic Drug Monitoring of Isavuconazole: Lessons Learnt from a Real-life Setting in a Tertiary Care Center in India. Indian J Crit Care Med 2023;27(6):451.

Ceftazidime-avibactam with or without Aztreonam vs Polymyxin-based Combination Therapy for Carbapenem-resistant Enterobacteriaceae: A Retrospective Analysis.

Introduction: Gram-negative sepsis remains one of the most difficult to treat infections in intensive care units (ICUs). Carbapenems are often considered to be robust and reliable options for treating infections due to Gram-negative bacteria. The dominance of carbapenem-resistant enterobacteriaceae (CRE) has emerged as one of the greatest challenges faced by the medical community today. Carbapenem-resistant enterobacteriaceae may be resistant to all beta lactam antimicrobials including carbapenems and often, are even resistant to other classes of drugs. There are limited studies comparing polymyxin-based therapies with ceftazidime-avibactam (CAZ-AVI)-based therapies for treating infections caused by CRE. Methods: A retrospective study comparing outcomes between patients with bacteremia caused by CRE treated with polymyxin-based combination therapy and CAZ-AVI-based therapy (with or without aztreonam). Results: Of total 104 patients, 78 (75%) were in the CAZ-AVI group. There was no significant difference in the underlying comorbidities between the two groups. The incidence of nephrotoxicity was significantly higher in the polymyxin group (p = 0.017). Ceftazidime-avibactam-based therapy was 66% less likely to be associated with day 14 mortality (p = 0.048) and 67% less likely to be associated with day 28 mortality (p = 0.039) as compared with polymyxin-based therapy. Conclusion: Ceftazidime-avibactam-based therapy may be a superior option to polymyxin-based therapy for infections caused by CRE. This can have significant practical applications, in terms of optimizing therapy for the individual patient as well as sparing polymyxins and reducing the use of polymyxins in our hospitals. How to cite this article: Prayag PS, Patwardhan SA, Panchakshari S, Sambasivam R, Dhupad S, Soman RN, et al. Ceftazidime-avibactam with or without Aztreonam vs Polymyxin-based Combination Therapy for Carbapenem-resistant Enterobacteriaceae: A Retrospective Analysis. Indian J Crit Care Med 2023;27(6):444-450.

Factors associated with subtherapeutic levels of oral posaconazole tablet: a detailed analysis from a tertiary care center in India.

OBJECTIVES: Posaconazole is a broad-spectrum triazole antifungal, with activity against various clinically important fungi. The delayed release (DR) tablet of posaconazole has been shown to have a superior pharmacokinetic profile in comparison with the oral suspension. METHODS: We retrospectively analyzed the factors associated with posaconazole levels <1.25 µg/ml in 164 patients receiving the DR tablet for therapeutic purposes. RESULTS: Of the 164 patients, 53 (32.3%) showed subtherapeutic trough levels of posaconazole. The use of proton pump inhibitors (95% CI 1.41-3.91; P-value = 0.028) and the presence of diarrhea (95% CI 1.95-6.93; P-value = 0.001) were significantly associated with subtherapeutic levels. A total of 13 of the 21 patients receiving posaconazole tablets through a nasogastric tube had therapeutic levels. CONCLUSION: This is the largest study from India that analyzed factors associated with subtherapeutic levels of the DR tablet of posaconazole. These findings reinforce the importance of therapeutic drug monitoring. Unlike in previous studies, obesity and hypoalbuminemia were not found to be significant factors in our settings. The use of proton pump inhibitors and diarrhea remained significant factors, as found in previous studies. Administering the DR tablet of posaconazole through a nasogastric tube may be a viable option.

The Dominance of Candida auris: A Single-center Experience of 79 Episodes of Candidemia from Western India.

Introduction: Invasive candidiasis is a serious infection seen in hospitalized or immunocompromised patients. Mortality rates for candidemia can be as high as 30-60%. Candida auris is an emerging species of Candida and is increasingly becoming a global public health problem. Methods: This was a retrospective observational study, in which we analyzed 79 episodes of candidemia. Blood cultures were done using the Bactec™ FX blood culturing instrument (Becton, Dickinson and Company Sparks, Maryland, USA). Species identification was done using VITEK® 2 YST panels (bioMérieux Inc., Durham, North Carolina, USA). Antifungal susceptibility testing was performed using VITEK® 2 AST-YSO8 panels (bioMérieux Inc., Durham, North Carolina, USA). Results: Among the 79 episodes, the most common species was found to be C. auris (43.03% of all the episodes). Candida tropicalis was found to be the second most common species in patients admitted to our hospital with candidemia. All the isolates of C. auris were resistant to fluconazole, while 32.35 % of the isolates were also resistant to amphotericin B. Crude mortality in patients with C. auris candidemia was higher than the crude mortality for the other species. Conclusion: This is the first study from India where C. auris was seen as the most predominant species among patients admitted with candidemia. This is a serious issue given the high rates of fluconazole resistance, mortality, and cost of therapy associated with C. auris bloodstream infections. Urgent attention needs to be diverted to infection control practices and antimicrobial stewardship programs. How to cite this article: Prayag PS, Patwardhan S, Panchakshari S, Rajhans PA, Prayag A. The Dominance of Candida auris: A Single-center Experience of 79 Episodes of Candidemia from Western India. Indian J Crit Care Med 2022;26(5):560-563.

COVID-19 Associated Vertebral Osteomyelitis Caused by Aspergillus Species-A Case Series.

Coronavirus Disease (COVID-19) associated fungal infections including pulmonary aspergillosis, mucormycosis and other invasive fungal infections have been increasingly described in the current pandemic. Aspergillus osteomyelitis is a rare clinical form of aspergillosis. Most cases of Aspergillus osteomyelitis are reported in immunocompromised patients. We describe four cases of vertebral osteomyelitis caused by Aspergillus species in the post COVID-19 setting. To the best of our knowledge, Aspergillus vertebral osteomyelitis has not been described in the post COVID-19 setting. None of the four patients described in this series were immunocompromised and all of them had received steroids during their hospitalization for COVID-19 pneumonitis. Vertebral osteomyelitis caused by Aspergillus species is a rare clinical manifestation of Aspergillosis. It requires a high index of suspicion and prompt efforts to establish a diagnosis. For a clinician involved in assessing a patient with Spondylodiscitis, the work up must not be limited to testing for Tuberculosis. Every attempt must be made to establish the microbiological diagnosis. Combined medical and surgical management is generally needed for Aspergillus osteomyelitis.

Rhino-Orbito-Cerebral Mycosis and COVID-19: From Bad to Worse?

Background: There has been an increase an alarming rise in invasive mycoses during COVID-19 pandemic, especially during the second wave. Aims: Compare the incidence of invasive mycoses in the last three years and study the risk factors, manifestations and outcomes of mycoses in the COVID era. Methodology: Multicentric study was conducted across 21 centres in a state of western India over 12-months. The clinico-radiological, laboratory and microbiological features, treatment and outcomes of patients were studied. We also analysed yearly incidence of rhino-orbito-cerebral mycosis. Results: There was more than five-times rise in the incidence of invasive mycoses compared to previous two-years. Of the 122 patients analysed, mucor, aspergillus and dual infection were seen in 86.9%, 4.1%, and 7.4% respectively. Fifty-nine percent had simultaneous mycosis and COVID-19 while rest had sequential infection. Common presenting features were headache (91%), facial pain (78.7%), diplopia (66.4%) and vison loss (56.6%). Rhino-orbito-sinusitis was present in 96.7%, meningitis in 6.6%, intracranial mass lesions in 15.6% and strokes in 14.8%. A total of 91.8% patients were diabetic, while 90.2% were treated with steroids during COVID-19 treatment. Mortality was 34.4%. Conclusion: Invasive fungal infections having high mortality and morbidity have increased burden on already overburdened healthcare system. Past illnesses, COVID-19 itself and its treatment and environmental factors seem responsible for the rise of fungal infection. Awareness and preventive strategies are the need of hours and larger studies are needed for better understanding of this deadly disease.

Preparedness of Acute Care Facility and a Hospital for COVID-19 Pandemic: What We Did!

BACKGROUND AND AIM: India is facing the pandemic of coronavirus disease (COVID-19) just like the whole world. The private sector is the backbone of a healthcare facility in India. Presently, only a few major hospitals in the country are actively dealing with the COVID-19 patients while others are facing troubles due to lack of manpower, management, and required experience to face the pandemic. Despite the lockdown, the cases are ever increasing and each and every hospital in the country should be prepared to face this pandemic the world has never seen before. As one of the largest multispecialty hospitals and a designated COVID center, we have developed and adopted some strategies for better preparedness to face the surge of this pandemic. We would like to share our experience and hope that the strategies laid down and adopted by us will help many other acute care facilities in many parts of India. MATERIALS AND METHODS: Different strategies are adopted to deal with the crisis situation of the COVID-19 pandemic. Our adopted strategies were directed to mitigate the challenges of administration, hospital space organization, management of staff and supplies, maintenance of standard of care, and specific COVID care and ethics during this pandemic. RESULTS: Based on strategies adopted by us, we feel more confident and prepared to deal with COVID-19 pandemic. CONCLUSION: Our approach for preparing for the COVID-19 pandemic may not be the best one but we believe that the basic managerial principles we adopted will guide many other institutions to find their path in tackling the pandemic in the best possible way. HOW TO CITE THIS ARTICLE: Jog S, Kelkar D, Bhat M, Patwardhan S, Godavarthy P, Dhundi U, et al. Preparedness of Acute Care Facility and a Hospital for COVID-19 Pandemic: What We Did! Indian J Crit Care Med 2020;24(6):385-392.

A Retrospective Observational Study of Hypoxic COVID-19 Patients Treated with Immunomodulatory Drugs in a Tertiary Care Hospital.

OBJECTIVES: To describe the demographics and evaluate the clinical outcomes of hypoxic coronavirus disease-2019 (COVID-19) patients treated with different immunomodulatory (IM) drugs in a resource-limited setting. MATERIALS AND METHODS: We conducted a retrospective cohort study of these patients admitted to our hospital between March 22 and May 31, 2020. Data were abstracted from multiple electronic data sources or patient charts to provide information on patient characteristics, clinical, laboratory variables, and outcomes. RESULTS: A total of 134 patients met the inclusion criteria and were followed up till June 7, 2020. The median age of the patients was 55.6 years (range 20-89 years) and 68% were men. At least one comorbidity was seen in 72% of the patients with diabetes (44%) and hypertension (46%) being the most common. At triage, fever (82%), shortness of breath (77%), and cough (61%) were the most common presenting symptoms. A PaO2/FiO2 ratio less than 300 was seen in 60%, and 4.5% required invasive mechanical ventilation within 72 hours of hospital admission. Five immunomodulatory agents (hydroxychloroquine, methylprednisolone, colchicine, etoricoxib, and tocilizumab) were administered in different combinations. Overall, in-hospital mortality was 26.9%, and 32% required mechanical ventilation. Around 69% of patients were discharged home. Five variables (SpO2, PaO2/FiO2 ratio, leucocytosis, lymphopenia, and creatinine) on admission were found to be significant in the patients who died. CONCLUSION: Our study provides the characteristics and outcomes of hypoxic COVID-19 patients treated with IM drugs in varied combination. Five independent variables were strong predictors of mortality. HOW TO CITE THIS ARTICLE: Mahale N, Rajhans P, Godavarthy P, Narasimhan VL, Oak G, Marreddy S, et al. A Retrospective Observational Study of Hypoxic COVID-19 Patients Treated with Immunomodulatory Drugs in a Tertiary Care Hospital. Indian J Crit Care Med 2020;24(11):1020-1027.