Presentation, management, and outcomes of norovirus in adult and pediatric solid organ and hematopoietic stem cell transplant recipients: A multicenter, retrospective study.

BACKGROUND: Norovirus (NoV) can cause chronic relapsing and remitting diarrhea in immunocompromised patients.  Few multicenter studies have described the clinical course, outcomes, and complications of chronic NoV in transplant recipients. METHODS: A multicenter retrospective study of adult and pediatric SOT and HSCT recipients diagnosed with NoV between November 1, 2017, and February 28, 2021. Data were obtained from electronic medical records (EMR) and entered into a central REDCap database. Descriptive statistics were calculated. RESULTS: A total of 280 NoV+ patients were identified across eight sites. The majority were adults (74.1%) and SOT recipients (91.4%). Initial diagnosis of NoV occurred a median of 36 months post-Tx (IQR [15.0, 90.0]). Most NoV cases had >3 diarrheal episodes daily (66.0%), nausea and vomiting (60.1%). Duration of diarrhea varied greatly (median = 10 days, mean = 85.9 days, range (1, 2100)). 71.3% were hospitalized. Adjustment of immunosuppression, including reduction and discontinuation of mToR inhibitor, CNI, and/or MMF, was the most common management intervention for NoV. Other therapies resulted only in temporary improvement. Four patients died within 30 days and three others died by 180 days postdiagnosis. Clinically significant renal dysfunction was observed in 12.5% by 30 days and 21.4% by 180 days post-NoV diagnosis. CONCLUSION: In HSCT and SOT patients, NoV frequently resulted in severe symptoms, prolonged diarrhea (30% persistent with diarrhea for >30 days), and clinically significant renal dysfunction (up to 21% of patients). Utilized therapies did not reliably result in the resolution of infection demonstrating the need for more effective treatment.

A conceptual framework for nomenclatural stability and validity of medically important fungi: a proposed global consensus guideline for fungal name changes supported by ABP, ASM, CLSI, ECMM, ESCMID-EFISG, EUCAST-AFST, FDLC, IDSA, ISHAM, MMSA, and MSGERC.

The rapid pace of name changes of medically important fungi is creating challenges for clinical laboratories and clinicians involved in patient care. We describe two sources of name change which have different drivers, at the species versus the genus level. Some suggestions are made here to reduce the number of name changes. We urge taxonomists to provide diagnostic markers of taxonomic novelties. Given the instability of phylogenetic trees due to variable taxon sampling, we advocate to maintain genera at the largest possible size. Reporting of identified species in complexes or series should where possible comprise both the name of the overarching species and that of the molecular sibling, often cryptic species. Because the use of different names for the same species will be unavoidable for many years to come, an open access online database of the names of all medically important fungi, with proper nomenclatural designation and synonymy, is essential. We further recommend that while taxonomic discovery continues, the adaptation of new name changes by clinical laboratories and clinicians be reviewed routinely by a standing committee for validation and stability over time, with reference to an open access database, wherein reasons for changes are listed in a transparent way.

Magnetic Susceptibility of Andreev Bound States in Superfluid

Nuclear magnetic resonance measurements of the magnetic susceptibility of superfluid ^{3}He imbibed in anisotropic aerogel reveal anomalous behavior at low temperatures. Although the frequency shift clearly identifies a low-temperature phase as the B phase, the magnetic susceptibility does not display the expected decrease associated with the formation of the opposite-spin Cooper pairs. This susceptibility anomaly appears to be the predicted high-field behavior corresponding to the Ising-like magnetic character of surface Andreev bound states within the planar aerogel structures.

Alcohol use as a mediator of the effect of two alcohol reduction interventions on mental health symptoms of ART clients in Vietnam.

We aimed to examine the mediating role of alcohol use in the pathway from the interventions to depression and anxiety symptoms using data from a randomized controlled trial among people living with HIV (PWH) with hazardous alcohol use (n = 440) in Thai Nguyen, Vietnam. Participants were randomized into either a combined intervention (CoI), a brief intervention (BI) and a standard of care arm. Both interventions were based on cognitive behavioral therapy and motivational enhancement therapy. Alcohol use was measured as the percentage of days abstinent from alcohol in the last 30 days. Symptoms of depression and anxiety were measured with the Patient Health Questionnaire-9 and Generalized Anxiety Disorder-7 scales. Alcohol use was a significant mediator of the effects of two alcohol interventions on depression symptoms, but not anxiety symptoms. There were significant indirect effects via alcohol use of both interventions on depression symptoms at 12 months (CoI: mean difference (MD) = -0.134; 95%CI: -0.251, -0.035); (BI: MD = -0.141; 95%CI: -0.261, -0.038). There were no significant direct or total effects of the interventions on either symptoms at 12 months. Interventions with a dual focus on mental health and alcohol disorders are needed to determine optimal ways to tackle these common comorbidities among PWH.

Complete genome sequence of a novel lytic phage of Xanthomonas oryzae pv. oryzae, the bacterial leaf blight pathogen in rice.

Bacteriophage L522, which infects Xanthomonas oryzae pv. oryzae, was isolated from a paddy leaf sample collected in Long An province, Vietnam. The phage shows myovirus morphology based on transmission electron microscopy. It displays a latent period and burst size of approximately 3 h and 63 new virions per infected cell (PFU/infected cell), respectively. The genome of L522 is 44,497 bp in length, with 52% GC content. Of the 63 genes identified, functions were predicted for 26. No virulence or antibiotic-resistance genes were detected. The results of a BLASTn search showed similarity to a previously reported Xanthomonas phage, with 85% average nucleotide sequence identity and 87.15% query coverage. Thus, this L522 is a representative of a new species in the genus Xipdecavirus.

Particle size as a driver of dewatering performance and its relationship to stabilization in fecal sludge.

Poor and unpredictable dewatering performance of fecal sludge is a major barrier to sanitation provision in urban areas not served by sewers. Fecal sludge comprises everything that accumulates in onsite containments, and its characteristics are distinct from wastewater sludges and from feces. There is little fundamental understanding of what causes poor dewatering in fecal sludge. For the first time, we demonstrate that particle size distribution is a driver of dewatering performance in fecal sludge, and is associated with level of stabilization. Higher concentrations of small particles (<10 µm) and smaller median aggregate size (D50) corresponded to poor dewatering performance (measured by capillary suction time (CST) and supernatant turbidity) in field samples from Kenya and Uganda and in controlled laboratory anaerobic storage experiments. More stabilized fecal sludge (higher C/N, lower VSS/TSS) had better dewatering performance, corresponding to lower concentrations of small particles. Samples with the largest aggregates (D50 > 90 µm) had higher abundance of Gammaproteobacteria Pseudomonas, and samples with the smallest aggregates (D50 ≤ 50 µm) were characterized by higher abundance of Bacteroidetes Vadin HA17 and Rikenellaceae. Contrary to common perceptions, stabilization, particle size distribution, and dewatering performance were not dependent on time intervals between emptying of onsite containments or on time in controlled anaerobic storage experiments. Our results suggest that the stabilization process in onsite containments, and hence the dewaterability of sludge arriving at treatment facilities, is not dependent on time in containment but is more likely associated with specific microbial populations and the in-situ environmental conditions which promote or discourage their growth.

Biological Characterization and Genomic Analysis of Novel Phages DLDT_So2 and BHDT_So9 Against Pseudomonas solanacearum, an Infectious Agent in Tomato in Vietnam.

Tomato (Solanum lycopersicum L.) is an important grown vegetable in Vietnam. Bacterial wilt caused by Pseudomonas solanacearum has been considered to be an important disease resulting in a harvest loss up to 90% and significant economic loss to farmers. In this study, two bacteriophages DLDT_So2 and BHDT_So9 specific to P. solanacearum were isolated. Morphological analysis indicated that DLDT_So2 and BHDT_So9 had podovirus morphology and were classified into Autographiviridae family. The latent period and burst size of DLDT_So2 was found to be approximately 120 min and 20.0 ± 2.4 virions per infected cell. Meanwhile, the latent period of BHDT_So9 was 140 min with a burst size of 11.5 ± 2.8 virions per infected cell. Of the 23 bacterial strains tested, the phages infected 7/11 strains of P. solanacearum and none of the other bacteria tested were susceptible to the phages. Stability of the phages at different temperatures, pHs, solvents was also investigated. The genomes of DLDT_So2 and BHDT_So9 are 41,341 bp and 41,296 bp and long with a total GC content of 63%, contains 48 and 46 predicted protein-encoding CDSs. No virulence or antibiotic resistance genes were found in the genomes, suggesting they would be useful biocontrol agents against P. solanacearum. Classification of the phage using average nucleotide identity, phylogenetic analysis was also carried out. The two phages represented new species when they had overall average nucleotide identity of < 95%. This is first report of the isolation and characterization of P. solanacearum-specific phages from tomato farms in Vietnam. Supplementary Information: The online version contains supplementary material available at 10.1007/s12088-023-01090-9.

Screening for Ocular Candidiasis Among Patients With Candidemia: Is It Time to Change Practice?

Ocular candidiasis (OC) complicates approximately 10% of candidemia and carries potentially severe morbidity. There are conflicting recommendations about the need for routine funduscopic examinations of candidemic patients. Indirect funduscopy is accurate and safe in diagnosing OC, and positive findings change recommended treatment. However, conclusive evidence that treatment changes improve outcomes is lacking. Bringing perspectives as infectious diseases physicians and ophthalmologists, we review controversies about OC and endorse routine screening during candidemia. We acknowledge difficulties in obtaining inpatient ophthalmologic consults and recommend studies to evaluate digital fundus photography and teleophthalmology as an alternative to funduscopic examinations by ophthalmologists in asymptomatic patients.

Molecular Epidemiology, Natural History, and Long-Term Outcomes of Multidrug-Resistant Enterobacterales Colonization and Infections Among Solid Organ Transplant Recipients.

BACKGROUND: Multidrug-resistant Enterobacterales (MDR-E), including carbapenem-resistant and third-generation cephalosporin-resistant Enterobacterales (CRE, CefR-E), are major pathogens following solid organ transplantation (SOT). METHODS: We prospectively studied patients who underwent lung, liver, and small bowel transplant from February 2015 through March 2017. Weekly perirectal swabs (up to 100 days post-transplant) were cultured for MDR-E. Whole-genome sequencing (WGS) was performed on gastrointestinal (GI) tract-colonizing and disease-causing isolates. RESULTS: Twenty-five percent (40 of 162) of patients were MDR-E GI-colonized. Klebsiella pneumoniae was the most common CRE and CefR-E. Klebsiella pneumoniae carbapenemases and CTX-M were leading causes of CR and CefR, respectively. Thirty-five percent of GI colonizers developed MDR-E infection vs 2% of noncolonizers (P < .0001). The attack rate was higher among CRE colonizers than CefR-E colonizers (53% vs 21%, P = .049). GI colonization and high body mass index were independent risk factors for MDR-E infection (P ≤ .004). Thirty-day mortality among infected patients was 6%. However, 44% of survivors developed recurrent infections; 43% of recurrences were late (285 days to 3.9 years after the initial infection). Long-term survival (median, 4.3 years post-transplant) did not differ significantly between MDR-E-infected and MDR-E-noninfected patients (71% vs 77%, P = .56). WGS phylogenetic analyses revealed that infections were caused by GI-colonizing strains and suggested unrecognized transmission of novel clonal group-258 sublineage CR-K. pneumoniae and horizontal transfer of resistance genes. CONCLUSIONS: MDR-E GI colonization was common following SOT and predisposed patients to infections by colonizing strains. MDR-E infections were associated with low short- and long-term mortality, but recurrences were frequent and often occurred years after initial infections. Findings provide support for MDR-E surveillance in our SOT program.

Remediation of Mucorales-contaminated Healthcare Linens at a Laundry Facility Following an Investigation of a Case Cluster of Hospital-acquired Mucormycosis.

BACKGROUND: In an investigation of hospital-acquired mucormycosis cases among transplant recipients, healthcare linens (HCLs) delivered to our center were found to be contaminated with Mucorales. We describe an investigation and remediation of Mucorales contamination at the laundry supplying our center. METHODS: We performed monthly RODAC cultures of HCLs upon hospital arrival, and conducted site inspections and surveillance cultures at the laundry facility. Remediation was designed and implemented by infection prevention and facility leadership teams. RESULTS: Prior to remediation, 20% of HCLs were culture-positive for Mucorales upon hospital arrival. Laundry facility layout and processes were consistent with industry standards. Significant step-ups in Mucorales and mold culture-positivity of HCLs were detected at the post-dryer step (0% to 12% [P = .04] and 5% to 29% [P = .01], respectively). Further increases to 17% and 40% culture-positivity, respectively, were noted during pre-transport holding. Site inspection revealed heavy Mucorales-positive lint accumulation in rooftop air intake and exhaust vents that cooled driers; intake and exhaust vents that were facing each other; rooftop and plant-wide lint accumulation, including in the pre-transport clean room; uncovered carts with freshly-laundered HCLs. Following environmental remediation, quality assurance measures and education directed toward these sources, Mucorales culture-positivity of newly-delivered HCLs was reduced to 0.3% (P = .0001); area of lint-contaminated rooftop decreased from 918 m2 to 0 m2 on satellite images. CONCLUSIONS: Targeted laundry facility interventions guided by site inspections and step-wise culturing significantly reduced Mucorales-contaminated HCLs delivered to our hospital. Collaboration between infection prevention and laundry facility teams was crucial to successful remediation.

Different Conformations Revealed by NMR Underlie Resistance to Ceftazidime/Avibactam and Susceptibility to Meropenem and Imipenem among D179Y Variants of KPC ß-Lactamase.

ß-Lactamase-mediated resistance to ceftazidime-avibactam (CZA) is a serious limitation in the treatment of Gram-negative bacteria harboring Klebsiella pneumoniae carbapenemase (KPC). Herein, the basis of susceptibility to carbapenems and resistance to ceftazidime (CAZ) and CZA of the D179Y variant of KPC-2 and -3 was explored. First, we determined that resistance to CZA in a laboratory strain of Escherichia coli DH10B was not due to increased expression levels of the variant enzymes, as demonstrated by reverse transcription PCR (RT-PCR). Using timed mass spectrometry, the D179Y variant formed prolonged acyl-enzyme complexes with imipenem (IMI) and meropenem (MEM) in KPC-2 and KPC-3, which could be detected up to 24 h, suggesting that IMI and MEM act as covalent ß-lactamase inhibitors more than as substrates for D179Y KPC-2 and -3. This prolonged acyl-enzyme complex of IMI and MEM by D179Y variants was not observed with wild-type (WT) KPCs. CAZ was studied and the D179Y variants also formed acyl-enzyme complexes (1 to 2 h). Thermal denaturation and differential scanning fluorimetry showed that the tyrosine substitution at position 179 destabilized the KPC ß-lactamases (KPC-2/3 melting temperature [Tm] of 54 to 55°C versus D179Y Tm of 47.5 to 51°C), and the D179Y protein was 3% disordered compared to KPC-2 at 318 K. Heteronuclear 1H/15N-heteronuclear single quantum coherence (HSQC) nuclear magnetic resonance (NMR) spectroscopy also revealed that the D179Y variant, compared to KPC-2, is partially disordered. Based upon these observations, we discuss the impact of disordering of the Ω loop as a consequence of the D179Y substitution. These conformational changes and disorder in the overall structure as a result of D179Y contribute to this unanticipated phenotype.

Structural Characterization of the D179N and D179Y Variants of KPC-2 ß-Lactamase: Ω-Loop Destabilization as a Mechanism of Resistance to Ceftazidime-Avibactam.

Klebsiella pneumoniae carbapenemases (KPC-2 and KPC-3) present a global clinical threat, as these ß-lactamases confer resistance to carbapenems and oxyimino-cephalosporins. Recent clinically identified KPC variants with substitutions at Ambler position D179, located in the Ω loop, are resistant to the ß-lactam/ß-lactamase inhibitor combination ceftazidime-avibactam, but susceptible to meropenem-vaborbactam. To gain insights into ceftazidime-avibactam resistance conferred by D179N/Y variants of KPC-2, crystal structures of these variants were determined. The D179N KPC-2 structure revealed that the change of the carboxyl to an amide moiety at position 179 disrupted the salt bridge with R164 present in wild-type KPC-2. Additional interactions were disrupted in the Ω loop, causing a decrease in the melting temperature. Shifts originating from N179 were also transmitted toward the active site, including ∼1-Å shifts of the deacylation water and interacting residue N170. The structure of the D179Y KPC-2 ß-lactamase revealed more drastic changes, as this variant exhibited disorder of the Ω loop, with other flanking regions also being disordered. We postulate that the KPC-2 variants can accommodate ceftazidime because the Ω loop is displaced in D179Y or can be more readily displaced in D179N KPC-2. To understand why the ß-lactamase inhibitor vaborbactam is less affected by the D179 variants than avibactam, we determined the crystal structure of D179N KPC-2 in complex with vaborbactam, which revealed wild-type KPC-2-like vaborbactam-active site interactions. Overall, the structural results regarding KPC-2 D179 variants revealed various degrees of destabilization of the Ω loop that contribute to ceftazidime-avibactam resistance, possible substrate-assisted catalysis of ceftazidime, and meropenem and meropenem-vaborbactam susceptibility.

Antibiotic use during pregnancy and the risk of preterm birth: a population-based Swedish cohort study.

OBJECTIVES: To assess the impact of gestational antibiotics on the risk of preterm birth, since a healthy maternal microbiome may be protective. METHODS: Population-based cohort study including all first pregnancies in Sweden (2006-16). The association between gestational and recent pre-conception systemic antibiotics and preterm birth was assessed by multivariable logistic regression presented as ORs and 95% CIs, adjusted for comorbidities (hypo- and hyperthyroidism, hypertension, or diabetes mellitus pre-gestation), trimester, antibiotic class and treatment duration. RESULTS: Compared with non-users, antibiotic exposure was associated with increased risks of preterm birth in mothers with comorbidities (OR = 1.32, 95% CI 1.18-1.48) and without (OR = 1.09, 95% CI 1.06-1.13). Pre-conception use showed no association, while risk was increased for first and second trimester use and decreased for third trimester use. The increased risks were seen for the following antibiotic groups in mothers without and with comorbidities, respectively: macrolides, lincosamides and streptogramins (OR = 1.63, 95% CI 1.45-1.83; OR = 2.48, 95% CI 1.72-3.56); quinolones (OR = 1.60, 95% CI 1.32-1.94; OR = 2.11, 95% CI 1.12-4.03); non-penicillin ß-lactams (OR = 1.15, 95% CI 1.07-1.24; OR = 1.39, 95% CI 1.07-1.83); other antibacterials (OR = 1.09, 95% CI 1.03-1.14; 1.38, 95% CI 1.16-1.63); and penicillins (OR = 1.04, 95% CI 1.01-1.08; 1.23, 95% CI 1.09-1.40). Antibiotic indications were not available, which could also affect preterm birth. CONCLUSIONS: Antibiotic use during pregnancy was associated with an increased risk of preterm birth, especially in mothers with chronic diseases.

Effects of Two Alcohol Reduction Interventions on Depression and Anxiety Symptoms of ART Clients in Vietnam.

Little is known about the potential mental health impacts of cognitive behavioral therapy and motivational interviewing interventions that focus on alcohol reduction among people with HIV (PWH). Our study aimed to assess the impact of two evidence-based alcohol reduction interventions on depression and anxiety symptoms of antiretroviral therapy (ART) clients with hazardous alcohol use. We conducted a secondary data analysis of data from a three-arm randomized controlled trial among ART clients in Thai Nguyen, Vietnam that evaluated the impacts of two alcohol reduction interventions in Vietnam. ART clients 18 years old or more with hazardous alcohol use (based on the Alcohol Use Disorders Identification Test-Consumption) were enrolled and randomized into one of three arms: Combined intervention, Brief intervention, and Standard of care (SOC). Symptoms of depression, measured with the Patient Health Questionnaire-9, and anxiety, measured with the Generalized Anxiety Disorder-7 scale, were assessed at baseline and 3, 6, and 12 months post-intervention. Generalized estimating equations were used to evaluate the effects of the interventions on depression and anxiety symptoms. The prevalence of depression and anxiety symptoms at baseline was 25.1% and 16.1%, respectively. Decreases in depression and anxiety symptoms were observed in all three arms from baseline to 12-month follow-up. There were no significant differences in depression and anxiety symptoms among participants receiving either intervention, relative to the SOC. Interventions with a dual focus on alcohol and mental health are needed to achieve more pronounced and sustainable improvements in depression and anxiety symptoms for PWH with hazardous alcohol use.

Clostridioides difficile infection in solid organ and hematopoietic stem cell transplant recipients: A prospective multinational study.

BACKGROUND: Clostridioides difficile infection (CDI) is a significant cause of morbidity and mortality in recipients of solid organ transplant (SOT) or hematopoietic stem cell transplant (HSCT). In retrospective single center analyses, severe disease and relapse are common. We undertook an international, prospective cohort study to estimate the response to physician determined antibiotic treatment for CDI in patients with SOT and HSCT. METHODS: Adults with a first episode of CDI within the first 2 years of SOT or HSCT were enrolled. Demographics, comorbidities, and medication history were collected, and over 90 days of follow-up clinical cure, recurrences, and complications were assessed. Logistic regression was used to study associations of baseline predictors of clinical cure and recurrence. Odds ratios (ORs) and 95% confidence intervals (CIs) are cited. RESULTS: A total of 132 patients, 81 SOT and 51 HSCT (32 allogeneic), were enrolled with a median age of 56 years; 82 (62%) were males and 128 (97%) were hospitalized at enrollment. One hundred and six (80.3%) were diagnosed by DNA assay. CDI occurred at a median of 20 days post-transplant (interquartile range, IQR: 6-133). One hundred and eight patients (81.8%) were on proton pump inhibitors; 126 patients (95.5%) received antibiotics within the 6 weeks before CDI. The most common initial CDI treatments prescribed, on or shortly before enrollment, were oral vancomycin alone (50%) and metronidazole alone (36%). Eighty-three percent (95% CI: 76, 89) of patients had clinical cure; 18% (95% CI: 12, 27) of patients had recurrent CDI; global clinical cure occurred in 65.2%. Of the 11 patients who died, two (1.5% of total) were related to CDI. In multivariable logistic regression analyses, the type of initial treatment was associated with clinical cure (p = .009) and recurrence (p = .014). A history of cytomegalovirus (CMV) after transplant was associated with increased risk of recurrence (44% with versus 13% without CMV history; OR: 5.7, 95% CI: 1.5, 21.3; p = .01). CONCLUSIONS: Among adults who develop CDI after SOT or HSCT, despite their immunosuppressed state, the percentage with clinical cure was high and the percentage with recurrence was low. Clinical cure and recurrence varied by type of initial treatment, and CMV viremia/disease was associated with an increased risk of recurrence.

A randomised controlled trial of a novel tramadol chewable tablet: pharmacokinetics and tolerability in children.

Tramadol is a bitter atypical opioid analgesic drug and is prescribed to treat postoperative pain in children. However, in many countries there is no licensed paediatric tramadol formulation available. We have formulated a novel chewable chocolate-based drug delivery system for the administration of tramadol to children. This pilot, single-centre, open-label, randomised clinical study assessed the taste tolerability and comparative population pharmacokinetics of the novel tramadol chewable tablet against a compounded tramadol hydrochloride oral liquid, at a dose of 1 mg.kg-1 . A 5-point facial hedonic scale was used by the children, parents and nurses to assess tolerability. One hundred and forty-one children aged 3-16 years were given tramadol 30 min before general anaesthesia. Blood samples were taken following the induction of anaesthesia and for up to 5 h following tramadol administration. Tramadol and its active metabolite O-desmethyltramadol were analysed using reversed-phase high-performance liquid chromatography. A population pharmacokinetic model was built using non-linear mixed effects modelling. The relative bioavailability for the tablet was 1.25 times higher (95%CI 1.16-1.35) than for tramadol hydrochloride oral liquid, while the absorption rate constant for the tablet was significantly lower (1.97 h-1 vs. 3.34 h-1 , p < 0.001). Larger inter-individual variability in absorption rates were observed with the liquid tramadol. The tramadol chewable tablet was more acceptable in taste to children when assessed by the children, parents and nurses (all p < 0.001). We conclude that the novel tramadol chewable tablet has favourable acceptability and more reliable relative bioavailability in children compared with tramadol hydrochloride oral liquid.

Systemic antifungal therapy with isavuconazonium sulfate or other agents in adults with invasive mucormycosis or invasive aspergillosis (non-fumigatus): A multicentre, non-interventional registry study.

BACKGROUND: Isavuconazole, administered as isavuconazonium sulfate (ISAVUSULF), is a broad-spectrum triazole agent for the treatment of invasive fungal disease. In phase 3 studies, ISAVUSULF showed comparable efficacy to voriconazole and amphotericin B for the treatment of invasive aspergillosis (IA) and invasive mucormycosis (IM), respectively. OBJECTIVES: The objective of this study is to determine all-cause mortality and safety outcomes among adults with IM and/or IA non-fumigatus (nf) treated with ISAVUSULF or other antifungal therapies (AFT). PATIENTS AND METHODS: This multicentre, non-interventional registry enrolled patients aged ≥18 years with IM or IA-nf who received systemic AFT from January 2016 to November 2018. Patients received primary ISAVUSULF, non-primary ISAVUSULF, or other AFT, as monotherapy or combination therapy. The primary end point was all-cause mortality at Days 42 and 84; safety outcomes were adverse drug reactions (ADRs) to ISAVUSULF. RESULTS: Of 204 patients enrolled, 74 received primary ISAVUSULF, 30 non-primary ISAVUSULF, and 100 other AFT. All-cause mortality through Day 42 was numerically lower in the non-primary ISAVUSULF group than in the primary ISAVUSULF and other AFT groups, for patients with IM (20.0% vs. 33.3% and 41.3%, respectively) or IA-nf (0% vs. 14.8% and 17.8%, respectively). All-cause mortality tended to be lower with combination therapy than with monotherapy, except for patients with IM receiving primary ISAVUSULF. Of 111 patients receiving ISAVUSULF, 14 (12.6%) reported ADRs, of whom three (2.7%) developed serious ADRs. There were no drug-related deaths. CONCLUSIONS: This study supports the effectiveness and tolerability of ISAVUSULF in clinical practice. Further research is required to confirm the value of ISAVUSULF combination therapy over monotherapy.

Impact of Revised Infectious Diseases Society of America and Society for Healthcare Epidemiology of America Clinical Practice Guidelines on the Treatment of Clostridium difficile Infections in the United States.

BACKGROUND: Our objective was to determine if oral vancomycin, fidaxomicin, and oral metronidazole use in the United States changed after publication of revised clinical practice guidelines for Clostridium difficile infection (CDI) in February 2018. METHODS: We obtained US antibiotic prescription data (IQVIA) from 2006-August 2019 and used guideline-recommended dosing regimens to estimate monthly numbers of 10-day treatment courses of vancomycin, fidaxomicin and metronidazole. Interrupted time-series analyses were performed, adjusted by month. We compared linear trends for monthly numbers of treatment courses in different time periods. RESULTS: Cumulative treatment courses of oral vancomycin and fidaxomicin increased by 54% (n = 226 166) and 48% (n = 18 518), respectively, in 18 months following guidelines compared with 18 months before; those of oral metronidazole decreased by 3% (n = 238 372). Monthly vancomycin and fidaxomicin use significantly increased throughout the period following revised guidelines (P < .0001 and P = .0002, respectively), whereas that of metronidazole decreased significantly (P < .0001). Monthly vancomycin use increased and metronidazole use decreased to a significantly greater extent after publication of revised guidelines than after publication of clinical trials establishing superiority of vancomycin over metronidazole (P < .0001). CONCLUSIONS: Revised practice guidelines have had a significant impact on CDI treatment in the US. Clinical trial data used for the revised guidelines were available since 2007-2014 and 2011-2012 for oral vancomycin and fidaxomicin, respectively. Guidelines or guidance documents for treating CDI and other infections should be updated in more timely fashion.

Changing Epidemiology and Decreased Mortality Associated With Carbapenem-resistant Gram-negative Bacteria, 2000-2017.

BACKGROUND: Carbapenem-resistant gram-negative bacteria (CRGNB) continue to present a global healthcare crisis. We aimed to identify emerging trends of CRGNB over nearly 2 decades and describe the impact of CRGNB on patient outcomes. METHODS: Patients from whom CRGNB were isolated between 2000 and 2017 were included in the study. Carbapenem resistance was defined by the most recent breakpoints and applied across the study period. Patient demographics, clinical characteristics, and outcomes were retrieved from the electronic health record. RESULTS: A total of 94 888 isolates from 64 422 patients were identified; 9882 (10%) isolates from 4038 patients were carbapenem-resistant. Pseudomonas aeruginosa was the most common CRGNB each year. The second most common CRGNB emerged in waves over time. Carbapenem daily defined doses increased in parallel with CRGNB rates (R2 = 0.8131). The overall 30-day mortality rate was 19%, which decreased from 24% in 2000 to 17% in 2017 (P = .003; R2 = .4330). Among patients with CRGNB bloodstream infections (n = 319), overall 30- and 90-day mortality rates were 27% and 38%, respectively. Charlson score (adjusted odds ratio [aOR], 1.11 per point), intensive care unit residence (aOR, 7.32), and severe liver disease (aOR, 4.8.4) were independent predictors of 30-day mortality, while receipt of transplantation was associated with lower rates of death (aOR, 0.39). Among patients admitted between 2011 and 2017 (n = 2230), 17% died during hospitalization, 32% were transferred to long-term care facilities, and 38% were discharged home. CONCLUSIONS: CRGNB emerged in waves over time, causing high rates of mortality. Despite increasing rates of CRGNB, overall patient outcomes have improved, suggesting that recognition and novel therapeutics have made a major impact.

Isavuconazole Is as Effective as and Better Tolerated Than Voriconazole for Antifungal Prophylaxis in Lung Transplant Recipients.

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: 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 (iAmB) 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 molds and yeasts, respectively, and breakthrough IFI (bIFI) rate was 3%. Outcomes did not significantly differ for patients receiving or not receiving iAmB. Independent risk factors for bIFI and breakthrough invasive mold infection (bIMI) were mold-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 = .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% vs 9%, P = .02). IFIs were associated with increased mortality (P = .0001) and longer hospitalizations (P = .0005). CONCLUSIONS: Isavuconazole was effective and well tolerated as antifungal prophylaxis following lung transplantation.