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.

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.

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.

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.

Impact of FKS1 Genotype on Echinocandin In Vitro Susceptibility in Candida auris and In Vivo Response in a Murine Model of Infection.

Echinocandins are frontline antifungal agents in the management of invasive infections due to multidrug resistant Candida auris. The study aimed to evaluate echinocandin resistance in C. auris isolates of multicentric origin, identify the resistance mechanism, and analyze the pharmacodynamic response to caspofungin in a neutropenic mouse model of infection. A total of 199 C. auris isolates originating from 30 centers across India were tested for susceptibility to echinocandins. Isolates with reduced susceptibility were evaluated for FKS1 mutations and in vivo response to caspofungin in a murine model of disseminated candidiasis. In addition, the response to echinocandins was assessed in light of in vitro growth kinetics, chitin content; and transcript levels of chitin synthase and FKS1 genes. We report 10 resistant C. auris isolates with four FKS1 mutations: F635Y (n = 2), F635L (n = 4), S639F (n = 3), and R1354S (n = 1). Of these, F635Y and R1354S exhibited the most profound resistance in mouse model of disseminated infection. S639F and F635L mutations conferred a moderate in vivo resistance, whereas wild-type isolates exhibiting borderline MIC were susceptible in vivo. FKS1 genotype was more accurate predictor of in vivo response than the MIC of the isolates. Isolates with high basal or inducible chitin content exhibited higher in vitro MIC in FKS1 mutant compared to wild type. FKS1 mutations play a major role in clinically relevant echinocandin resistance in C. auris with differential in vivo outcomes. This study could have implications for clinical practice and, therefore, warrants further studies.

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.

Is it time to move away from polymyxins?: evidence and alternatives.

Increasing burden of carbapenem resistance and resultant difficult-to-treat infections are of particular concern due to the lack of effective and safe treatment options. More recently, several new agents with activity against certain multidrug-resistant (MDR) and extensive drug-resistant (XDR) Gram-negative pathogens have been approved for clinical use. These include ceftazidime-avibactam, meropenem-vaborbactam, imipenem-cilastatin-relebactam, plazomicin, and cefiderocol. For the management of MBL infections, clinically used triple combination comprising ceftazidime-avibactam and aztreonam is hindered due to non-availability of antimicrobial susceptibility testing methods and lack of information on potential drug-drug interaction leading to PK changes impacting its safety and efficacy. Moreover, in several countries including Indian subcontinent and developing countries, these new agents are yet to be made available. Under these circumstances, polymyxins are the only last resort for the treatment of carbapenem-resistant infections. With the recent evidence of suboptimal PK/PD particularly in lung environment, limited efficacy and increased nephrotoxicity associated with polymyxin use, the Clinical and Laboratory Standards Institute (CLSI) has revised both colistin and polymyxin B breakpoints. Thus, polymyxins 'intermediate' breakpoint for Enterobacterales, P. aeruginosa, and Acinetobacter spp. are now set at ≤ 2 mg/L, implying limited clinical efficacy even for isolates with the MIC value 2 mg/L. This change has questioned the dependency on polymyxins in treating XDR infections. In this context, recently approved cefiderocol and phase 3 stage combination drug cefepime-zidebactam assume greater significance due to their potential to act as polymyxin-supplanting therapies.

Activity of cefepime/zidebactam against MDR Escherichia coli isolates harbouring a novel mechanism of resistance based on four-amino-acid inserts in PBP3.

BACKGROUND: Recent reports reveal the emergence of Escherichia coli isolates harbouring a novel resistance mechanism based on four-amino-acid inserts in PBP3. These organisms concomitantly expressed ESBLs or/and serine-/metallo-carbapenemases and were phenotypically detected by elevated aztreonam/avibactam MICs. OBJECTIVES: The in vitro activities of the investigational antibiotic cefepime/zidebactam and approved antibiotics (ceftazidime/avibactam, ceftolozane/tazobactam, imipenem/relebactam and others) were determined against E. coli isolates harbouring four-amino-acid inserts in PBP3. METHODS: Whole-genome sequenced E. coli isolates (n = 89) collected from a large tertiary care hospital in Southern India (n = 64) and from 12 tertiary care hospitals located across India (n = 25) during 2016-18, showing aztreonam/avibactam MICs ≥1 mg/L (≥4 times the aztreonam epidemiological cut-off) were included in this study. The MICs of antibiotics were determined using the reference broth microdilution method. RESULTS: Four-amino-acid inserts [YRIK (n = 30) and YRIN (n = 53)] were found in 83/89 isolates. Among 83 isolates, 65 carried carbapenemase genes [blaNDM (n = 39), blaOXA-48-like (n = 11) and blaNDM + blaOXA-48-like (n = 15)] and 18 isolates produced ESBLs/class C ß-lactamases only. At least 16 unique STs were noted. Cefepime/zidebactam demonstrated potent activity, with all isolates inhibited at ≤1 mg/L. Comparator antibiotics including ceftazidime/avibactam and imipenem/relebactam showed limited activities. CONCLUSIONS: E. coli isolates concurrently harbouring four-amino-acid inserts in PBP3 and NDM are an emerging therapeutic challenge. Assisted by the PBP2-binding action of zidebactam, the cefepime/zidebactam combination overcomes both target modification (PBP3 insert)- and carbapenemase (NDM)-mediated resistance mechanisms in E. coli.

Bacteremia due to Streptococcus gallolyticus: A Name with an Ominous Significance?

Streptococcus bovis is an underrecognized agent of systemic infections. It underwent reclassification into different subtypes and is currently termed as Streptococcus gallolyticus. Bacteremia due to S. gallolyticus has been traditionally associated with colon cancer or hepatobiliary disease and can result in endocarditis. Detection of S. gallolyticus in blood cultures prompts a thorough clinical evaluation in order to clarify the source of the bloodstream infection and the presence of complications. Subspeciation is crucial to understand the disease association, which is now possible with the use of phenotypic detection methods, such as, Vitek 2. The retrospective study by Niyas et al. serves to call attention to this organism and optimal approach to management. How to cite this article: Soman R, Eashwernath R. Bacteremia due to Streptococcus gallolyticus: A Name with an Ominous Significance? Indian J Crit Care Med 2020;24(10):901-902.

Trichosporon-Blood Stream Infection.

AIM: Trichosporon species are the major emerging opportunistic pathogen in immunocompromised patients. Its diverse refractoriness to conventional antifungal drugs and association with high mortality rate is worrisome. The present study aims to determine the risk factors, treatment outcome and antifungal susceptibility pattern of Trichosporon species in blood stream infections. MATERIAL AND METHODS: All patients with blood culture positive for Trichosporon species from January 2012 to August 2016 at PD Hinduja National Hospital and research centre were evaluated retrospectively. Species identification and antifungal susceptibility by broth microdilution method for various drugs was determined using Vitek2 compact automated system. RESULTS: 12 patients were found to have Trichosporon blood stream infection. 9 isolates that were speciated all were T. asahii. All patients had central venous catheter and received prior antibiotics. Overall mortality rate was 50%. CONCLUSION: Higher mortality was associated with central venous catheter and voriconazole should be used as drug of choice for treatment. Identification of Trichosporon species along with its sensitivity and proper treatment of patients is of utmost importance.

Indian Antimicrobial Prescription Guidelines in Critically Ill Immunocompromised Patients.

How to cite this article: Kulkarni AP, Sengar M, Chinnaswamy G, Hegde A, Rodrigues C, Soman R, Khilnani GC, Ramasubban S, Desai M, Pandit R, Khasne R, Shetty A, Gilada T, Bhosale S, Kothekar A, Dixit S, Zirpe K, Mehta Y, Pulinilkunnathil JG, Bhagat V, Khan MS, Narkhede AM, Baliga N, Ammapalli S, Bamne S, Turkar S, Bhat KV, Choudhary J, Kumar R, Divatia JV. Indian Journal of Critical Care Medicine 2019;23(Suppl 1): S64-S96.

Paradoxical Response in Cerebral Nocardiosis in a Renal Transplant Recipient.

Paradoxical response (PR) in patients on anti-tuberculosis drugs and immune reconstitution inflammatory syndrome (IRIS) in patients started on antiretroviral therapy are well known phenomenon. We encountered a case of a paradoxical response in cerebral nocardiosis in a renal transplant recipient. To our knowledge this phenomenon in cerebral nocardiosis has not been reported earlier in literature.

Implications for Diagnosis and Treatment of Infective Endocarditis: Eight year Experience of an Infectious Disease Team in a Private Tertiary Care Centre.

Background: The profile of Infective endocarditis (IE) has been evolving continuously. Like other infectious Diseases (ID) syndromes, IE has not escaped from antibiotic resistance issues. The aim of this study was to determine the implications for diagnosis and treatment by studying the clinical profile and outcome of patients admitted with IE in a tertiary care centre in Mumbai during the period from 2007-2015. Methods: 53 patients having definite or possible IE as per Modified Duke's Criteria (MDC), that were referred to the ID division, were included in this study. Results: 44 (83%) patients had definite IE and 9 (17%) patients had possible IE. 77.4% of the patients were above 40 years of age. 3 patients presented as euthermic IE. Vegetations were not seen on transthoracic echocardiography (TTE) in 3 patients and were seen only on transesophageal echocardiography (TEE). 15 patients had prosthetic valve IE. 7 patients had rheumatic heart disease. 3 patients had bicuspid aortic valve and 4 had ventricular septal defect (VSD). The rest had no apparent underlying heart disease (45.3%). 41 patients (77.3%) had culture-positive IE and 12 patients (22.6%) had culture-negative IE. Streptococcus spp. was found in 14 (26.4%) patients, Enterococcus spp. in 9 patients (17%). Other organisms isolated were methicillin-sensitive S. aureus (3), Methicillin Resistant S. aureus (1), Eikenella corrodens (1), B. cepacia (2), Salmonella Typhi (1), P. aeruginosa (1), M. abscessus (2) and other rapidly growing mycobacteria (RGM) (5), Candida parapsilosis (1), Candida pelliculosa (1) and Aspergillus fumigatus (1). Notably there was only one case of MRSA. Among the Streptococcus spp., Penicillin MIC testing was done in 11 cases of the 14 cases of Strep spp. 3 of them showed intermediate resistance and 2 were resistant. Among enterococcal IE, 3 had high level aminoglycoside resistance (HLAR) and 2 had ß-lactamase producing enterococci with HLAR and 1 had Vancomycin resistance. These were successfully treated with combinations of Ampicillin with Ceftriaxone, Ampicillin-Sulbactam with Imipenem and Daptomycin respectively. The only case of MRSA prosthetic valve endocarditis was successfully treated with Vancomycin and Rifampicin in addition to surgery. Surgery for IE was performed in 26 out of 53 (49%) patients. Early valve surgery (within 15 days of hospital admission) was performed in 6 of these 26 patients. . Conclusion: There is a change in the spectrum and antimicrobial susceptibility of organisms causing IE. We encountered several difficulties with the use of the MDC as 43.5% patients had no predisposing factors for IE and blood cultures were negative in 22.6% cases. In our study, PVE was the most common predisposing condition for IE. VGS followed by enterococci were found to be the commonest cause for IE in our setting. Both organisms show variable drug resist patterns. MRSA was isolated in 1 patient only. Thus vancomycin may not be required as empiric treatment in our setting. This is important from the perspective of antimicrobial stewardship Good infection control practices are essential to prevent nosocomial IE due to pathogens such as non-tuberculous mycobacteria (NTM). Important changes in the disease characteristic, treatment, and outcome are noted. Surgery, whenever indicated, helps in improving outcome in these patients thus reiterating the need for a team approach for optimal management of this complex, challenging condition..

Issues in antifungal stewardship: an opportunity that should not be lost.

Many countries have observed an increase in the incidence of invasive fungal infections (IFIs) over the past two decades with emergence of new risk factors and isolation of new fungal pathogens. Early diagnosis and appropriate antifungal treatment remain the cornerstones of successful outcomes. However, due to non-specific clinical presentations and limited availability of rapid diagnostic tests, in more than half of cases antifungal treatment is inappropriate. As a result, the emergence of antifungal resistance both in yeasts and mycelial fungi is becoming increasingly common. The Delhi Chapter of the Indian Association of Medical Microbiologists (IAMM-DC) organized a 1 day workshop in collaboration with BSAC on 10 December 2015 in New Delhi to design a road map towards the development of a robust antifungal stewardship programme in the context of conditions in India. The workshop aimed at developing a road map for optimizing better outcomes in patients with IFIs while minimizing unintended consequences of antifungal use, ultimately leading to reduced healthcare costs and prevention development of resistance to antifungals. The workshop was a conclave of all stakeholders, eminent experts from India and the UK, including clinical microbiologists, critical care specialists and infectious disease physicians. Various issues in managing IFIs were discussed, including epidemiology, diagnostic and therapeutic algorithms in different healthcare settings. At the end of the deliberations, a consensus opinion and key messages were formulated, outlining a step-by-step approach to tackling the growing incidence of IFIs and antifungal resistance, particularly in the Indian scenario.

Fosfomycin Susceptibility in Urinary Tract Enterobacteriaceae.

INTRODUCTION: Antibiotic treatment of Urinary Tract Infections (UTI) is becoming increasingly difficult due to emergence of multi-drug resistant (ESBLs, AmpC, CRE) uropathogens. Fosfomycin is an old antibiotic that has evoked renewed interest with unique properties of not sharing any structural similarity and lack of cross-resistance with other antimicrobial agents. Our aim is to evaluate in-vitro activity of Fosfomycin against urinary tract Enterobacteriaceae. MATERIAL & METHODS: The study period was March 2014 to September 2015. All 72 isolates were identified using conventional biochemical tests. Antimicrobial susceptibility testing was performed using the automated broth microdilution system Vitek 2 (bio- Mérieux, Inc., Durham, NC). Fosfomycin susceptibility was determined by the E-test (bioMérieux, Inc., Durham, NC) method. Interpretive criteria from the Clinical and Laboratory Standards Institute (CLSI) for fosfomycin susceptibility are not available for the Enterobacteriaceae other than Escherichia coli. Therefore, results were interpreted according to criteria for E. coli (i.e., susceptible at a MIC of ≤ 64 µg/ml), as has been reported previously. RESULTS: Overall, 79.16% (57/72) isolates were susceptible to fosfomycin w i t h 92.00% (23/25) susceptibility in ESBL producing enterobacteriaceae and 72.34% (34/47) in CRE. One CRE isolate has developed resistant while on treatment. There was not much difference in number of susceptible isolates CLSI:EUCAST = 57:53,but number of resistant isolates was more with EUCAST (CLSI:EUCAST = 10:19). CONCLUSION: Study demonstrate that, a considerable proportion (79.16%) of the multidrug-resistant Enterobacteriaceae with diverse resistance mechanisms, including ESBL and CRE, found susceptible to fosfomycin. Consequently, fosfomycin may currently be considered a useful antibiotic agent in the treatment armamentarium of UTIs.

Successful Management of Elizabethkingia meningoseptica Meningitis with Intraventricular Vancomycin.

Elizabethkingia meningoseptica, formerly Chryseobacterium meningosepticum usually causes neonatal meningitis and is a rare cause of nosocomial meningitis in adults. E. meningoseptica is resistant to most antibiotics, and the use of inactive drugs as empirical therapy may contribute to poor outcome in many patients. Vancomycin, alone or in combination with rifampicin, has been successful in the treatment of meningitis in infants1. We present a case of E. meningoseptica meningitis in an adult who was treated initially with intravenous vancomycin and oral rifampicin, but did not respond to the treatment. Thereafter, intraventricular vancomycin was added which resulted in good treatment response.