Effect of antibiotic de-escalation on clinical outcomes in patients with carbapenem-resistant Enterobacteriaceae bacteremia (CRE) in the hematology-oncology setting.

Introduction: Carbapenem-resistant Enterobacteriaceae (CRE) infections are associated with poor outcomes, particularly among hematology-oncology patients. Appropriate use (selection and de-escalation) of antibiotics is a key component of management of febrile neutropenia particularly in high CRE prevalence regions like India. Methods: This was a retrospective study done (April 2019-December 2021) in a dedicated oncology center in North India, which assessed the case records of the patients undergoing therapy for hematological malignancies who were diagnosed with CRE bacteremia. Demographic, clinical and microbiological data, as well as antibiotic prescription patterns were studied. Inter-group analysis was done between an antibiotic stewardship cohort (avoiding CRE therapy empirically or stopping CRE therapy if cultures negative; as per suggestions of the AMS team) and a non-antibiotic stewardship cohort (continuation of empirical CRE therapy; de-escalation advice was not followed). Results: A total of 139 patients were identified, with median age of 41 years (range 13-74) out of which 82 (58.9%) were males. Acute myeloid leukemia (66.2%) was the most common malignancy, followed by lymphoma (8.6%) and myeloma (8.6%). Nearly 30% of patients were post allogenic stem cell transplant. Klebsiella pneumoniae was the predominant organism (78.4%) and combination of NDM+OXA-48 (46.3%) was the most common carbapenemase gene detected followed by OXA-48 alone (34.7%). Overall, 28-day mortality was 26.6%. On binary logistic regression analysis, lack of compliance with antibiotic stewardship intervention was an independent predictor of mortality (p=0.005). Conclusions: Prior exposure to empirical CRE therapy or failure to de-escalate was associated with poor outcomes in patients with CRE bacteremia, which gives us a window of antibiotic stewardship in febrile neutropenia.

Impact of improving infection control and antibiotic stewardship practices on nosocomial infections and antimicrobial resistance in an oncology centre from India.

BACKGROUND: Improving basic infection control (IC) practices, diagnostics and anti-microbial stewardship (AMS) are key tools to handle antimicrobial resistance (AMR). MATERIALS AND METHODS: This is a retrospective study done over 6 years (2016-2021) in an oncology centre in North India with many on-going interventions to improve IC practices, diagnostics and AMS. This study looked into AMR patterns from clinical isolates, rates of hospital acquired infections (HAI) and clinical outcomes. RESULTS: Over all, 98,915 samples were sent for culture from 158,191 admitted patients. Most commonly isolated organism was E. coli (n â€‹= â€‹6951; 30.1%) followed by Klebsiella pneumoniae (n â€‹= â€‹5801; 25.1%) and Pseudomonas aeroginosa (n â€‹= â€‹3041; 13.1%). VRE (Vancomycin resistant Enterococcus) rates fell down from 43.5% in Jan-June 2016 to 12.2% in July-Dec 2021, same was seen in CR (carbapenem resistant) Pseudomonas (23.0%-20.6%, CR Acinetobacter (66.6%-17.02%) and CR E. coli (21.6%-19.4%) over the same study period. Rate of isolation of Candida spp. from non-sterile sites also showed reduction (1.68 per 100 patients to 0.65 per 100 patients). Incidence of health care associated infections also fell from 2.3 to 1.19 per 1000 line days for CLABSI, 2.28 to 1.88 per 1000 catheter days for CAUTI. There was no change in overall mortality rates across the study period. CONCLUSION: This study emphasizes the point that improving compliance to standard IC recommendations and improving diagnostics can help in reducing the burden of antimicrobial resistance.

Multimodal analysis of the COVID-19-associated mucormycosis outbreak in Delhi, India indicates the convergence of clinical and environmental risk factors.

BACKGROUND: The aetiology of the major outbreak of COVID-19-associated mucormycosis (CAM) in India in spring 2021 remains incompletely understood. Herein, we provide a multifaceted and multi-institutional analysis of clinical, pathogen-related, environmental and healthcare-related factors during CAM outbreak in the metropolitan New Delhi area. METHODS: We reviewed medical records of all patients diagnosed with biopsy-proven CAM (n = 50) at 7 hospitals in the New Delhi, and NCR area in April-June 2021. Two multivariate logistic regression models were used to compare clinical characteristics of CAM cases with COVID-19-hospitalised contemporary patients as controls (n = 69). Additionally, meteorological parameters and mould spore concentrations in outdoor air were analysed. Selected hospital fomites were cultured. Mucorales isolates from CAM patients were analysed by ITS sequencing and whole-genome sequencing (WGS). RESULTS: Independent risk factors for CAM identified by multivariate analysis were previously or newly diagnosed diabetes mellitus, active cancer and severe COVID-19 infection. Supplemental oxygen, remdesivir therapy and ICU admission for COVID-19 were associated with reduced CAM risk. The CAM incidence peak was preceded by an uptick in environmental spore concentrations in the preceding 3-4 weeks that correlated with increasing temperature, high evaporation and decreasing relative humidity. Rhizopus was the most common genus isolated, but we also identified two cases of the uncommon Mucorales, Lichtheimia ornata. WGS found no clonal population of patient isolates. No Mucorales were cultured from hospital fomites. CONCLUSIONS: An intersection of host and environmental factors contributed to the emergence of CAM. Surrogates of access to advanced COVID-19 treatment were associated with lower CAM risk.

Candida Empyema in Febrile Neutropenia - Augmented value of direct inoculation into BacT/Alert blood culture vials.

Candida empyema is an uncommon complication of febrile neutropenia. We present 4 such cases which highlight the importance of direct inoculation of body fluids in automated blood culture bottle leading to increased yield. Our cases and review of literature also highlight that echinocandins have poor penetration into pleural fluid; azoles (especially voriconazole) should be preferred as drug of choice.

Emergence of clonal fluconazole-resistant Candida parapsilosis clinical isolates in a multicentre laboratory-based surveillance study in India.

OBJECTIVES: The emergence of fluconazole resistance in Candida parapsilosis healthcare-associated infections has recently been increasingly reported. Antifungal susceptibility profiles and mechanisms of fluconazole resistance in C. parapsilosis (n = 199) from nine hospitals in India collected over a period of 3 years were studied. Further, clonal transmission of fluconazole-resistant isolates in different hospitals was investigated. METHODS: Antifungal susceptibility testing of five azoles, amphotericin B and 5-flucytosine was performed by the CLSI microbroth dilution method. The azole target ERG11 gene was sequenced, and the significance of a novel ERG11 mutation in C. parapsilosis was determined using a gap-repair cloning approach in Saccharomyces cerevisiae. In addition, microsatellite analysis was performed to determine the clonal lineage of C. parapsilosis-resistant strains circulating among different hospitals. RESULTS: A total of 64 (32%) C. parapsilosis isolates were non-susceptible to fluconazole, which included resistant (n = 55; MIC >4 mg/L) and susceptible dose-dependent (n = 9) isolates. Of these 64 non-susceptible isolates, a novel K143R amino acid substitution was noted in 92%, and the remaining five isolates had the Y132F substitution. Elevated azole MICs (≥16-fold) were detected in S. cerevisiae upon expression of C. parapsilosis ERG11 alleles carrying Y132F or K143R substitutions. Two major clusters of non-susceptible isolates were circulating in seven Indian hospitals. CONCLUSIONS: We report a novel K143R amino acid substitution in ERG11p causing fluconazole resistance in C. parapsilosis. Fluconazole-non-susceptible C. parapsilosis isolates carrying the novel K143R amino acid substitution should be identified in clinical microbiology laboratories to prevent further clonal transmission.

Absence of Azole or Echinocandin Resistance in Candida glabrata Isolates in India despite Background Prevalence of Strains with Defects in the DNA Mismatch Repair Pathway.

Candida glabrata infections are increasing worldwide and exhibit greater rates of antifungal resistance than those with other species. DNA mismatch repair (MMR) gene deletions, such as msh2Δ, in C. glabrata resulting in a mutator phenotype have recently been reported to facilitate rapid acquisition of antifungal resistance. This study determined the antifungal susceptibility profiles of 210 C. glabrata isolates in 10 hospitals in India and investigated the impact of novel MSH2 polymorphisms on mutation potential. No echinocandin- or azole-resistant strains and no mutations in FKS hot spot regions were detected among the C. glabrata isolates, supporting our in vitro susceptibility testing results. CLSI antifungal susceptibility data showed that the MICs of anidulafungin (geometric mean [GM], 0.12 µg/ml) and micafungin (GM, 0.01 µg/ml) were lower and below the susceptibility breakpoint compared to that of caspofungin (CAS) (GM, 1.31 µg/ml). Interestingly, 69% of the C. glabrata strains sequenced contained six nonsynonymous mutations in MSH2, i.e., V239L and the novel mutations E459K, R847C, Q386K, T772S, and V239/D946E. Functional analysis of MSH2 mutations revealed that 49% of the tested strains (40/81) contained a partial loss-of-function MSH2 mutation. The novel MSH2 substitution Q386K produced higher frequencies of CAS-resistant colonies upon expression in the msh2Δ mutant. However, expression of two other novel MSH2 alleles, i.e., E459K or R847C, did not confer selection of resistant colonies, confirming that not all mutations in the MSH2 MMR pathway affect its function or generate a phenotype of resistance to antifungal drugs. The lack of drug resistance prevented any correlations from being drawn with respect to MSH2 genotype.

A multicentre study of antifungal susceptibility patterns among 350 Candida auris isolates (2009-17) in India: role of the ERG11 and FKS1 genes in azole and echinocandin resistance.

Background: Candida auris has emerged globally as an MDR nosocomial pathogen in ICU patients. Objectives: We studied the antifungal susceptibility of C. auris isolates (n = 350) from 10 hospitals in India collected over a period of 8 years. To investigate azole resistance, ERG11 gene sequencing and expression profiling was conducted. In addition, echinocandin resistance linked to mutations in the C. auris FKS1 gene was analysed. Methods: CLSI antifungal susceptibility testing of six azoles, amphotericin B, three echinocandins, terbinafine, 5-flucytosine and nystatin was conducted. Screening for amino acid substitutions in ERG11 and FKS1 was performed. Results: Overall, 90% of C. auris were fluconazole resistant (MICs 32 to ≥64 mg/L) and 2% and 8% were resistant to echinocandins (≥8 mg/L) and amphotericin B (≥2 mg/L), respectively. ERG11 sequences of C. auris exhibited amino acid substitutions Y132 and K143 in 77% (n = 34/44) of strains that were fluconazole resistant whereas WT genotypes, i.e. without substitutions at these positions, were observed in isolates with low fluconazole MICs (1-2 mg/L) suggesting that these substitutions confer a phenotype of resistance to fluconazole similar to that described for Candida albicans. No significant expression of ERG11 was observed, although expression was inducible in vitro with fluconazole exposure. Echinocandin resistance was linked to a novel mutation S639F in FKS1 hot spot region I. Conclusions: Overall, 25% and 13% of isolates were MDR and multi-azole resistant, respectively. The most common resistance combination was azoles and 5-flucytosine in 14% followed by azoles and amphotericin B in 7% and azoles and echinocandins in 2% of isolates.

Voriconazole-Resistant Penicillium oxalicum: An Emerging Pathogen in Immunocompromised Hosts.

Penicillium species are rarely reported agents of infections in immunocompromised patients. We report 3 cases of invasive mycosis caused by voriconazole-resistant Penicillium oxalicum in patients with acute myeloid leukemia, diabetes mellitus, and chronic obstructive pulmonary disease, while on voriconazole therapy. Penicillium oxalicum has not been previously recognized as a cause of invasive mycoses.