Real-world reporting rates of administration-site reactions with on-demand treatment of hereditary angioedema attacks.

Background: Hereditary angioedema (HAE) is characterized by recurrent and unpredictable episodes of subcutaneous and/or submucosal swelling. Objective: To characterize the real-world treatment burden associated with existing on-demand therapies, we analyzed administration-site adverse drug reactions (ADR) associated with approved on-demand HAE therapies reported in the U.S. Food and Drug Administration's (FDA) Adverse Event Reporting System (FAERS). Methods: We searched the FAERS database from October 1, 2009, to March 31, 2022, for reports of all FDA-approved on-demand therapies for HAE: plasma-derived C1-inhibitor (pdC1-INH), ecallantide, icatibant, and recombinant C1-inhibitor (rhC1-INH). ADRs in which the drug was listed as the "primary suspect" were recorded for each drug. ADR preferred terms were grouped into 18 ADR domains based on semantic and/or clinical similarity, and the number of reports for each drug was calculated per year from the time of approval through March 2022, and descriptive results were presented. Preferred terms associated with administration-site ADRs identified from clinical trials and denoted on approved HAE drug U.S. package inserts were examined in a complementary analysis. Results: The highest reported rates of administration-site ADRs per year were site pain (17.9 reports per year), site erythema (7.4 per year), and site swelling (6.7 per year). RhC1-INH was the only drug for which access-site complications and/or malfunctions were reported (9.5 per year). PdC1-INH had the highest rate of incorrect route of product administration (3.7 per year). PdC1-INH showed statistically significant elevated reporting rate of injection-site reactions (reporting odds ratio [ROR] 3.59 [2.36-5.46]; empirical Bayesian geometric mean [EBGM] 1.97 [1.39]). Icatibant and rhC1-INH showed a statistical trend toward an increased reporting rate of administration-site reactions. Conclusion: Real-world data from FAERS were generally consistent with adverse events reported in clinical trials and suggest that patients experience substantial treatment burden associated with FDA-approved parenteral on-demand therapies for HAE attacks. It should be noted that ADR rates are not exposure adjusted and are based on spontaneous reporting.

Advent of oral medications for the treatment of hereditary angioedema.

BACKGROUND: Hereditary angioedema (HAE) is a rare genetic disorder characterized by unpredictable, debilitating episodes of submucosal and/or subcutaneous tissue swelling, which may be life-threatening depending on anatomic location. The two primary management strategies for HAE are ready access to effective on-demand treatment in all patients and the prevention of attacks (short-term prophylaxis [STP] and long-term prophylaxis [LTP]) in appropriate patients. All approved on-demand and most LTP medications require subcutaneous or intravenous administration. Injection-related challenges include trypanophobia (fear of needles), difficulty with self-administration, injection-site reactions (e.g., pain, erythema, bleeding, bruising), and anxiety-all contributing to poor compliance and administration delays. Oral HAE treatments may improve outcomes by reducing treatment barriers. AIM: To review oral therapies, approved or in development, for on-demand treatment and/or prevention of HAE attacks. MATERIALS AND METHODS: To provide a comprehensive review, data was obtained from publicly available resources through a targeted PubMed literature review and supplemented by information provided on company websites (search cutoff of May 31, 2024). RESULTS: Berotralstat, an oral plasma kallikrein (PKa) inhibitor, is approved for LTP. Sebetralstat, another PKa inhibitor, is the investigational first oral on-demand HAE treatment to complete a phase 3 trial. Deucrictibant, an oral bradykinin B2 receptor antagonist, has completed phase 2 trials for on-demand therapy and LTP. Several other oral PKa inhibitors (ATN249, VE-4666, and VE-4062) are in early development for LTP. CONCLUSION: Substantial advances have been made in the development of oral treatments for HAE. These treatments have the potential to improve and optimize clinical outcomes, satisfaction, and quality of life among patients with HAE.

Bloodstream and non-invasive isolates of Candida glabrata have similar population structures and fluconazole susceptibilities.

We have compared multilocus sequence typing (MLST) and fluconazole susceptibility profiles of Candida glabrata bloodstream isolates obtained during active, population-based surveillance to those obtained from non-sterile sites of individuals with no evidence of fungal disease (i.e., non-invasive isolates) in the same US city during an overlapping time period. In each of the two populations, different proportions of the same six major sequence types (STs) encompassed 82% of the isolates. One ST was more prevalent in the candidemia population and two other STs were more prevalent in the non-invasive population, but the overall allelic frequencies within the groups suggested little, if any, genotypic diversity between them. Fluconazole susceptibility profiles of isolates from the patients in the two groups were not significantly different and were not associated with a particular sequence type. Our results support the hypothesis that C. glabrata strains causing bloodstream infections are genetically indistinguishable from those normally residing in/on the host, suggesting that relative pathogenicity may be closely tied to commensalism.

Transmission of Cryptococcus neoformans by Organ Transplantation.

BACKGROUND: This article describes transmission of Cryptococcus neoformans by solid organ transplantation. METHODS: We reviewed medical records and performed molecular genotyping of isolates to determine potential for donor transmission of Cryptococcus. RESULTS: Cryptococcosis was diagnosed in 3 recipients of organs from a common donor with an undifferentiated neurologic condition at the time of death. Cryptococcal meningoencephalitis was later diagnosed in the donor at autopsy. The liver and 1 kidney recipient developed cryptococcemia and pneumonia and the other kidney recipient developed cryptococcemia and meningitis; 2 patients recovered with prolonged antifungal therapy. We tested 4 recipient isolates with multilocus sequence typing and found they had identical alleles. CONCLUSIONS: Our investigation documents the transmission of Cryptococcus neoformans by organ transplantation. Evaluation for cryptococcosis in donors with unexplained neurologic symptoms should be strongly considered.

Azole resistance in Aspergillus fumigatus isolates from the ARTEMIS global surveillance study is primarily due to the TR/L98H mutation in the cyp51A gene.

We surveyed 497 isolates of Aspergillus fumigatus collected from 2008 to 2009 as part of the ARTEMIS global surveillance study for elevated MIC values to itraconazole, voriconazole, and posaconazole. Sequencing of the cyp51A gene revealed that 8/29 isolates with elevated MIC values to one or more triazoles, all originating in China, contained the TR/L98H mutation associated with resistant European isolates of A. fumigatus. This is the first time the TR/L98H mutation has been identified outside Europe.

Multilocus sequence type analysis reveals both clonality and recombination in populations of Candida glabrata bloodstream isolates from U.S. surveillance studies.

The human commensal yeast Candida glabrata is becoming increasingly important as an agent of nosocomial bloodstream infection. However, relatively little is known concerning the genetics and population structure of this species. We have analyzed 230 incident bloodstream isolates from previous and current population-based surveillance studies by using multilocus sequence typing (MLST). Our results show that in the U.S. cities of Atlanta, GA; Baltimore, MD; and San Francisco, CA during three time periods spanning 1992 to 2009, five populations of C. glabrata bloodstream isolates are defined by a relatively small number of sequence types. There is little genetic differentiation in the different C. glabrata populations. We also show that there has been a significant temporal shift in the prevalence of one major subtype in Atlanta. Our results support the concept that both recombination and clonality play a role in the population structure of this species.

Candidemia surveillance in Brazil: evidence for a geographical boundary defining an area exhibiting an abatement of infections by Candida albicans group 2 strains.

Prospective population surveillance has been conducted for candidemia in Brazil (A. L. Colombo, M. Nucci, B. J. Park, et al., J. Clin. Microbiol. 44:2816-2823, 2006). In the present study, a total of 63 isolates from 61 patients, representing 11 medical centers from nine geographic regions, were characterized by multilocus sequence typing (MLST). A total of 48 unique profiles or diploid sequence types (DSTs) were observed, with nine new sequence types (STs) and 32 new DSTs. There were no apparent correlations between center/region and DST patterns. Subtypes were compared to those in a known characterized reference set, including a large database of strains obtained worldwide. Significantly, only one C. albicans group 2 isolate was found in our collection, although isolates from this particular group are commonly found worldwide. These data, combined with information from other previously reported studies, establish a statistically significant diminishment of group 2 strains in Central and South America, including Mexico and portions of the Southwestern United States.

Multilocus sequence typing of sequential Candida albicans isolates from patients with persistent or recurrent fungemia.

Multilocus sequence typing (MLST) is a useful tool to explore the phylogenetics and epidemiology of Candida albicans isolates recovered from cases of invasive candidiasis. The goal of this study was to determine whether the same or different strains were responsible for persistent or recurrent fungemia through the use of MLST and ABC typing on sequential C. albicans isolates from the same patient. We applied both typing methods to 21 C. albicans strains recovered from 8 patients with persistent or recurrent candidemia. The isolates were collected during a multicenter surveillance study in four public tertiary care hospitals in Brazil. Persistent candidemia was defined as two or more blood cultures positive for C. albicans on 2 or more separate days. Recurrent candidemia was defined as an episode of candidemia occurring at least 1 month after the apparent complete resolution of an infectious episode caused by Candida species. We observed that, except for one patient, all strains from the first and second samples of the same patient showed the same MLST diploid sequence type (DST), ABC type and susceptibility profile to antifungals. Three distinct strains, well discriminated by MLST, were found in the seven samples collected sequentially over 10 days from one patient. The strains from the first four samples were indistinguishable, the fifth and sixth were also indistinguishable but different from the first four and seventh samples. Significantly, the seventh strain was the only C. albicans clade 2 isolate found in our total collection involving 61 patients, although clade 2 is commonly found worldwide. To the best of our knowledge, this is the first study describing the recovery of three distinct C. albicans strains in the same patient with a persistent blood stream infection within a short period of time.

Rapid quantification of drug resistance gene expression in Candida albicans by reverse transcriptase LightCycler PCR and fluorescent probe hybridization.

We developed a rapid, sensitive, and reproducible assay to quantify Candida albicans ACT1, CDR1, CDR2, ERG11, and MDR1 mRNA using a two-step reverse transcription and LightCycler real-time PCR (RT-LightCycler PCR) method with sequence-specific hybridization probes. We compared RT-LightCycler PCR with Northern hybridization for quantitative analysis of gene expression in isolates with various fluconazole susceptibilities. Specificity of each LightCycler PCR was verified by LightCycler melting curve analysis and agarose gel electrophoresis of amplified products. Correlation of quantification results between RT-LightCycler PCR and Northern hybridization yielded correlation coefficients of > or = 0.91 for all genes except MDR1 (0.74). In this case, reduced correlation was due to the inability of Northern hybridization to accurately quantify the high MDR1 expression in a susceptible dose-dependent isolate which was shown by RT-LightCycler PCR to overexpress MDR1 >200-fold relative to the other isolates tested. In four isolates, low levels of CDR2 mRNA were detected by RT-LightCycler PCR but were undetectable by Northern hybridization. mRNA quantification by RT-LightCycler PCR correlates with Northern hybridization and offers additional advantages, including increased sensitivity and speed of analysis, along with lower RNA concentration requirements and an increased dynamic range of signal detection.

Comparison of visual and spectrophotometric methods of broth microdilution MIC end point determination and evaluation of a sterol quantitation method for in vitro susceptibility testing of fluconazole and itraconazole against trailing and nontrailing Candida isolates.

Visual determination of MIC end points for azole antifungal agents can be complicated by the trailing growth phenomenon. To determine the incidence of trailing growth, we performed testing of in vitro susceptibility to fluconazole and itraconazole using the National Committee for Clinical Laboratory Standards broth microdilution M27-A reference procedure and 944 bloodstream isolates of seven Candida spp., obtained through active population-based surveillance between 1998 and 2000. Of 429 C. albicans isolates, 78 (18.2%) showed trailing growth at 48 h in tests with fluconazole, and 70 (16.3%) showed trailing in tests with itraconazole. Of 118 C. tropicalis isolates, 70 (59.3%) showed trailing growth in tests with fluconazole, and 35 (29.7%) showed trailing in tests with itraconazole. Trailing growth was not observed with any of the other five Candida spp. tested (C. dubliniensis, C. glabrata, C. krusei, C. lusitaniae, and C. parapsilosis). To confirm whether or not isolates that showed trailing growth in fluconazole and/or itraconazole were resistant in vitro to these agents, all isolates that showed trailing growth were retested by the sterol quantitation method, which measures cellular ergosterol content rather than growth inhibition after exposure to azoles. By this method, none of the trailing isolates was resistant in vitro to fluconazole or itraconazole. For both agents, a 24-h visual end point or a spectrophotometric end point of 50% reduction in growth relative to the growth control after 24 or 48 h of incubation correlated most closely with the result of sterol quantitation. Our results indicate that MIC results determined by either of these end point rules may be more predictive of in vivo outcome for isolates that give unclear visual end points at 48 h due to trailing growth.