We determined imipenem, imipenem-relebactam, ceftazidime, and ceftazidimeavibactam MICs against 100 CRE isolates that underwent whole-genome sequencing. Klebsiella pneumoniae carbapenemases (KPCs) were the most common carbapenemases. Forty-six isolates carried extended-spectrum -lactamases (ESBLs). With the addition of relebactam, imipenem susceptibility increased from 8% to 88%. With the addition of avibactam, ceftazidime susceptibility increased from 0% to 85%. Neither imipenem-relebactam nor ceftazidime-avibactam was active against metallo--lactamase (MBL) producers. Ceftazidime-avibactam (but not imipenem-relebactam) was active against OXA-48-like producers, including a strain not harboring any ESBL. Major OmpK36 porin mutations were independently associated with higher imipenemrelebactam MICs (P Ͻ 0.0001) and showed a trend toward independent association with higher ceftazidime-avibactam MICs (P ϭ 0.07). The presence of variant KPC-3 was associated with ceftazidime-avibactam resistance (P Ͻ 0.0001). In conclusion, imipenem-relebactam and ceftazidime-avibactam had overlapping spectra of activity and niches in which each was superior. Major OmpK36 mutations in KPC-K. pneumoniae may provide a foundation for stepwise emergence of imipenem-relebactam and ceftazidime-avibactam resistance.
Background Invasive fungal infections (IFIs) are common following lung transplantation. Isavuconazole is unstudied as prophylaxis in organ transplant recipients. We compared effectiveness and tolerability of isavuconazole and voriconazole prophylaxis in lung transplant recipients. Methods We conducted a single-center, retrospective study of patients who received isavuconazole (September 2015-February 2018) or voriconazole (September 2013-September 2015) for antifungal prophylaxis. IFIs were defined by EORTC/MSG criteria. Results Patients received isavuconazole (n=144) or voriconazole (n=156) for median 3.4 and 3.1 months, respectively. Adjunctive inhaled amphotericin B was administered to 100% and 41% of patients in the respective groups. At 1-year, 8% of patients receiving isavuconazole or voriconazole developed IFIs. For both groups, 70% and 30% of IFIs were caused by moulds and yeasts, respectively, and breakthrough IFI (bIFI) rates were 3%. Outcomes did not significantly differ for patients receiving or not receiving inhaled amphotericin B. Independent risk factors for bIFI and breakthrough mould infection (bIMI) were mould-positive respiratory culture and red blood cell transfusion >7 units at transplant. Bronchial necrosis >2 cm from anastomosis and basiliximab induction were also independent risk factors for bIMI. Isavuconazole and voriconazole were discontinued prematurely due to adverse events in 11% and 36% of patients, respectively (p=0.0001). Most common causes of voriconazole and isavuconazole discontinuation were hepatotoxicity and lack of oral intake, respectively. Patients receiving ≥90 days prophylaxis had fewer IFIs at 1-year (3% versus 9%, p=0.02). IFIs were associated with increased mortality (p=0.0001) and longer hospitalizations (p=0.0005). Conclusions Isavuconazole was effective and well-tolerated as antifungal prophylaxis following lung transplantation.
Data on invasive mold infections (IMIs) after chimeric antigen receptor-modified T-cell (CAR-T-cell) therapy are limited. We describe 2 patients with post–CAR-T-cell IMI (Fusarium, Mucorales) and review the published literature. We propose strategies to prevent IMIs in patients, based on the IMI rate and presence of neutropenia or steroid use.
Mycobacterium tuberculosis is a major opportunistic pathogen in transplant recipients. Compared to that in the general population, the frequency of tuberculosis (TB) is 10 to 40 times higher in hematopoietic stem cell transplant (HSCT) recipients and 20 to 74 times higher in solid-organ transplant (SOT) recipients. Transplant recipients with TB are also more likely to develop disseminated disease, have longer time to definitive diagnosis, require more invasive diagnostic procedures, and experience greater anti-TB treatment-related toxicity than the general population. Specific risk factors for TB in SOT recipients include previous exposure to M. tuberculosis (positive tuberculin skin tests and/or residual TB lesions in pretransplant chest X ray) and the intensity of immunosuppression (use of antilymphocyte antibodies, type of basal immunosuppression, and intensification of immunosuppressive therapy for allograft rejection). Risk factors in HSCT recipients are allogeneic transplantation from an unrelated donor; chronic graft-versus-host disease treated with corticosteroids; unrelated or mismatched allograft; pretransplant conditioning using total body irradiation, busulfan, or cyclophosphamide; and type and stage of primary hematological disorder. Transplant recipients with evidence of prior exposure to M. tuberculosis should receive treatment appropriate for latent TB infection. Optimal management of active TB disease is particularly challenging due to significant drug interactions between the anti-TB agents and the immunosuppressive therapy. In this chapter, we address the epidemiology, clinical presentation, diagnostic considerations, and management strategies for TB in SOT and HSCT recipients.
Studies describing invasive fungal infections (IFIs) after chimeric antigen receptor-modified T-cell (CAR-T-cell) therapy are limited. Although post-CAR-T-cell IFIs appear to be uncommon, they are associated with significant morbidity and mortality. Specific risk factors for IFIs in CAR-T-cell recipients have not been fully characterized and are often extrapolated from variables contributing to IFIs in patients with other hematologic malignancies or those undergoing hematopoietic cell transplant. Optimal prophylaxis strategies, including the use of yeast versus mold-active azoles, also remain ill-defined. Further research should investigate key risk factors for IFIs and establish an evidence-based approach to antifungal prophylaxis in these patients in order to improve clinical outcomes.
India contributes heavily to the global burden of visceral leishmaniasis (VL, kala-azar) and human immunodeficiency virus (HIV)/AIDS. The prevalence of HIV seropositivity in VL patients at a tertiary care centre in northern India, as observed during a prospective study over a period of 2 years, is presented. Of the 104 cases of VL/post-kala-azar dermal leishmaniasis, six (5?7 %) were found to be HIV positive, compared to 11 (5?5 %) seropositive for HIV of 198 patients with fever due to other causes. Four of the six (67 %) VL/HIV co-infected patients had a chronic/relapsing course, not responding to antileishmanial treatment. A CD4 T-cell count of <200 mm "3 was found in four of the five (80 %) co-infected patients in whom the test was done. Although the level of HIV/VL co-infection in the present study was lower than that of Mediterranean countries, there is a trend towards rising co-infection. The VL-endemic states of India have a huge population of migrant labourers, who work in high-HIV-prevalence states. The reported increase in the prevalence of HIV in the VL-endemic, populous states of India is a cause of grave concern, and co-infection may assume epidemic proportions in the coming decade if left unchecked.
Background Candida empyema thoracis (pleural empyema) is an uncommon manifestation of invasive candidiasis, for which optimal treatment is unknown. Methods This is a retrospective study of patients with Candida empyema at 2 academic medical centers from September 2006 through December 2015. Results We identified 81 patients with Candida empyema (median age, 62 years; 68% men). Sixty-five percent of patients underwent surgery or an invasive intervention of the thorax or abdomen within the preceding 90 days. Candida empyema originated from intrathoracic (51%) or intra-abdominal sources (20%), spontaneous esophageal rupture (12%), pleural space manipulation (9%), and pneumonia (6%). Eighty-four percent and 41% of patients were intensive care unit residents and in septic shock, respectively, within 3 days of diagnosis. Causative species were Candida albicans (65%), Candida glabrata (26%), Candida parapsilosis (11%), Candida tropicalis (4%), Candida krusei (2%), and Candida dubliniensis (1%). Bacteria were recovered from empyemas in 51% of patients. Concurrent candidemia was diagnosed in only 2% of patients. Management included pleural drainage and antifungal treatment in 98% and 85% of patients, respectively. Mortality at 100 days was 27%, and it was highest for cases stemming from esophageal rupture (67%). Spontaneous esophageal rupture and echinocandin rather than fluconazole treatment were independent risk factors for death at 100 days (P = .003 and .04, respectively); receipt of antifungal therapy was an independent predictor of survival (P = .046). Conclusions Candida empyema mortality rates were lower than reported previously. Optimal management included pleural drainage and fluconazole treatment. Superiority of fluconazole over echinocandins against Candida empyema needs to be confirmed in future studies.
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