The urobiome in men and women: a clinical review.

BACKGROUND: Antibiotic therapy alone is unable to control recurrent urinary tract infection (UTI); uropathogens have become multiresistant, and alternative strategies are needed. Far from sterile, the urinary tract contains various low-biomass microbiota, some of whose members appear to protect against clinical UTI. OBJECTIVES: This narrative review summarizes (a) the current knowledge of male and female urobiomes in healthy and diseased states, as well as their interplay among sexual partners and (b) clinical trials to date assessing probiotic and other nonantibiotic measures to reduce UTI. SOURCES: We used the PubMed interface to search Ovid Medline for articles describing urogenital flora, UTI, UTI dysbiosis, the effects of sexual intercourse on urogenital flora, and clinical trials of probiotics as UTI prophylaxis. CONTENT: The healthy urobiome of women contains several Lactobacillus species, some of which may impede Escherichia coli growth in the urinary tract. Although Lactobacilli have been found in male urethral microbiota, their presence in male bladder microbiota is less certain. Distal male urethral and vaginal microbiomes of male and sexual female partners influence one another, but more research is needed on the direct interplay of their full urobiomes. Clinical trials assessing the therapeutic potential of Lactobacilli have been largely underpowered and highly varied in tested formulations and routes and frequencies of administration; as such, they have failed to show a clear benefit. Faecal microbiota transplantation for recurrent Clostridium difficile infection was shown, in a retrospective study of seven patients, to reduce recurrent UTI as a side effect. IMPLICATIONS: The urobiome in men and women is complex, variable, and still understudied. Although there is hope that Lactobacilli and faecal microbial transplantation could be future nonantibiotic options for recurrent UTI, both require more pharmacologic and clinical research to identify optimal preparations and routes of administration.

When and how do we stop antifungal treatment for an invasive mould infection in allogeneic haematopoietic cell transplant recipients?

BACKGROUND: Limited data exist to describe end-of-treatment (EOT) parameters of antifungal therapy for invasive mould infections (IMI). METHODS: In a 10-year cohort of consecutive adult allogeneic haematopoietic cell transplant recipients with proven/probable IMI, we describe treatment duration and patient profile at EOT. RESULTS: There were 61 patients with 66 proven/probable IMI identified: 47/66 (71%) invasive aspergillosis (IA), 11/66 (17%) mucormycosis, and 8/66 (12%) other-IMI. Excluding 5 (8%) patients lost to follow-up, treatment was prematurely discontinued due to death or palliative care in 29/56 (51.8%) patients. Antifungal treatment was completed in 27 (48.2%) patients, for a median duration of 280 days (IQR: 110, 809): 258 (IQR: 110, 1905) and 307.5 (99, 809) days in IA and non-IA IMI, respectively. Treatment was continued after 90 and 180 days in 43/56 (76.8%) and 30/56 (53.6%) patients, respectively. At EOT, most patients were not neutropenic (ANC: 2.12 G/L, IQR: 0.04, 5.3), with CD4+ counts at 99 cells/µl (IQR: 0, 759) and immunoglobulins at 5.6 g/L (IQR: 2.3, 10.6). Most patients (16/27, 59.3%) were not receiving steroids at EOT, while 14/27 (53.9%) were on another type of immunosuppression. Amongst 15 patients with imaging at EOT, 12 (80%) had complete/partial radiologic response. Any chart documentation or an infectious disease consultation on treatment discontinuation was observed in 12/56 (21%) and 11/56 (20%) patients, respectively. CONCLUSIONS: Long treatment courses are observed in patients with IMI, due to prolonged immunosuppression. Although immune reconstitution and radiological response were frequently observed at EOT, consistent documentation of treatment discontinuation based on well-defined parameters is lacking.

Invasive Mold Infections in Allogeneic Hematopoietic Cell Transplant Recipients in 2020: Have We Made Enough Progress?

BACKGROUND: Despite progress in diagnostic, prevention, and treatment strategies, invasive mold infections (IMIs) remain the leading cause of mortality in allogeneic hematopoietic cell transplant (allo-HCT) recipients. METHODS: We describe the incidence, risk factors, and mortality of allo-HCT recipients with proven/probable IMI in a retrospective single-center 10-year (01/01/2010-01/01/2020) cohort study. RESULTS: Among 515 allo-HCT recipients, 48 (9.3%) patients developed 51 proven/probable IMI: invasive aspergillosis (IA; 34/51, 67%), mucormycosis (9/51, 18%), and other molds (8/51, 15%). Overall, 35/51 (68.6%) breakthrough IMIs (bIMIs) were identified: 22/35 (62.8%) IA and 13/35 (37.1%) non-IA IMI. One-year IMI cumulative incidence was 7%: 4.9% and 2.1% for IA and non-IA IMI, respectively. Fourteen (29.2 %), 10 (20.8%), and 24 (50.0%) patients were diagnosed during the first 30, 31-180, and >180 days post-HCT, respectively. Risk factors for IMI included prior allo-HCT (sub hazard ratio [SHR], 4.06; P = .004) and grade ≥2 acute graft-vs-host disease (aGvHD; SHR, 3.52; P < .001). All-cause 1-year mortality was 33% (170/515): 48% (23/48) and 31.5% (147/467) for patients with and without IMI (P = .02). Mortality predictors included disease relapse (hazard ratio [HR], 7.47; P < .001), aGvHD (HR, 1.51; P = .001), CMV serology-positive recipients (HR, 1.47; P = .03), and IMI (HR, 3.94; P < .001). All-cause 12-week mortality for patients with IMI was 35.4% (17/48): 31.3% (10/32) for IA and 43.8% (7/16) for non-IA IMI (log-rank P = .47). At 1 year post-IMI diagnosis, 70.8% (34/48) of the patients were dead. CONCLUSIONS: IA mortality has remained relatively unchanged during the last 2 decades. More than two-thirds of allo-HCT recipients with IMI die by 1 year post-IMI diagnosis. Dedicated intensified research efforts are required to further improve clinical outcomes.

Frequency and causes of antifungal treatment changes in allogeneic haematopoïetic cell transplant recipients with invasive mould infections.

BACKGROUND: Antifungal treatment duration and changes for invasive mould infections (IMI) have been poorly described. METHODS: We performed a 10-year cohort study of adult (≥18-year-old) allogeneic haematopoietic cell transplant recipients with proven/probable IMI to describe the duration and changes of antifungal treatment. All-cause-12-week mortality was described. RESULTS: Sixty-one patients with 66 IMI were identified. Overall treatment duration was 157 days (IQR: 14-675) and 213 (IQR: 90-675) days for patients still alive by Day 84 post-IMI diagnosis. There was at least one treatment change in 57/66 (86.4%) cases: median 2, (IQR: 0-6, range:0-8). There were 179 antifungal treatment changes due to 193 reasons: clinical efficacy (104/193, 53.9%), toxicity (55/193, 28.5%), toxicity or drug interactions resolution (15/193, 7.8%) and logistical reasons (11/193, 5.7%) and 15/193 (7.8%) changes due to unknown reasons. Clinical efficacy reasons included lack of improvement (34/104, 32.7%), targeted treatment (30/104, 28.8%), subtherapeutic drug levels (14/104, 13.5%) and other (26/104, 25%). Toxicity reasons included hepatotoxicity, nephrotoxicity, drug interactions, neurotoxicity and other in 24 (43.6%), 12 (21.8%), 12 (21.8%), 4 (7.4%) and 3 (5.5%) cases respectively. All-cause 12-week mortality was 31% (19/61), higher in patients whose antifungal treatment (logrank 0.04) or appropriate antifungal treatment (logrank 0.01) was started >7 days post-IMI diagnosis. All-cause 1-year mortality was higher in patients with ≥2 changes of treatment during the first 6 weeks post-IMI diagnosis (logrank 0.008) with an OR: 4.00 (p = .04). CONCLUSIONS: Patients with IMI require long treatment courses with multiple changes for variable reasons and potential effects on clinical outcomes, demonstrating the need more effective and safer treatment options. Early initiation of appropriate antifungal treatment is associated with improved outcomes.

Real-Life Considerations on Antifungal Treatment Combinations for the Management of Invasive Mold Infections after Allogeneic Cell Transplantation.

BACKGROUND: Antifungal combination treatment is frequently administered for invasive mold infections (IMIs) after allogeneic hematopoietic cell transplantation (HCT). Here, we describe the indications, timing, and outcomes of combination antifungal therapy in post-HCT IMI. METHODS: A single-center, 10-year, retrospective cohort study including all adult HCT recipients with proven/probable IMI between 1 January 2010 and 1 January 2020 was conducted. RESULTS: During the study period, 515 patients underwent HCT, of whom 47 (9.1%) presented 48 IMI episodes (46 patients with one IMI episode and 1 patient with two separate IMI episodes): 33 invasive aspergillosis (IA) and 15 non-IA IMIs. Almost half (51%) of the patients received at least one course of an antifungal combination (median: 2/patient): 23 (49%), 20 (42%), and 4/47 (9%) patients received pure monotherapy, mixed monotherapy/combination, and pure combination treatment, respectively. Combination treatment was started at a median of 8 (IQR: 2, 19) days post-IMI diagnosis. Antifungal management was complex, with 163 treatment courses prescribed overall, 48/163 (29.4%) concerning antifungals in combination. The clinical reasons motivating the selection of initial combination antifungal therapy included severe IMI (18, 38%), lack of antifungal susceptibility data (14, 30%), lack of pathogen identification (5, 11%), and combination treatment until reaching a therapeutic azole serum level (6, 13%). The most common combination treatments were azole/liposomal amphotericin-B (28%) and liposomal amphotericin-B/echinocandin (21%). Combination treatment was administered cumulatively for a median duration of 28 days (IQR: 7, 47): 14 (IQR: 6, 50) days for IA and 28 (IQR: 21, 34) days for non-IA IMI (p = 0.18). Overall, 12-week mortality was 30%. Mortality was significantly higher among patients receiving ≥50% of treatment as combination (logrank = 0.04), especially those with non-IA IMI (logrank = 0.03). CONCLUSIONS: Combination antifungal treatment is frequently administered in allogeneic HCT recipients with IMI to improve clinical efficacy, albeit in an inconsistent and variable manner, suggesting a lack of relevant data and guidance, and an urgent need for new studies to improve therapeutic options.