Risk Factors for Nontuberculous Mycobacteria Infections in Solid Organ Transplant Recipients: A Multinational Case-Control Study.

BACKGROUND: Risk factors for nontuberculous mycobacteria (NTM) infections after solid organ transplant (SOT) are not well characterized. Here we aimed to describe these factors. METHODS: Retrospective, multinational, 1:2 matched case-control study that included SOT recipients ≥12 years old diagnosed with NTM infection from 1 January 2008 to 31 December 2018. Controls were matched on transplanted organ, NTM treatment center, and post-transplant survival greater than or equal to the time to NTM diagnosis. Logistic regression on matched pairs was used to assess associations between risk factors and NTM infections. RESULTS: Analyses included 85 cases and 169 controls (59% male, 88% White, median age at time of SOT of 54 years [interquartile range {IQR} 40-62]). NTM infection occurred in kidney (42%), lung (35%), heart and liver (11% each), and pancreas transplant recipients (1%). Median time from transplant to infection was 21.6 months (IQR 5.3-55.2). Most underlying comorbidities were evenly distributed between groups; however, cases were older at the time of NTM diagnosis, more frequently on systemic corticosteroids and had a lower lymphocyte count (all P < .05). In the multivariable model, older age at transplant (adjusted odds ratio [aOR] 1.04; 95 confidence interval [CI], 1.01-1.07), hospital admission within 90 days (aOR, 3.14; 95% CI, 1.41-6.98), receipt of antifungals (aOR, 5.35; 95% CI, 1.7-16.91), and lymphocyte-specific antibodies (aOR, 7.73; 95% CI, 1.07-56.14), were associated with NTM infection. CONCLUSIONS: Risk of NTM infection in SOT recipients was associated with older age at SOT, prior hospital admission, receipt of antifungals or lymphocyte-specific antibodies. NTM infection should be considered in SOT patients with these risk factors.

Leukocyte telomere length in patients with schizophrenia and related disorders: a meta-analysis of case-control studies.

CONTEXT: Telomere length may serve as a biomarker of cellular aging. The literature assessing telomere length in schizophrenia contains conflicting results. OBJECTIVE: To assess differences in leukocyte telomere length (LTL) in peripheral blood in patients with schizophrenia and related disorders and healthy controls and to explore the effect of potential confounding variables. DATA SOURCES: A search of Ovid MEDLINE, and Proquest databases was conducted to identify appropriate studies published from database inception through December 2020. The review protocol was registered with PROSPERO-ID: CRD42021233280. STUDY SELECTION: The initial literature search yielded 192 studies. After study selection in 3 phases, we included 29 samples from 22 studies in the meta-analysis database. DATA EXTRACTION: We used random effects and meta-regression models to derive Cohen d values with pooled 95% confidence intervals (CI) as estimates of effect size (ES) and to test effects of potential moderators. RESULTS: The overall meta-analysis included 4145 patients with schizophrenia and related disorders and 4184 healthy controls and showed that LTL was significantly shorter in patients, with a small to medium effect size (ES, -0.388; 95% CI, -0.492 to -0.283; p < 0.001). Subgroup meta-analyses did not find a significant effect of age or illness duration on differences in LTL in patients with psychosis relative to controls. Meta-regression analyses showed that none of the putative moderators had a significant effect on effect size estimates. CONCLUSIONS: This meta-analysis find further support for the hypothesis of accelerated cellular aging in schizophrenia and related disorders and highlights the need for large longitudinal studies with repeated LTL measurements over time and appropriate assessments of associated factors.

Ceftolozane/tazobactam for difficult-to-treat Gram-negative infections: A real-world tertiary hospital experience.

OBJECTIVE: To evaluate the real-world clinical efficacy of ceftolozane/tazobactam (C/T) in difficult-to-treat infections caused by multi-drug resistant Gram-negative microorganisms, including carbapenem-resistant Pseudomonas aeruginosa. METHODS: Retrospective cohort study of adult patients treated with C/T for at least 48 hours for infections caused by multi-drug resistant Gram-negative bacteria in a tertiary hospital from May 2016 until August 2019. The primary outcome analysed was clinical failure, defined as a composite of symptomatology persistence after 7 days of C/T treatment, infection recurrence, and/or all-cause mortality within 30 days of follow-up. RESULTS AND DISCUSSION: 96 episodes of C/T treatment were included, mostly consisting of targeted treatments (83.9%) for the following sources of infection: intra-abdominal (22.6%), urinary tract (25.8%), skin and soft tissue (19.4%), hospital-acquired pneumonia (14%), and other (6.4%). The most frequently isolated bacteria were carbapenem-resistant (88, 94.6%). Clinical failure rate was 30.1%, due to persistent infection at day 7 (4.3%), recurrence of the initial infection (16.1%), or 30-day all-cause mortality (8.6%). Adverse events most frequently reported were Clostridium difficile infection (9%) and cholestasis (8%). WHAT IS NEW AND CONCLUSION: C/T showed a favourable clinical profile for difficult-to-treat multidrug-resistant and carbapenem-resistant Gram-negative infections, regardless of the source of infection.

Tuberculosis prevention in patients undergoing kidney transplantation: A nurse-led program for screening and treatment.

BACKGROUND: Systematic screening for, and treatment of, latent tuberculosis (TB) infection is recommended prior to kidney transplant. However, little is known about patient compliance with, or the safety profile of, preventive therapies used in clinical practice. METHODS: This was a retrospective observational study of patients who were eligible for kidney transplant and were evaluated for TB infection between January 2013 and June 2019 at the TB clinic of a tertiary care teaching hospital. All patient data were registered prospectively as part of our nurse-led program before kidney transplant. We assessed completion rates, tolerance with therapy, development of TB, and associated workload. RESULTS: In total, 1568 patients were referred to our TB clinic for evaluation. Preventive therapy was given to 385 patients and completed by 340 (88.3%). Of these, 89 (23.1%) experienced some intolerance, with 27 requiring full discontinuation. After a median follow-up of 45 months (1426 patient-years), 206 (53.5%) of the treated patients received a kidney transplant; only one patient, who failed to complete treatment, developed post-transplant TB (7.01 cases per 10 000 patient-years; 95% confidence interval, 0.35-34.59). Extra nurse or medical visits were required by 268 (69.6%) patients. CONCLUSION: Despite the complexity and workload generated by patients with ESRD awaiting kidney transplant, preventive therapy for TB is effective in most cases. Our experience provides important evidence on the feasibility of preventive therapy for TB before kidney transplant when delivered as part of a comprehensive nurse-led program.

Clinical Management and Outcomes of Nontuberculous Mycobacterial Infections in Solid Organ Transplant Recipients: A Multinational Case-control Study.

BACKGROUND: The management and outcomes of nontuberculous mycobacterial (NTM) infections in solid organ transplant (SOT) recipients are poorly characterized. We aimed to describe the management and 1-y mortality of these patients. METHODS: Retrospective, multinational, 1:2 matched case-control study included SOT recipients aged 12 y old or older diagnosed with NTM infection between January 1, 2008, and December 31, 2018. Controls were matched on transplanted organs, NTM treatment center, and posttransplant survival at least equal to the time to NTM diagnosis. The primary aim was 1-y mortality after NTM diagnosis. Differences between cases and controls were compared using the log-rank test, and Cox regression models were used to identify factors associated with mortality at 12 mo among cases. RESULTS: In 85 patients and 169 controls, the median age at the time of SOT was 54 y (interquartile range, 40-62 y), 59% were men, and the lungs were the most common site of infection after SOT (57.6%). One-year mortality was significantly higher in cases than in controls (20% versus 3%; P < 0.001), and higher mortality was associated with lung transplantation (hazard ratio 3.27; 95% confidence interval [1.1-9.77]; P = 0.034). Median time (interquartile range) from diagnosis to treatment initiation (20 [4-42] versus 11 [3-21] d) or the reduction of net immunosuppression (36% versus 45%, hazard ratio 1.35 [95% CI, 0.41-4.43], P = 0.618) did not differ between survivors and those who died. CONCLUSIONS: NTM disease in SOT recipients is associated with a higher mortality risk, especially among lung transplant recipients. Time to NTM treatment and reduction in net immunosuppression were not associated with mortality.

Does identification to species level provide sufficient evidence to confirm catheter-related fungemia caused by Candida albicans?

We retrospectively studied 22 patients with catheter-related candidemia caused by Candida albicans. Strains isolated simultaneously from blood and catheter tips were genotyped using six microsatellite markers. Matches between genotypes of isolates recovered from both sample sources were found in 20/22 (91%) patients. Consequently, identification of the same species from both the catheter tip and blood could be used to confirm catheter-related candidemia.

Reversions of QuantiFERON-TB Gold Plus in tuberculosis contact investigation: A prospective multicentre cohort study.

BACKGROUND: Interferon-y Release Assays (IGRA) reversions have been reported in different clinical scenarios for the diagnosis of tuberculosis (TB) infection. This study aimed to determine the rate of QuantiFERON-TB Gold Plus (QFT-Plus) reversions during contact investigation as a potential strategy to reduce the number of preventive treatments. METHODS: Prospective, multicentre cohort study of immunocompetent adult contacts of patients with pulmonary TB tested with QFT-Plus. Contacts with an initial positive QFT-Plus (QFT-i) underwent a second test within 4 weeks (QFT-1), and if negative, underwent a repeat test 4 weeks later (QFT-2). Based on the QFT-2 result, we classified cases as sustained reversion if they remained negative and as temporary reversion if they turned positive. RESULTS: We included 415 contacts, of whom 96 (23.1%) had an initial positive test (QFT-i). Following this, 10 had negative QFT-1 results and 4 (4.2%) of these persisted with a negative result in the QFT-2 (sustained reversions). All four sustained reversions occurred in contacts with IFN-γ concentrations between ≥0.35 and ≤0.99 IU•mL-1 in one or both QFT-i tubes. CONCLUSION: In this study, TB contact investigations rarely reveal QFT-Plus reversion. These results do not support retesting cases with an initial positive result to reduce the number of preventive treatments.

In vitro acquisition of secondary azole resistance in Aspergillus fumigatus isolates after prolonged exposure to itraconazole: presence of heteroresistant populations.

Secondary resistance to azoles in Aspergillus fumigatus isolates from patients taking long-term itraconazole therapy has been described. We studied the acquisition of secondary azole resistance in 20 A. fumigatus isolates with no mutations at codon 54, 98, 138, 220, 432, or 448 in the cyp51A gene. Adjusted conidium inocula (3 × 10(7) CFU/ml) of each isolate were prepared and progressively or directly exposed to increasing itraconazole concentrations, ranging from 0.5 µg/ml to 16 µg/ml. Itraconazole, voriconazole, and posaconazole MICs were determined using the CLSI M38-A2 procedure before (MIC(initial)) and after (MIC(final)) exposure to itraconazole. In both procedures, the MIC(final) was significantly higher than the MIC(initial). However, after progressive exposure to itraconazole, the MICs of the three azoles were higher than after direct exposure. No mutations were found at codon 54, 98, 138, 220, 432, or 448 in the cyp51A gene of isolates growing at the highest concentration of itraconazole. More concentrated conidium inocula (2 × 10(9) CFU/ml) plated in itraconazole at 4 µg/ml revealed the presence of heteroresistant populations in two initially wild-type isolates. These isolates became resistant to itraconazole and posaconazole only after use of the concentrated inoculum. These heteroresistant isolates harbored a mutation at codon G54, and the MICs of itraconazole and posaconazole were >16 µg/ml. In all procedures, A. fumigatus short tandem repeat (STRAf) typing was used to demonstrate that the genotype did not change before or after exposure to itraconazole.

Rapid detection and identification of Aspergillus from lower respiratory tract specimens by use of a combined probe-high-resolution melting analysis.

Diagnosis of invasive aspergillosis (IA) requires increasingly rapid molecular methods that enable sensitive detection and discrimination between species. We designed and evaluated a real-time PCR-based method that combined melting temperature (T(m)) calling analysis of a specific probe with high-resolution melting analysis of the full amplicon. The test correctly identified 78 isolates of Aspergillus section Fumigati and non-Fumigati sections of Aspergillus with a limit of detection of 10(2) conidia/ml (10(2) fg/ml). No cross-reactivity with other fungi was found. The assay was further validated on lower respiratory tract specimens containing Aspergillus or not. It successfully identified Aspergillus to section level in 56 of 59 specimens. With culture as the gold standard, our assay shows 100% sensitivity and specificity and constitutes an efficient alternative for identification of Aspergillus in lower respiratory tract samples.

Comparison of three short-course rifamycin-based regimens for the prevention of tuberculosis in patients with end-stage kidney disease: Study protocol for a randomised clinical trial (RIFAKiD-TB trial).

BACKGROUND AND PURPOSE: Screening for and treatment of latent tuberculosis (TB) in patients with end-stage kidney disease (ESKD) are recommended. However, there is limited evidence on safety and treatment completion in this population. The objective of the study is to evaluate three short-course rifamycin-based regimens for the treatment of latent TB in ESKD patients. METHODS: Study design and setting. This is a prospective, open label, randomized clinical trial, that will be conducted at seven teaching hospitals in Spain. Study population, randomization, and interventions. Consecutive adult patients with ESKD requiring treatment for a latent TB infection will be randomly allocated (1:1:1) to receive one of the three treatment regimens of the study: three months of daily isoniazid plus rifampicin (3HR); three months of once-weekly isoniazid plus rifapentine (3HP); or four months of daily rifampicin (4R). Participants will be followed regularly through pre-established visits and a blood test schedule from enrolment to a month after finishing the assigned treatment. Outcomes. The primary outcome will be treatment completion, while the secondary outcomes will be discontinuation of the assigned treatment due to adverse events, related or unrelated to the study treatment; definitive discontinuation of the assigned treatment because of adverse events related to the treatment of the study, and death. Sample size. Two hundred and twenty-five subjects (75 per arm) will be enrolled, which will enable the demonstration, if it exists, of an increase of 0.16 in treatment completion rates either in the 3HP or 4R arm with respect to the 3HR arm. DISCUSSION: Results of this clinical trial will contribute to evidence-based recommendations on the management of latent TB infection in ESKD patients. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT05021731.

Aspergillus fumigatus strains with mutations in the cyp51A gene do not always show phenotypic resistance to itraconazole, voriconazole, or posaconazole.

We performed molecular identification of 98 Aspergillus fumigatus complex isolates with MICs of 1 to 4 µg/ml for itraconazole and searched for the presence of mutations in cyp51A. Most of the isolates (91%) belonged to A. fumigatus sensu stricto. We found 14 different mutations in nine isolates at codons different from G54, M220, G138, G448, and L98. We report new mutations at positions 165, 262, 479, and 497 (silent). The role of these mutations should be analyzed.

Identification of Recent Tuberculosis Exposure Using QuantiFERON-TB Gold Plus, a Multicenter Study.

We investigated whether the difference of antigen tube 2 (TB2) minus antigen tube 1 (TB1) (TB2-TB1) of the QuantiFERON-TB gold plus test, which has been postulated as a surrogate for the CD8+ T-cell response, could be useful in identifying recent tuberculosis (TB) exposure. We looked at the interferon gamma (IFN-γ) responses and differences in TB2 and TB1 tubes for 686 adults with QFT-plus positive test results. These results were compared among groups with high (368 TB contacts), low (229 patients with immune-mediated inflammatory diseases [IMID]), and indeterminate (89 asylum seekers or people from abroad [ASPFA]) risks of recent TB exposure. A TB2-TB1 value >0.6 IU·ml-1 was deemed to indicate a true difference between tubes. In the whole cohort, 13.6%, 10.9%, and 11.2% of cases had a TB2>TB1 result in the contact, IMID, and ASPFA groups, respectively (P = 0.591). The adjusted odds ratios (aORs) for an association between a TB2-TB1 result of >0.6 IU·ml-1 and risk of recent exposure versus contacts were 0.71 (95% confidence interval [CI], 0.31 to 1.61) for the IMID group and 0.86 (95% CI, 0.49 to 1.52) for the ASPFA group. In TB contact subgroups, 11.4%, 15.4%, and 17.7% with close, frequent, and sporadic contact had a TB2>TB1 result (P = 0.362). The aORs versus the close subgroup were 1.29 (95% CI, 0.63 to 2.62) for the frequent subgroup and 1.55 (95% CI, 0.67 to 3.60) for the sporadic subgroup. A TB2-TB1 difference of >0.6 IU·ml-1 was not associated with increased risk of recent TB exposure, which puts into question the clinical potential as a proxy marker for recently acquired TB infection. IMPORTANCE Contact tuberculosis tracing is essential to identify recently infected people, who therefore merit preventive treatment. However, there are no diagnostic tests that can determine whether the infection is a result of a recent exposure or not. It has been suggested that by using the QuantiFERON-TB gold plus, an interferon gamma (IFN-γ) release assay, a difference in IFN-γ production between the two antigen tubes (TB2 minus TB1) of >0.6 IU·ml-1 could serve as a proxy marker for recent infection. In this large multinational study, infected individuals could not be classified according to the risk of recent exposure based on differences in IFN-γ in TB1 and TB2 tubes that were higher than 0.6 IU·ml-1. QuantiFERON-TB gold plus is not able to distinguish between recent and remotely acquired tuberculosis infection, and it should not be used for that purpose in contact tuberculosis tracing.

In vitro antifungal activities of isavuconazole and comparators against rare yeast pathogens.

We compared the in vitro activities of isavuconazole, posaconazole, voriconazole, and fluconazole against Dipodascus capitatus (n = 21), Saccharomyces cerevisiae (n = 20), Rhodotorula mucilaginosa (n = 18), and Trichosporon spp. (n = 15). The MIC(50)s, MIC(90)s, and MIC ranges (in microg/ml) obtained using the CLSI M27-A3 procedure were as follows: isavuconazole, 0.125, 0.5, and < or = 0.015 to 2; posaconazole, 0.5, 2, and < or = 0.015 to > 16; voriconazole, 0.125, 2, and < or = 0.015 to 8; and fluconazole, 4, > 128, and < or = 0.125 to > 128. Isavuconazole showed potent activity against the isolates studied.

Rapid antifungal susceptibility determination for yeast isolates by use of Etest performed directly on blood samples from patients with fungemia.

We prospectively determined the antifungal susceptibility of yeast isolates causing fungemia using the Etest on direct blood samples (195 prospectively collected and 133 laboratory prepared). We compared the Etest direct (24 h of incubation) with CLSI M27-A3 and the standard Etest methodologies for fluconazole, voriconazole, posaconazole, isavuconazole, caspofungin, and amphotericin B. Strains were classified as susceptible, resistant, or nonsusceptible using CLSI breakpoints (voriconazole breakpoints were used for posaconazole and isavuconazole). Categorical errors between Etest direct and CLSI M27-A3 for azoles were mostly minor. No errors were detected for caspofungin, and high percentages of major errors were detected for amphotericin B. For the azoles, false susceptibility (very major errors) was found in only two (0.6%) isolates (Candida tropicalis and C. glabrata). False resistance (major errors) was detected in 46 (14%) isolates for the three azoles (in 23 [7%] after excluding posaconazole). Etest direct of posaconazole yielded a higher number of major errors than the remaining azoles, especially for C. glabrata, Candida spp., and other yeasts. Excluding C. glabrata, Candida spp., and other yeasts, the remaining species did not yield major errors. Etest direct for fluconazole, voriconazole, isavuconazole, and caspofungin shows potential as an alternative to the CLSI M27-A3 procedure for performing rapid antifungal susceptibility tests on yeast isolates from patients with fungemia. Etest direct is a useful tool to screen for the presence of azole-resistant and caspofungin-nonsusceptible strains.

Oxidative Stress and Inflammation in First-Episode Psychosis: A Systematic Review and Meta-analysis.

Despite mixed findings, increasing evidence suggests that people with first-episode psychosis (FEP) show increased pro-inflammatory and pro-oxidative status. We used the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines to conduct a systematic literature search of cross-sectional studies comparing in vivo inflammatory and oxidative blood markers between FEP patients and healthy controls. We analyzed 61 independent samples from 59 publications, including 3002 patients with FEP (ie, patients with FEP, early psychosis, first-episode schizophrenia or early schizophrenia) and 2806 controls. After controlling for multiple comparisons, our meta-analysis showed that total antioxidant status and docosahexaenoic acid levels were significantly lower in FEP patients than in controls, whereas levels of homocysteine, interleukin-6 and tumor necrosis factor alpha were significantly higher in FEP patients than in controls. This suggests that FEP patients had reduced antioxidant status and a pro-inflammatory imbalance, and that these biological processes may be targets for managing FEP.

Clinical isolates of Aspergillus species remain fully susceptible to voriconazole in the post-voriconazole era.

We studied the activity of voriconazole against 400 clinical strains of Aspergillus from the pre-voriconazole (1999 to 2002) and post-voriconazole (2003 to 2007) periods. Although the mean MICs of strains from the post-voriconazole period were slightly higher (0.39 versus 0.57 microg/ml; P < 0.001), all strains were susceptible to voriconazole and presented an MIC of

In vitro antifungal activities of isavuconazole (BAL4815), voriconazole, and fluconazole against 1,007 isolates of zygomycete, Candida, Aspergillus, Fusarium, and Scedosporium species.

Isavuconazole (BAL4815) is a promising novel broad-spectrum triazole in late-stage clinical development that has proven active in vitro against Aspergillus and Candida species. We compared the in vitro activities of this agent with those of voriconazole and fluconazole by the CLSI (formerly NCCLS) M38-A and M27-A2 procedures against a large collection of 1,007 relevant opportunistic fungi collected from 1986 to 2007: Aspergillus spp. (n = 702), Candida spp. (n = 218), Zygomycetes (n = 45), Scedosporium spp. (n = 22), and Fusarium spp. (n = 20). All Candida isolates were from patients with candidemia. For isavuconazole, these techniques were also compared with the Etest. Isavuconazole and voriconazole had MICs at which 50% and 90% of isolates were inhibited (MIC50 and MIC90), respectively, of 1 and 1 microg/ml and 0.5 and 1 microg/ml against Aspergillus spp. and of < or = 0.015 [corrected] and 0.03 microg/ml and 0.25 and 0.125 microg/ml against Candida spp. (including fluconazole-resistant strains). The MIC50 partial and complete inhibition end points of isavuconazole and voriconazole against the non-Aspergillus molds were as follows: 1 and 2 microg/ml and 16 and >16 mug/ml against Zygomycetes; 1 and 4 microg/ml and 0.25 and 0.5 microg/ml against Scedosporium apiospermum; 4 to 16 and >16 microg/ml and 4 to 8 and 16 to >16 microg/ml (ranges) against Scedosporium prolificans; and 16 and 16 microg/ml and 4 and 4 microg/ml against Fusarium spp. Isavuconazole showed minimal fungicidal concentrations for 50% and 90% of the isolates of 1 and 1 microg/ml against Aspergillus, 16 and >16 microg/ml against Candida, and 4 and >16 microg/ml against Zygomycetes, respectively, and >16 microg/ml against the remaining molds. The Etest proved to be a suitable alternative method for determining the antifungal activities of isavuconazole against Aspergillus and Candida; the Etest results showed 96% and 93% agreement with the results of the CLSI M38-A and M27-A2 methods, respectively.