Regional variations in antimicrobial susceptibility of community-acquired uropathogenic Escherichia coli in India: Findings of a multicentric study highlighting the importance of local antibiograms.

Objectives: Evidence-based prescribing is essential to optimize patient outcomes in cystitis. This requires knowledge of local antibiotic resistance rates. Diagnostic and Antimicrobial Stewardship (DASH) to Protect Antibiotics (https://dashuti.com/) is a multicentric mentorship program guiding centers in preparing, analyzing and disseminating local antibiograms to promote antimicrobial stewardship in community urinary tract infection. Here, we mapped the susceptibility profile of Escherichia coli from 22 Indian centers. Methods: These centers spanned 10 Indian states and three union territories. Antibiograms for urinary E. coli from the outpatient departments were collated. Standardization was achieved by regional online training; anomalies were resolved via consultation with study experts. Data were collated and analyzed. Results: Nationally, fosfomycin, with 94% susceptibility (inter-center range 83-97%), and nitrofurantoin, with 85% susceptibility (61-97%), retained the widest activity. The susceptibility rates were lower for co-trimoxazole (49%), fluoroquinolones (31%), and oral cephalosporins (26%). The rates for third- and fourth-generation cephalosporins were 46% and 52%, respectively, with 54% (33-58%) extended-spectrum ß-lactamase prevalence. Piperacillin-tazobactam (81%), amikacin (88%), and meropenem (88%) retained better activity; however, one center in Delhi recorded only 42% meropenem susceptibility. Susceptibility rates were mostly higher in South, West, and Northeast India; centers in the heavily populated Gangetic plains, across north and northwest India, had greater resistance. These findings highlight the importance of local antibiograms in guiding appropriate antimicrobial choices. Conclusions: Fosfomycin and nitrofurantoin are the preferred oral empirical choices for uncomplicated E. coli cystitis in India, although elevated resistance in some areas is concerning. Empiric use of fluoroquinolones and third-generation cephalosporins is discouraged, whereas piperacillin/tazobactam and aminoglycosides remain carbapenem-sparing parenteral agents.

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.

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.

Successful treatment of sino-pulmonary infection & skull base osteomyelitis caused by New Delhi metallo-ß-lactamase-producing Pseudomonas aeruginosa in a renal transplant recipient by using an investigational antibiotic cefepime/zidebactam (WCK 5222).

A case of sino-pulmonary infection with skull base osteomyelitis due to XDR-Pseudomonas aeruginosa in renal transplant recipient was successfully treated with investigational antibiotic, cefepime/zidebactam (WCK 5222). This case highlights challenges in managing XDR-pseudomonal infection where source control was infeasible, antibiotic options were extremely limited and individualized dose adjustments were needed.

Global guideline for the diagnosis and management of cryptococcosis: an initiative of the ECMM and ISHAM in cooperation with the ASM.

Cryptococcosis is a major worldwide disseminated invasive fungal infection. Cryptococcosis, particularly in its most lethal manifestation of cryptococcal meningitis, accounts for substantial mortality and morbidity. The breadth of the clinical cryptococcosis syndromes, the different patient types at-risk and affected, and the vastly disparate resource settings where clinicians practice pose a complex array of challenges. Expert contributors from diverse regions of the world have collated data, reviewed the evidence, and provided insightful guideline recommendations for health practitioners across the globe. This guideline offers updated practical guidance and implementable recommendations on the clinical approaches, screening, diagnosis, management, and follow-up care of a patient with cryptococcosis and serves as a comprehensive synthesis of current evidence on cryptococcosis. This Review seeks to facilitate optimal clinical decision making on cryptococcosis and addresses the myriad of clinical complications by incorporating data from historical and contemporary clinical trials. This guideline is grounded on a set of core management principles, while acknowledging the practical challenges of antifungal access and resource limitations faced by many clinicians and patients. More than 70 societies internationally have endorsed the content, structure, evidence, recommendation, and pragmatic wisdom of this global cryptococcosis guideline to inform clinicians about the past, present, and future of care for a patient with cryptococcosis.

Revised ISHAM-ABPA working group clinical practice guidelines for diagnosing, classifying and treating allergic bronchopulmonary aspergillosis/mycoses.

BACKGROUND: The International Society for Human and Animal Mycology (ISHAM) working group proposed recommendations for managing allergic bronchopulmonary aspergillosis (ABPA) a decade ago. There is a need to update these recommendations due to advances in diagnostics and therapeutics. METHODS: An international expert group was convened to develop guidelines for managing ABPA (caused by Aspergillus spp.) and allergic bronchopulmonary mycosis (ABPM; caused by fungi other than Aspergillus spp.) in adults and children using a modified Delphi method (two online rounds and one in-person meeting). We defined consensus as ≥70% agreement or disagreement. The terms "recommend" and "suggest" are used when the consensus was ≥70% and <70%, respectively. RESULTS: We recommend screening for A. fumigatus sensitisation using fungus-specific IgE in all newly diagnosed asthmatic adults at tertiary care but only difficult-to-treat asthmatic children. We recommend diagnosing ABPA in those with predisposing conditions or compatible clinico-radiological presentation, with a mandatory demonstration of fungal sensitisation and serum total IgE ≥500 IU·mL-1 and two of the following: fungal-specific IgG, peripheral blood eosinophilia or suggestive imaging. ABPM is considered in those with an ABPA-like presentation but normal A. fumigatus-IgE. Additionally, diagnosing ABPM requires repeated growth of the causative fungus from sputum. We do not routinely recommend treating asymptomatic ABPA patients. We recommend oral prednisolone or itraconazole monotherapy for treating acute ABPA (newly diagnosed or exacerbation), with prednisolone and itraconazole combination only for treating recurrent ABPA exacerbations. We have devised an objective multidimensional criterion to assess treatment response. CONCLUSION: We have framed consensus guidelines for diagnosing, classifying and treating ABPA/M for patient care and research.

Overcoming clinical challenges in the management of invasive fungal infections in low- and middle-income countries (LMIC).

INTRODUCTION: The management of invasive fungal infections (IFIs) in low- and middle-income countries (LMIC) is a serious challenge due to limited epidemiology studies, sub-optimal laboratory facilities, gap in antifungal management training and resources. Limited studies highlighted distinctive epidemiology of IFIs in those countries, and difficulty in distinguishing from closely related infections. To overcome the gaps for appropriate management of IFIs, innovative approaches are required. AREAS COVERED: Extensive literature search and discussion with experts have helped us to summarize the epidemiology, diagnostic and management difficulties in managing IFIs in LMIC, and recommend certain solutions to overcome the challenges. EXPERT OPINION: The strategies to overcome the challenges in diagnosis may include local epidemiology study, training of healthcare workers, association of fungal infections with already existing budgeted national programs, development and incorporation of point-of-care test (POCT) for prompt diagnosis, simplifying clinical diagnostic criteria suitable for LMIC, judicious use of available expertise, and diagnostic stewardship. For management strategies judicious use of antifungal, partnering with industry for inexpensive antifungal agents, development of LMIC specific guidelines for cost-effective management of IFIs and fungal outbreaks, improvement of infection control practices, advocacy for implementation of WHO recommended antifungal use, and integration of IFIs with public health.

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.

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.

South Asian Transplant Infectious Disease Guidelines for Solid Organ Transplant Candidates, Recipients, and Donors.

These guidelines discuss the epidemiology, screening, diagnosis, posttransplant prophylaxis, monitoring, and management of endemic infections in solid organ transplant (SOT) candidates, recipients, and donors in South Asia. The guidelines also provide recommendations for SOT recipients traveling to this region. These guidelines are based on literature review and expert opinion by transplant physicians, surgeons, and infectious diseases specialists, mostly from South Asian countries (India, Pakistan, Bangladesh, Nepal, and Sri Lanka) as well as transplant experts from other countries. These guidelines cover relevant endemic bacterial infections (tuberculosis, leptospirosis, melioidosis, typhoid, scrub typhus), viral infections (hepatitis A, B, C, D, and E; rabies; and the arboviruses including dengue, chikungunya, Zika, Japanese encephalitis), endemic fungal infections (mucormycosis, histoplasmosis, talaromycosis, sporotrichosis), and endemic parasitic infections (malaria, leishmaniasis, toxoplasmosis, cryptosporidiosis, strongyloidiasis, and filariasis) as well as travelers' diarrhea and vaccination for SOT candidates and recipients including travelers visiting this region. These guidelines are intended to be an overview of each topic; more detailed reviews are being published as a special supplement in the Indian Journal of Transplantation .

The mystery behind a 1000 day fever in a young male.

This case is of a 23 year old diabetic male who presented with fever and splenic lesions. He continued to have fever off and on over the next 3 years despite empirical antibiotics and anti-tubercular therapy. No definitive diagnosis could be made despite exhaustive investigations. Finally, a splenectomy resulted in sustained defervescence. The splenic histopathology showed caseating granulomas but aerobic cultures, Xpert MTB/Rif ULTRA, TB and fungal cultures were negative. A final diagnosis of splenic melioidosis was made based on the clinical features, radiology, histopathology, literature review and absence of an alternative diagnosis.

Posaconazole or isavuconazole as sole or predominant antifungal therapy for COVID-19-associated mucormycosis. A retrospective observational case series.

The surge of COVID-19 associated Mucormycosis (CAM) in India during the second wave of COVID-19 led to lack of availability of amphotericin B(AmB). We retrospectively evaluated the outcome in 28 consecutive patients with CAM who received posaconazole (PCZ) or isavuconazole (ISVCZ) as sole or predominant therapy, based on factors like availability, affordability, site of infection or lack of treatment response. Therapeutic drug monitoring was used for PCZ in all cases & for ISVCZ in some cases. Higher trough levels were aimed to ensure therapeutic effect. Overall, 16 patients were cured, 5 patients improved, 6 patients died, of which 2 deaths were attributable to mucormycosis and 1 patient was lost to follow-up. The outcomes and survival were comparable to those reported in the literature. Although wider applicability of these results cannot be assumed, it leads to a speculation that treatment of mucormycosis with PCZ or ISVCZ, without AmB, is possible.

Definition, diagnosis, and management of COVID-19-associated pulmonary mucormycosis: Delphi consensus statement from the Fungal Infection Study Forum and Academy of Pulmonary Sciences, India.

COVID-19-associated pulmonary mucormycosis (CAPM) remains an underdiagnosed entity. Using a modified Delphi method, we have formulated a consensus statement for the diagnosis and management of CAPM. We selected 26 experts from various disciplines who are involved in managing CAPM. Three rounds of the Delphi process were held to reach consensus (≥70% agreement or disagreement) or dissensus. A consensus was achieved for 84 of the 89 statements. Pulmonary mucormycosis occurring within 3 months of COVID-19 diagnosis was labelled CAPM and classified further as proven, probable, and possible. We recommend flexible bronchoscopy to enable early diagnosis. The experts proposed definitions to categorise dual infections with aspergillosis and mucormycosis in patients with COVID-19. We recommend liposomal amphotericin B (5 mg/kg per day) and early surgery as central to the management of mucormycosis in patients with COVID-19. We recommend response assessment at 4-6 weeks using clinical and imaging parameters. Posaconazole or isavuconazole was recommended as maintenance therapy following initial response, but no consensus was reached for the duration of treatment. In patients with stable or progressive disease, the experts recommended salvage therapy with posaconazole or isavuconazole. CAPM is a rare but under-reported complication of COVID-19. Although we have proposed recommendations for defining, diagnosing, and managing CAPM, more extensive research is required.

Assessment of In-Vitro Synergy of Fosfomycin with Meropenem, Amikacin and Tigecycline in Whole Genome Sequenced Extended and Pan Drug Resistant Klebsiella Pneumoniae: Exploring A Colistin Sparing Protocol.

Fosfomycin has emerged as a very useful antimicrobial in management of extremely drug resistant (XDR) and pan drug resistant (PDR) Klebsiella pneumoniae. In this study, we assessed in-vitro synergy of colistin sparing combinations of fosfomycin (FOS) with meropenem (MEM), tigecycline (TGC) and amikacin (AK) against XDR and PDR Klebsiella pneumoniae. METHOD: Non-replicate fully characterised 18 clinical isolates of K. pneumoniae (15 XDR and 3 PDR strains) were subjected to in-vitro synergy testing by checkerboard and time kill assay. Combinations tested were FOS-MEM, FOS-TGC and FOS-AK with glucose-6-phosphate being incorporated in all runs.WGS was carried out on the Illumina next-generation sequencing platform. RESULTS: FOS-MEM and FOS-AK both demonstrated excellent synergy against all PDRs and all but one XDR. Synergy led to lowering of MICs to susceptible breakpoints. FOS-TGC demonstrated antagonism. MLST-231 K. pneumoniae predominated (14), followed by ST-395 (3) and ST147 (1). Majority harboured OXA-232 (n = 15), while n = 2 carried NDM-1 type and n = 1 co-carried NDM-5 + OXA-232. Mortality was high in both ST-231 (57.1%) and ST-395 (66.6%). Synergy was observed despite widespread presence of resistance markers against aminoglycosides [aph(3')-Ic, aacA4, and rmtf], beta-lactams [blaSHV-11, blaTEM-1b, blaCTX-M-15, and blaOXA-232], fosfomycin [fosA6 and fosA5] and presence of porin proteins OmpK37, OmpA and K. pneumoniae antibiotic efflux pumps Kpn F, H, G, and E. CONCLUSION: FOS + MEM and FOS + AK are excellent colistin sparing combinations against ST 231, ST-395 and ST-147 XDR and PDR K. pneumoniae. FOS with fewer side effects than colistin, excellent tissue distribution and minimal side effects may be recommended in combination with meropenem.

Salvaging lives in carbapenem-resistant Gram-negative osteoarticular and soft tissue infections: early compromises save lives.

PURPOSE: Incidence of carbapenem-resistant Gram-negative infections has risen alarmingly all across the globe, both in developed and developing countries alike. The purpose of this study was to assess whether challenges of life-threatening infections with very high resistance pattern can be successfully addressed by a modified approach. METHODS: This is a retrospective study of 26 patients with osteoarticular and soft tissue infections with carbapenem-resistant Gram-negative bacilli treated between 2001 and 2017 with at least two year follow-up after stopping antibiotics. All were treated by a multispecialty team approach with primary aim of "source control at the earliest and avoiding recurrence at all cost". The protocol involved opting for early compromises especially in at "risk individuals", such as resorting to early amputations, especially if salvage meant multiple bony and soft tissue reconstructive procedures, explanation of prosthesis than staged revision, avoiding internal fixations, opting for shortest possible time in external fixators with reshaping and telescoping bone ends to get bony stability and increase surface area even if it meant compromising length. RESULTS: There were five amputations, two excision arthroplasty of hip, many minor but acceptable malunions and shortening. However, lives of 24/26 patients could be salvaged, much better than most of the published data. The two patients who died had peri-prosthetic joint infection after total hip arthroplasty and presented very late in sepsis and died within days of explantation. Infection remission could be achieved in remaining patients. CONCLUSION: These "risk to life" cases can be successfully treated by lowering the aims and expectations from "excellent function to salvage of life and infection remission". Therein lies the "success" in these complex high-risk cases.

"Locking in" a rare pathogen.

Since its identification as a unique species in 1982, Escherichia hermannii has only recently been implicated as a pathogenic organism in human diseases. Literature search indicates removal of hemodialysis catheter as being essential to the success of treatment for bacteremia with this organism. However, having no alternative access for hemodialysis led to the attempt to salvage the catheter with the use of Antibiotic lock therapy. This case highlights Antibiotic lock therapy as an indication in Escherichia hermanii Catheter related Bloodstream infection.

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.