Real-world Experience of Posaconazole Therapeutic Drug Monitoring in Oncology Patients: Clinical Implications of Hypoalbuminemia as a Predictor of Subtherapeutic Posaconazole Levels.

Background: Posaconazole maintains broad antifungal activity and is employed for prevention and treatment of invasive fungal infections in oncology patients. Older formulations required therapeutic drug monitoring, and specific plasma drug levels have been recommended. This study evaluated factors associated with subtherapeutic concentrations with the newer delayed-release tablet formulation. Methods: In this retrospective, single-center cohort study at a national comprehensive cancer center, all oncology patients receiving delayed-release posaconazole at standard dosing of 300 mg orally per day from 06/2021 to 07/2023 with plasma drug concentration evaluation were identified. Demographic, clinical, and laboratory data were evaluated to identify risk factors associated with subtherapeutic drug levels at targets of ≥1.25 µg/mL and ≥1.8 µg/mL. Results: Of 110 patients identified, 98 met criteria for inclusion in the study. The median time from initiation of posaconazole to drug level assessment was 13 days, and the median concentration was 1.29 µg/mL. Of the 22 patients receiving posaconazole for prophylaxis, 5 (22.7%) failed to achieve concentrations ≥0.7 µg/mL, and of 76 patients receiving posaconazole for treatment, 38 (50%) failed to achieve concentrations of ≥1.25 µg/mL. In multivariable analysis, albumin of ≤3 g/dL and ideal body weight ≥60 kg were found to be associated with subtherapeutic levels. For a higher target of ≥1.8 µg/mL, only albumin ≤3 g/dL was associated with subtherapeutic levels for the variables evaluated. Conclusions: A higher initial dosing strategy and therapeutic drug monitoring for oncology patients with albumin ≤3 g/dL receiving posaconazole, particularly for the treatment of invasive fungal infection, could be considered.

Corrigendum: Case report: Initial treatment adjustments and complications in ovarian cancer patient with inborn error of immunity.

[This corrects the article DOI: 10.3389/fonc.2022.843741.].

The epidemiology, demographics, and comorbidities of pulmonary and extra-pulmonary non-tuberculous mycobacterial infections at a large central Florida Academic Hospital.

RATIONALE: In the United States, non-tuberculous mycobacterium (NTM) infections are considered an important cause of morbidity and mortality, especially in people with progressive lung disease. The state of Florida has an extremely high incidence and prevalence of NTM disease which is likely a rapidly emerging infection in the state due to environmental and demographic factors. OBJECTIVES: Adjemian et al. [1] To determine the burden of NTM disease of patients admitted to a large Central Florida academic center, Falkinham [2] to identify the most common risk factors associated with developing NTM disease in this area, and Sfeir et al. [4] to categorize antimicrobial susceptibilities and genetic resistance markers. METHODS: We conducted a retrospective case review from January 1, 2011 to December 31, 2017 in a large university-associated metropolitan hospital in west-central Florida. NTM infections were identified using TheraDoc® during the study period with the inclusion criteria of any inpatient admission, culture confirmed NTM at any site, and age ≥ 12 years. Demographic variables (including residential zip code) and comorbidity data (including solid organ transplant status, HIV status and subsequent testing results, intrinsic pulmonary disease, and cancer diagnosis of any site) were collected for each patient. Microbiologic data collected included NTM species/subspecies, anatomic location of specimen collection, antimicrobial susceptibility including minimum inhibitory concentration (MIC). All collected data were analyzed within Stata/IC14.2. Geospatial relationships between zip codes, diagnosis type, and co-morbidities were computed using Arc GIS Pro. RESULTS: Our results demonstrated that a substantial number of our inpatient cases with NTM were of the M. abscessus group, and with M. avium complex and M. fortuitum also representing the pathogen in numerous cases. Novel findings included compilation of the first hospital wide comprehensive NTM resistance plot to our knowledge. Our results did show a concordance with previous data with expected predominance of NTM inpatient cases in Caucasian males with pre-existing pulmonary disease, though additional work could be done with isolates within the transplant and immunosuppressed populations. CONCLUSIONS: Our data set demonstrates the most common species/subspecies of NTM infections and their associated conditions seen at our central Florida hospital, and includes an antimicrobial sensitivity analysis in toto. This could be insight into the possible prevalence of NTM in the area, and provides the foundation for future studies on both the acquisition and prevention for NTM infections in central Florida.

Anaphylactic Reactions Due to Triatoma protracta (Hemiptera, Reduviidae, Triatominae) and Invasion into a Home in Northern California, USA.

BACKGROUND: Triatoma protracta is a triatomine found naturally throughout many regions of California and has been shown to invade human dwellings and bite residents. A man living in Mendocino County, California, reported developing anaphylactic reactions due to the bite of an "unusual bug", which he had found in his home for several years. METHODS: We conducted environmental, entomological, and clinical investigations to examine the risk for kissing bug invasion, presence of Trypanosoma cruzi, and concerns for Chagas disease at this human dwelling with triatomine invasion. RESULTS: Home assessment revealed several risk factors for triatomine invasion, which includes pack rat infestation, above-ground wooden plank floor without a concrete foundation, canine living in the home, and lack of residual insecticide use. Triatomines were all identified as Triatoma protracta. Midgut molecular analysis of the collected triatomines revealed the detection of T. cruzi discrete typing unit I among one of the kissing bugs. Blood meal PCR-based analysis showed these triatomines had bitten humans, canine and unidentified snake species. The patient was tested for chronic Chagas disease utilizing rapid diagnostic testing and laboratory serological testing, and all were negative. CONCLUSIONS: Triatoma protracta is known to invade human dwellings in the western portions of the United States. This is the first report of T. cruzi-infected triatomines invading homes in Mendocino County, California. Triatoma protracta is a known vector responsible for autochthonous Chagas disease within the United States, and their bites can also trigger serious systemic allergic reactions, such as anaphylaxis.

Severe Case of Plasmodium falciparum Malaria in a Pregnant Woman from Nigeria.

Human malaria has arguably affected more of human history than any other pathogen. Pregnant women have a higher risk of developing severe malaria as well as the risk of severe complications. We present a case of severe malaria in a pregnant patient from sub-Saharan Africa who was treated successfully with artesunate. A 28-year-old Nigerian woman with a 20-week intrauterine pregnancy presented with a five-day history of fever and diffuse joint pains. Evaluation of peripheral thin blood smear demonstrated a parasitemia of 9.8%. The patient was admitted to the intensive care unit, and oral clindamycin/quinine was initiated until intravenous artesunate was obtained. The patient completed four doses of IV artesunate, and after the 4th dose of artesunate, no blood parasites were seen on peripheral smear. The patient was discharged home and, upon clinic follow-up, did not have any further complications associated with either her disease or therapy. A review on the treatment of severe malaria in all trimesters of pregnancy supports the WHO recommendation for intravenous artesunate as the drug of choice. This case illustrates the importance of recognizing malaria in pregnant women from endemic countries and shows that artesunate compounds can be used safely in pregnancy, particularly with high parasitemia.

Outbreak of Acinetobacter baumannii associated with extrinsic contamination of ultrasound gel in a tertiary centre burn unit.

BACKGROUND: During 2011 and 2012, an increase in occurrence of multidrug-resistant Acinetobacter baumannii infections was recorded in the Shands Hospital Burn Intensive Care Unit (BICU). An epidemic curve together with strain typing was consistent with an intermittent common source outbreak. An investigation was therefore initiated. AIM: To identify risk factors for A. baumannii infection, characterize the source of the pathogen, implement control measures to terminate the outbreak, and institute preventive measures. METHODS: We conducted a retrospective case-control study; reviewed BICU infection control policies, practices and procedures, and patient exposure to healthcare workers (HCWs), and obtained epidemiologically-directed environmental cultures. FINDINGS: Eleven patients met the case definition. On multivariate analysis, case-patients were more likely to have undergone an ultrasound procedure in the BICU (adjusted odds ratio [AOR]: 19.5; confidence interval [CI]: 2.4-435) or have a FlexiSeal™ device (AOR: 11.9, CI:1.3-276). Epidemiologically-directed cultures of the environment, ultrasound equipment, and ultrasound gel from opened containers on the ultrasound trolley and in the Ultrasound Department were negative for the outbreak pathogen. Culture of an open ultrasound gel dispenser stored in the Ultrasound Department yielded an A. baumannii strain with DNA banding patterns identical to the outbreak strain. CONCLUSIONS: Based on data from our epidemiologic, microbiologic, and observational studies, we believe that inadvertent extrinsic contamination of the gel dispenser occurred in the Ultrasound Department. Contaminated gel was then dispensed into multiuse vials of gel stored on the mobile carts. The outbreak was stemmed by instituting changes in practices in the Ultrasound Department, including introduction of single-use ultrasound vials and storage of ultrasound gel.

Magnetoelectric Radical Hydrocarbons.

The molecular radicals, systems with unpaired electrons of open-shell electronic structures, set the stage for a multidisciplinary science frontier relevant to the cooperative magnetic exchange interaction and magnetoelectric effect. Here ferroelectricity together with magnetic spin exchange coupling in molecular radical hydrocarbon solids is reported, representing a new class of magnetoelectrics. Electronic correlation through radical-radical interactions plays a decisive role in the coupling between magnetic and charge orders. A substantial photoconductance and visible-light photovoltaic effect are found in radical hydrocarbons. The ability to simultaneously control and retrieve the changes in magnetic and electrical responses opens up a new breadth of applications, such as radical magnetoelectrics, magnets, and optoelectronics.

Case Report: Olecranon Bursitis due to Prototheca wickerhamii in an Immunocompromised Patient.

Human protothecosis is a rare algal infection caused by Prototheca; it is a ubiquitous achlorophyllic alga, which rarely causes human disease. Currently, the pathogenesis remains unclear and no treatment options have been elucidated. We present a case of olecranon bursitis caused by Prototheca wickerhamii in an immunocompromised patient. A 45-year-old man presented with left elbow pain after scraping his elbow on a tree. He reported significant pain and swelling of the elbow after injury, which resolved without intervention. He was diagnosed with HIV/AIDS infection and started on antiretroviral therapy. Afterward, he experienced recurrent elbow swelling and pain; an incision and drainage was performed and cultures demonstrated P. wickerhamii. Unsuccessful treatment with oral voriconazole led to an attempt at therapy with parental amphotericin and oral doxycycline; however the patient left against medical advice. He presented to our facility and both parental amphotericin and doxycycline were initiated with planned outpatient bursectomy. He clinically improved on that regimen but left against medical advice before completing his recommended course of IV amphotericin and oral doxycycline. Patients diagnosed with disseminated protothecosis can have a mortality rate upward of 67%. Given the rarity of this pathogen, no official treatment guidelines exist and there are few studies analyzing the antimicrobial susceptibility of Prototheca. Management is challenging because of slow-growing nature of the algae, paucity of research studies, and limited susceptibility of this pathogen. This case adds to the limited body of literature by demonstrating the clinical presentation of protothecosis and highlighting the pathology and current treatment options.

Seroepidemiology of Burkholderia pseudomallei, Etiologic Agent of Melioidosis, in the Ouest and Sud-Est Departments of Haiti.

Burkholderia pseudomallei, the etiological agent of melioidosis, has been hypothesized to be endemic throughout the Caribbean, including the impoverished nation of Haiti. However, because of the protean clinical manifestations, presence of asymptomatic infections, and limited medical diagnostic capacity, the identification of active melioidosis cases remains challenging. A seroepidemiological study was conducted using a novel enzyme-linked immunosorbent assay (ELISA) to detect antibodies toward B. pseudomallei in the native population. The performance of an indirect ELISA with purified lipopolysaccharide (LPS) from B. pseudomallei was evaluated using serum collected from rhesus macaques exposed to aerosolized B. pseudomallei. After optimization, serum collected from asymptomatic population members (n = 756) was screened for polyvalent (immunoglobulin M [IgM]/ immunoglobulin G [IgG]/ immunoglobulin A) and monoclonal (IgG or IgM) immunoglobulins against B. pseudomallei LPS. The population seroprevalence was 11.5% (95% confidence interval [CI]: 9.2, 13.8) for polyvalent immunoglobulins, 9.8% (95% CI: 7.7, 11.9) for IgG, and 1.7% (95% CI: 0.8, 2.6%) for IgM. The seroprevalence was not significantly different by gender (P = 0.16), but increased significantly (P < 0.001) with age, yielding an estimated annual seroconversion rate of 1.05% (95% CI: 0.81, 1.3). The detection of both recent (IgM+) and previous (IgG+) exposure to B. pseudomallei provides serological evidence that melioidosis is endemic in Haiti.

Deciphering the mechanism of O2 reduction with electronically tunable non-heme iron enzyme model complexes.

A homologous series of electronically tuned 2,2',2''-nitrilotris(N-arylacetamide) pre-ligands (H3LR ) were prepared (R = NO2, CN, CF3, F, Cl, Br, Et, Me, H, OMe, NMe2) and some of their corresponding Fe and Zn species synthesized. The iron complexes react rapidly with O2, the final products of which are diferric mu-oxo bridged species. The crystal structure of the oxidized product obtained from DMA solutions contain a structural motif found in some diiron proteins. The mechanism of iron mediated O2 reduction was explored to the extent that allowed us to construct an empirically consistent rate law. A Hammett plot was constructed that enabled insightful information into the rate-determining step and hence allows for a differentiation between two kinetically equivalent O2 reduction mechanisms.

Structural diversity in pyridine and polypyridine adducts of ring slipped manganocene: correlating ligand steric bulk with quantified deviation from ideal hapticity.

We have synthesized several new manganocene-adduct ([Cp2Mn(L)] = 1-L) complexes using pyridine and polypyridine ligands and report their molecular structures and characterization data. Consistent with other molecules in this class [(ηx-Cp)2MnLn] or [(ηx-Cp)2Mn(L-L)] (n = 1, 2; x = 1, 3, or 5), the manganese-cyclopentadienide interaction deviates from the classical ηx interactions (x = 3 or 5). Such deviations have been ascribed to steric factors and often called non-ideal hapticity. However, there is no quantification of this non-ideal hapticity and thus it is difficult to evaluate the extent of ring slippage or assign hapticity. Furthermore, the hypothesis that non-ideal hapticity in high-spin MnII complexes is induced by steric interactions has not been systematically evaluated. Therefore, we report herein a quantified scale for deviation from ideal hapticity between zero (ideal η5 interaction) and one ("η1" interaction). This quantified deviation from ideal hapticity has an empirical relationship with the ligand's steric properties, which strongly supports the premise that steric interactions cause the deviations in ionic M-Cp interactions.

Photochemical Water-Splitting with Organomanganese Complexes.

Certain organometallic chromophores with water-derived ligands, such as the known [Mn(CO)3(µ3-OH)]4 (1) tetramer, drew our attention as possible platforms to study water-splitting reactions. Herein, we investigate the UV irradiation of various tricarbonyl organomanganese complexes, including 1, and demonstrate that dihydrogen, CO, and hydrogen peroxide form as products in a photochemical water-splitting decomposition reaction. The organic and manganese-containing side products are also characterized. Labeling studies with 18O-1 suggest that the source of oxygen atoms in H2O2 originates from free water that interacts with 1 after photochemical dissociation of CO (1-CO) constituting the oxidative half-reaction of water splitting mediated by 1. Hydrogen production from 1 is the result of several different processes, one of which involves the protons derived from the hydroxido ligands in 1 constituting the reductive half-reaction of water splitting mediated by 1. Other processes that generate H2 are also operative and are described. Collectively the results from the photochemical decomposition of 1 provide an opportunity to propose a mechanism, and it is discussed within the context of developing new strategies for water-splitting reactions with organomanganese complexes.

T cell subtypes and reciprocal inflammatory mediator expression differentiate P. falciparum memory recall responses in asymptomatic and symptomatic malaria patients in southeastern Haiti.

Asymptomatic Plasmodium falciparum infection is responsible for maintaining malarial disease within human populations in low transmission countries such as Haiti. Investigating differential host immune responses to the parasite as a potential underlying mechanism could help provide insight into this highly complex phenomenon and possibly identify asymptomatic individuals. We performed a cross-sectional analysis of individuals who were diagnosed with malaria in Sud-Est, Haiti by comparing the cellular and humoral responses of both symptomatic and asymptomatic subjects. Plasma samples were analyzed with a P. falciparum protein microarray, which demonstrated serologic reactivity to 3,877 P. falciparum proteins of known serologic reactivity; however, no antigen-antibody reactions delineating asymptomatics from symptomatics were identified. In contrast, differences in cellular responses were observed. Flow cytometric analysis of patient peripheral blood mononuclear cells co-cultured with P. falciparum infected erythrocytes demonstrated a statistically significant increase in the proportion of T regulatory cells (CD4+ CD25+ CD127-), and increases in unique populations of both NKT-like cells (CD3+ CD8+ CD56+) and CD8mid T cells in asymptomatics compared to symptomatics. Also, CD38+/HLA-DR+ expression on γδ T cells, CD8mid (CD56-) T cells, and CD8mid CD56+ NKT-like cells decreased upon exposure to infected erythrocytes in both groups. Cytometric bead analysis of the co-culture supernatants demonstrated an upregulation of monocyte-activating chemokines/cytokines in asymptomatics, while immunomodulatory soluble factors were elevated in symptomatics. Principal component analysis of these expression values revealed a distinct clustering of individual responses within their respective phenotypic groups. This is the first comprehensive investigation of immune responses to P. falciparum in Haiti, and describes unique cell-mediated immune repertoires that delineate individuals into asymptomatic and symptomatic phenotypes. Future investigations using large scale biological data sets analyzing multiple components of adaptive immunity, could collectively define which cellular responses and molecular correlates of disease outcome are malaria region specific, and which are truly generalizable features of asymptomatic Plasmodium immunity, a research goal of critical priority.

Brucella melitensis T cell epitope recognition in humans with brucellosis in Peru.

Brucella melitensis, one of the causative agents of human brucellosis, causes acute, chronic, and relapsing infection. While T cell immunity in brucellosis has been extensively studied in mice, no recognized human T cell epitopes that might provide new approaches to classifying and prognosticating B. melitensis infection have ever been delineated. Twenty-seven pools of 500 major histocompatibility complex class II (MHC-II) restricted peptides were created by computational prediction of promiscuous MHC-II CD4(+) T cell derived from the top 50 proteins recognized by IgG in human sera on a genome level B. melitensis protein microarray. Gamma interferon (IFN-γ) and interleukin-5 (IL-5) enzyme-linked immunospot (ELISPOT) analyses were used to quantify and compare Th1 and Th2 responses of leukapheresis-obtained peripheral blood mononuclear cells from Peruvian subjects cured after acute infection (n = 9) and from patients who relapsed (n = 5). Four peptide epitopes derived from 3 B. melitensis proteins (BMEI 1330, a DegP/HtrA protease; BMEII 0029, type IV secretion system component VirB5; and BMEII 0691, a predicted periplasmic binding protein of a peptide transport system) were found repeatedly to produce significant IFN-γ ELISPOT responses in both acute-infection and relapsing patients; none of the peptides distinguished the patient groups. IL-5 responses against the panel of peptides were insignificant. These experiments are the first to systematically identify B. melitensis MHC-II-restricted CD4(+) T cell epitopes recognized by the human immune response, with the potential for new approaches to brucellosis diagnostics and understanding the immunopathogenesis related to this intracellular pathogen.

Pathogenomic inference of virulence-associated genes in Leptospira interrogans.

Leptospirosis is a globally important, neglected zoonotic infection caused by spirochetes of the genus Leptospira. Since genetic transformation remains technically limited for pathogenic Leptospira, a systems biology pathogenomic approach was used to infer leptospiral virulence genes by whole genome comparison of culture-attenuated Leptospira interrogans serovar Lai with its virulent, isogenic parent. Among the 11 pathogen-specific protein-coding genes in which non-synonymous mutations were found, a putative soluble adenylate cyclase with host cell cAMP-elevating activity, and two members of a previously unstudied ∼15 member paralogous gene family of unknown function were identified. This gene family was also uniquely found in the alpha-proteobacteria Bartonella bacilliformis and Bartonella australis that are geographically restricted to the Andes and Australia, respectively. How the pathogenic Leptospira and these two Bartonella species came to share this expanded gene family remains an evolutionary mystery. In vivo expression analyses demonstrated up-regulation of 10/11 Leptospira genes identified in the attenuation screen, and profound in vivo, tissue-specific up-regulation by members of the paralogous gene family, suggesting a direct role in virulence and host-pathogen interactions. The pathogenomic experimental design here is generalizable as a functional systems biology approach to studying bacterial pathogenesis and virulence and should encourage similar experimental studies of other pathogens.

Antigen-specific acquired immunity in human brucellosis: implications for diagnosis, prognosis, and vaccine development.

Brucella spp., are Gram negative bacteria that cause disease by growing within monocyte/macrophage lineage cells. Clinical manifestations of brucellosis are immune mediated, not due to bacterial virulence factors. Acquired immunity to brucellosis has been studied through observations of naturally infected hosts (cattle, goats), mouse models (mice), and human infection. Even though Brucella spp. are known for producing mechanisms that evade the immune system, cell-mediated immune responses drive the clinical manifestations of human disease after exposure to Brucella species, as high antibody responses are not associated with protective immunity. The precise mechanisms by which cell-mediated immune responses confer protection or lead to disease manifestations remain undefined. Descriptive studies of immune responses in human brucellosis show that TH(1) (interferon-γ-producing T cells) are associated with dominant immune responses, findings consistent with animal studies. Whether these T cell responses are protective, or determine the different clinical responses associated with brucellosis is unknown, especially with regard to undulant fever manifestations, relapsing disease, or are associated with responses to distinct sets of Brucella spp. antigens are unknown. Few data regarding T cell responses in terms of specific recognition of Brucella spp. protein antigens and peptidic epitopes, either by CD4+ or CD8+ T cells, have been identified in human brucellosis patients. Additionally because current attenuated Brucella vaccines used in animals cause human disease, there is a true need for a recombinant protein subunit vaccine for human brucellosis, as well as for improved diagnostics in terms of prognosis and identification of unusual forms of brucellosis. This review will focus on current understandings of antigen-specific immune responses induced Brucella peptidic epitopes that has promise for yielding new insights into vaccine and diagnostics development, and for understanding pathogenetic mechanisms of human brucellosis.

Serial kinetics of the antibody response against the complete Brucella melitensis ORFeome in focal vertebral brucellosis.

Human brucellosis is a common zoonosis worldwide. Here we present a case of focal vertebral brucellosis in a 71-year-old Mexican-American woman who contracted infection from unpasteurized goat milk. Standard agglutination serology was negative; the diagnosis was established by the isolation of Brucella melitensis from abscess fluid. A B. melitensis protein microarray comprised of nearly all proteins encoded by the bacterial genome was used to determine the kinetics of this patient's antibody responses to the complete collection of open reading frames existing in the genome (ORFeome). Three patterns of antibody responses against B. melitensis antigens were seen for serum samples obtained on days 0 (pretreatment), 14, 49, 100, and 180: (i) stable titers over time, (ii) a steady fall in titers, and (iii) an initial rise in titers followed by declining titers. Sera from this patient with chronic brucellosis recognized some of the same B. melitensis proteins as those recognized by sera from acute/subacute, blood culture-positive brucellosis patients but also recognized a distinct set of proteins. This study is the first to determine the kinetics of the human antibody responses to the complete repertoire of proteins encoded by a bacterial genome and demonstrates fundamentally different immunopathogenetic mechanisms between acute human brucellosis and chronic human brucellosis. While an extension of these findings to a larger patient population is necessary, these findings have important clinical and diagnostic implications and lead toward new insights into the fundamental immunopathogenesis of brucellosis.

A cluster of cutaneous leishmaniasis associated with human smuggling.

Cutaneous leishmaniasis (CL) is rarely seen in the United States, and the social and geographic context of the infection can be a key to its diagnosis and management. Four Somali and one Ethiopian, in U.S. Border Patrol custody, came to the United States by the same human trafficking route: Djibouti to Dubai to Moscow to Havana to Quito; and then by ground by Columbia/Panama to the United States-Mexico border where they were detained. Although traveling at different times, all five patients simultaneously presented to our institution with chronic ulcerative skin lesions at different sites and stages of evolution. Culture of biopsy specimens grew Leishmania panamensis. Soon thereafter, three individuals from East Africa traveling the identical route presented with L. panamensis CL to physicians in Tacoma, WA. We document here the association of a human trafficking route and new world CL. Clinicians and public health officials should be aware of this emerging infectious disease risk.