Search

Bruton's tyrosine kinase inhibitors (BTKis) are the preferred treatment for chronic lymphocytic leukemia (CLL). Despite their therapeutic benefits, these targeted agents have been associated with an increased risk of invasive infections. We describe a 68-year-old male who developed multiple bacterial, fungal and viral infections while on treatment with acalabrutinib. To our knowledge, this is the first reported case of concomitant CNS infections with Cryptococcus neoformans and Aspergillus fumigatus, along with cytomegalovirus (CMV) and herpes simplex virus type 1 (HSV-1) pneumonia while on acalabrutinib. This case adds to the scarce literature of fungal and bacterial infections associated with acalabrutinib, raising the suspicion that infection risk is a medication class effect for BTKis., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: BPW is on the speaker’s bureau for Melinta.

Background: Patients with B-cell lymphoma and acute lymphoblastic leukemia (ALL) who receive chimeric antigen receptor T-cell (CAR-T) therapy may experience clinically significant cytomegalovirus infection (CS-CMVi). However, risk factors for CS-CMVi are not well defined. The aims of our study were to identify risk factors for CS-CMVi and the association between CS-CMVi and nonrelapse mortality (NRM) in lymphoma and ALL patients after CAR-T therapy., Methods: We performed a retrospective single-center cohort analysis of CAR-T recipients between January 2018 and February 2021 for treatment of lymphoma and ALL. We collected data on demographics, oncologic history, CAR-T therapy-related complications, and infectious complications within 1 year of therapy., Results: Of 230 patients identified, 22 (10%) had CS-CMVi. At 1 year following CAR-T therapy, 75 patients (33%) developed relapsed disease and 95 (41%) died; NRM at 1 year was 37%. On Cox regression analysis, Asian or Middle Eastern race (adjusted hazard ratio [aHR], 13.71 [95% confidence interval {CI}, 5.41-34.74]), treatment of cytokine release syndrome/immune effector cell-associated neurotoxicity syndrome with steroids (aHR, 6.25 [95% CI, 1.82-21.47]), lactate dehydrogenase at time of CAR-T therapy (aHR, 1.09 [95% CI, 1.02-1.16]), and CMV surveillance (aHR, 6.91 [95% CI, 2.77-17.25]) were independently associated with CS-CMVi. CS-CMVi was independently associated with NRM at 1 year after CAR-T therapy (odds ratio, 2.49 [95% CI, 1.29-4.82])., Conclusions: Further studies of immunologic correlatives and clinical trials to determine the efficacy of prophylactic strategies are needed to understand the role of CS-CMVi and post-CAR-T mortality., Competing Interests: Potential conflicts of interest. F. K. received research grants paid to his institution from Eurofins Viracor. S. A. received research support paid to the institution for clinical trials from Nektar, Merck, Xencor, Chimagen, Janssen, and Genmab; has served on the scientific advisory committee for Chimagen and the data and safety monitoring board for Myeloid Therapeutics; and is a consultant for ADC Therapeutics and KITE/Gilead. S. P. I. has received research grants paid to his institution from Legend, CRISPR Therapeutics, Spectrum, Takeda, Rhizen, Merck, Yingli, Affrirmed, Innate, and Myeloid; has received honoraria from CureBio and Target Oncology; and has served as a consultant for Salarius Pharmaceuticals, Yingli, and Target Oncology. J. S. received research grants paid to his institution from Ansun BioPharma, Cidara Therapeutics, Community Infusion Solutions, F2G, and Shionogi. K. K. P. has served on the consulting/advisory board and/or scientific committee/chair for BMS, Celgene, Janssen, Kite, Pfizer, Regeneron, AbbVie, Genentech, Sanofi, AstraZeneca, Merck, Caribou Sciences, Oricel, and Arcellx. R. F. C. serves as a consultant, speaker, or scientific advisor for ADMA Biologics, Merck/MSD, Partner Therapeutics, Takeda, Shinogi, AiCuris, Roche/Genentech, Astellas, Adagio Therapeutics, Tether, Pfizer, Oxford Immunotec, InflaRx, Moderna, Karius, and Ansun Pharmaceuticals. He received research grants paid to his institution from Merck, Karius, AiCuris, Ansun Pharmaceuticals, Takeda, Roche/Genentech, Oxford Immunotec, Freestyle, and Eurofins Viracor. All other authors report no potential conflicts., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: Herpesviruses represent common and significant infectious complications after allogeneic haematopoietic cell transplantation (HCT). In the last decade, major advances in the prevention and treatment of these infections were accomplished., Objectives: The aim of this paper is to review the recent advances in the prophylaxis and treatment of herpesvirus infections after allogeneic HCT, to assess the persisting challenges, and to offer future directions for the prevention and management of these infections., Sources: We searched PubMed for relevant literature regarding specific herpesviruses complicating allogeneic HCT through March 2024., Content: The largest advances in this past decade were witnessed for cytomegalovirus (CMV) with the advent of letermovir for primary prophylaxis and the development of maribavir as an option for refractory and/or resistant CMV infections in transplant recipients. For varicella zoster virus, prevention of reactivation with the recombinant zoster vaccine offers an additional prophylactic intervention. Pritelivir is being explored for the treatment of drug-resistant or refractory Herpes simplex virus infections. Although rituximab is now an established option for preemptive therapy for Epstein-Barr virus, Human Herpesvirus-6 remains the most elusive virus of the herpesvirus family, with a lack of evidence supporting the benefit of any agent for prophylaxis or for optimal preemptive therapy., Implications: Although considerable advances have been achieved for the treatment and prevention of herpes virus infections, most notably with CMV, the coming years should hold additional opportunities to tame the beast in these herpesviruses postallogeneic HCT, with the advent of new antivirals, cell-mediated immunity testing, and cytotoxic T lymphocytes infusions., (Copyright © 2024 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Background: There are limited data describing outcomes of patients treated with ceftaroline for infections with CNS or ocular involvement., Objectives: To describe outcomes of patients treated with ceftaroline for methicillin-resistant staphylococcal infections involving the CNS or eye., Patients and Methods: This was a retrospective review of 10 patients at an academic medical centre who received ceftaroline for CNS or ocular infections., Results: All patients were treated with ceftaroline as part of a combination for salvage therapy. Four patients died, whereas six patients experienced clinical cure. Only one experienced microbiological recurrence., Conclusions: These preliminary data suggest that ceftaroline may be an option for salvage therapy of severe staphylococcal infections when used in combination., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy.)

Objectives: Allogeneic haematopoietic cell transplant (allo-HCT) recipients who are cytomegalovirus (CMV)-seronegative have better post-transplant outcomes than CMV-seropositive recipients. Letermovir (LTV) is approved for CMV primary prophylaxis in adults who are CMV-seropositive after allo-HCT, and its use is associated with improved long-term post-transplant outcomes. We analysed whether LTV has affected the relationship between CMV serostatus and post-transplant outcomes., Methods: We conducted a retrospective single-centre cohort study of allo-HCT recipients, stratified according to donor (D) and recipient (R). CMV serostatus and the use of LTV: D - /R - , R + /LTV - , and R + /LTV + . Outcomes measured were all-cause and non-relapse mortality, clinically significant CMV infection, graft-versus-host disease, and relapse up to week 48 after allo-HCT. The D - /R - group served as the reference for comparisons in univariate, competing risk regression, and cumulative incidence functions., Results: The analysis included 1071 consecutive allo-HCT recipients: 131 D - /R - , 557 R+/LTV - , and 383 R+/LTV+. All-cause mortality by day 100 was 6.1% for the D - /R - group, compared with 14.0% (p 0.024) and 7.8% (p 0.7) for the R+/LTV - and R+/LTV + groups, respectively. Non-relapse mortality by day 100 was 11.0%, 6.8% and 3.8% for R+/LTV - , R+/LTV+, and D - /R - groups, respectively, without significant difference. When including relapse as a competing event, the hazard ratio for non-relapse mortality was 1.83 (95% CI: 1.12-2.99, p 0.017) for R+/LTV - compared with D - /R - and 1.05 (95% CI 0.62-1.77, p 0.85) for R+/LTV + compared with D - /R - ., Discussion: CMV primary prophylaxis with LTV abrogated the mortality gap based on CMV serostatus, a protective effect that persisted after discontinuation of primary prophylaxis., (Copyright © 2024 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Background: Coccidioidomycosis is a systemic fungal disease endemic to arid regions of the Western Hemisphere. In the south-western US, Coccidioides spp. may account for up to 20%-25% of all cases of community acquired pneumonia. Clinical manifestations vary widely, from asymptomatic infection to life-threatening disease, especially in immunocompromised hosts., Objectives: The primary objective of the study was to characterise cases of coccidioidomycosis in an area of the United States not considered traditionally endemic for the disease., Methods: We performed a single-centre retrospective study of all cases of coccidioidomycosis from 1 January 2000 to 31 December 2020, in the University of Oklahoma Health Sciences Medical Center., Results: A total of 26 patients were included for analysis. The central nervous system (CNS) and the lungs were the sites most frequently involved. Twenty (77%) had travelled to a coccidioidomycosis endemic region. Most were male (81%) with a median age of 42 years (range: 3-78 years). The majority (46%) were Caucasians, 19% were African American, 19% Hispanic, and 12% Native American. The most common comorbidities were diabetes mellitus and acquired immunodeficiency syndrome, identified in 27% and 23% of patients, respectively. Patients on immunosuppressive therapy accounted for 12% of all cases., Conclusion: Our study is one of the largest single-centre case series of coccidioidomycosis from a non-endemic area. Diabetes mellitus was the most frequent comorbidity. Compared to other case series of coccidioidomycosis, our patient population had higher rates of immunosuppression and had both a higher rate of disseminated disease and overall mortality., (© 2024 Wiley‐VCH GmbH. Published by John Wiley & Sons Ltd.)

Background: Human mpox has increasingly been reported worldwide since May 2022, with higher incidence in men who have sex with men (MSM) and persons living with HIV (PLHIV) with presentation typical for generalized macules and papules., Case Presentation: We are describing a case of human mpox, which presented as widespread, atypical round verrucous lesions that went undiagnosed in the community for six months and was treated with antibacterials and antifungals given the similarity to skin manifestations associated with endemic mycoses., Conclusions: Suspicion for human mpox should be high in young MSM and PLHIV who present with rash and mpox should be ruled out earlier., (© 2023. The Author(s).)

Mpox virus is an emergent human pathogen. While it is less lethal than smallpox, it can still cause significant morbidity and mortality. In this review, we explore 3 antiviral agents with activity against mpox and other orthopoxviruses: cidofovir, brincidofovir, and tecovirimat. Cidofovir, and its prodrug brincidofovir, are inhibitors of DNA replication with a broad spectrum of activity against multiple families of double-stranded DNA viruses. Tecovirimat has more specific activity against orthopoxviruses and inhibits the formation of the extracellular enveloped virus necessary for cell-to-cell transmission. For each agent, we review basic pharmacology, data from animal models, and reported experience in human patients., Competing Interests: Potential conflicts of interest. The authors: No reported conflicts of interest. Both authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

While the use of intraperitoneal (i.p.) gentamicin is common in the treatment of peritoneal dialysis (PD)-related infections, the ability of these regimens to attain pharmacodynamic target indices of interest in blood and dialysate has not been widely reported. Pharmacokinetic (PK) data were obtained and analyzed from a multiple-dose PK study of i.p. gentamicin with 24 patients who received the drug at 0.6 mg/kg dose of body weight. The probability of target attainment (PTA) for indices of treatment success (i.p. peak/MIC ratio > 10) and toxicity (plasma area under the concentration-time curve [AUC] < 120 mg·h/L) was determined for 0.3- to 1.2-mg/kg i.p. regimens every 24 h for dwell times of 2 to 6 h and for the duration of a 2-week course. In the peritoneum, successful PTA was achieved by all of the simulated regimens up to an MIC of 1 mg/L and by doses equal to or greater than 0.6 mg/kg up to the MIC of 2 mg/L. At the susceptibility breakpoint of 4 mg/L, only the highest dose of 1.2 mg/kg is likely to provide adequate PTA. The probability of achieving exposure below the threshold of 120 mg·h/L in the daily AUC in plasma seems acceptable for all regimens at or below 0.6 mg/kg. Based on the model we developed, a gentamicin dose of 0.6 mg/kg is sufficient to treat organisms with an MIC of ≤2 mg/L without the risk of significant systemic exposure. The 1.2-mg/kg dose necessary to reach the pharmacodynamic target for efficacy at the clinical breakpoint of 4 mg/L is likely to produce early toxic levels of exposure that are expected to be detrimental to the renal system.

Background: Cytomegalovirus (CMV) reactivation is one of the most common infectious complications after allogeneic hematopoietic cell transplant (HCT) and may result in significant morbidity and mortality. Primary prophylaxis with letermovir demonstrated a reduction in clinically significant CMV infections (CS-CMVi) in clinical trials of CMV-seropositive HCT recipients. This study aims at exploring the effect of primary letermovir prophylaxis in this population on the incidence and outcomes of refractory or resistant CMV infections., Methods: This is a single-center, retrospective cohort study of 537 consecutive CMV-seropositive allogeneic HCT recipients cared for between March 2016 and October 2018. Baseline demographics, HCT characteristics, CMV infections, treatment, and mortality data were collected from the electronic medical record. CMV outcomes were defined according to the recently standardized definitions for clinical trials. Characteristics and outcomes were assessed according to receipt of primary letermovir prophylaxis., Results: Of 537 patients identified, 123 received letermovir for primary prophylaxis during the first 100 days after HCT; 414 did not. In a multivariate analysis, primary prophylaxis with letermovir was associated with reductions in CS-CMVi (hazard ratio [HR] 0.26; 95% confidence interval [CI], 0.16-0.41), CMV end-organ disease (HR 0.23; 95% CI, 0.10-0.52), refractory or resistant CMV infection (HR 0.15; 95% CI, 0.04-0.52), and nonrelapse mortality at week 48 (HR 0.55; 95% CI, 0.32-0.93). There was neither resistant CMV nor CMV-related mortality in the primary letermovir prophylaxis group., Conclusions: Primary letermovir prophylaxis effectively prevents refractory or resistant CMV infections and decreases nonrelapse mortality at week 48, as well as CS-CMVi and CMV disease after allogeneic HCT., (© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Bacteria encase their cytoplasmic membrane with peptidoglycan (PG) to maintain the shape of the cell and protect it from bursting. The enlargement of the PG layer is facilitated by the coordinated activities of PG synthesising and -cleaving enzymes. In Escherichia coli , the cytoplasmic membrane-bound lytic transglycosylase MltG associates with PG synthases and was suggested to terminate the polymerisation of PG glycan strands. Using pull-down and surface plasmon resonance, we detected interactions between MltG from Bacillus subtilis and two PG synthases; the class A PBP1 and the class B PBP2B. Using in vitro PG synthesis assays with radio-labelled or fluorophore-labelled B. subtilis -type and/or E. coli -type lipid II, we showed that both, Bs MltG and Ec MltG, are lytic tranglycosylases and that their activity is higher during ongoing glycan strand polymerisation. MltG competed with the transpeptidase activity of class A PBPs, but had no effect on their glycosyltransferase activity, and produced glycan strands with a length of 7 disaccharide units from cleavage in the nascent strands. We hypothesize that MltG cleaves the nascent strands to produce short glycan strands that are used in the cell for a yet unknown process., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2021 The Author(s).)

The peptidoglycan layer is responsible for maintaining bacterial cell shape and permitting cell division. Cell wall growth is facilitated by peptidoglycan synthases and hydrolases and is potentially modulated by components of the central carbon metabolism. In Bacillus subtilis, UgtP synthesises the glucolipid precursor for lipoteichoic acid and has been suggested to function as a metabolic sensor governing cell size. Here we show that ugtP mutant cells have increased levels of cell wall precursors and changes in their peptidoglycan that suggest elevated DL-endopeptidase activity. The additional deletion of lytE, encoding a DL-endopeptidase important for cell elongation, in the ugtP mutant background produced cells with severe shape defects. Interestingly, the ugtP lytE mutant recovered normal rod-shape by acquiring mutations that decreased the expression of the peptidoglycan synthase PBP1. Together our results suggest that cells lacking ugtP must re-adjust the balance between peptidoglycan synthesis and hydrolysis to maintain proper cell morphology.

Tuberculosis claims >1 million lives annually, and its causative agent Mycobacterium tuberculosis is a highly successful pathogen. Protein kinase B (PknB) is reported to be critical for mycobacterial growth. Here, we demonstrate that PknB-depleted M. tuberculosis can replicate normally and can synthesize peptidoglycan in an osmoprotective medium. Comparative phosphoproteomics of PknB-producing and PknB-depleted mycobacteria identify CwlM, an essential regulator of peptidoglycan synthesis, as a major PknB substrate. Our complementation studies of a cwlM mutant of M. tuberculosis support CwlM phosphorylation as a likely molecular basis for PknB being essential for mycobacterial growth. We demonstrate that growing mycobacteria produce two forms of CwlM: a non-phosphorylated membrane-associated form and a PknB-phosphorylated cytoplasmic form. Furthermore, we show that the partner proteins for the phosphorylated and non-phosphorylated forms of CwlM are FhaA, a fork head-associated domain protein, and MurJ, a proposed lipid II flippase, respectively. From our results, we propose a model in which CwlM potentially regulates both the biosynthesis of peptidoglycan precursors and their transport across the cytoplasmic membrane., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: There is growing evidence that patients with community-onset pneumonia and recent healthcare exposure are not at equally high risk of infection with MDR organisms. An individualized approach is necessary with regard to risk assessment and choice of antibiotics., Methods: We reviewed the records of 102 patients admitted for community-onset pneumonia, before and after the implementation of a revised risk assessment programme for MDR organisms using the drug resistance in pneumonia (DRIP) score. The primary aim of the study was to identify the effects of this intervention on antibiotic days of therapy (DOT), and secondary outcomes included all-cause readmissions and time to clinical improvement. Statistical analysis was performed using generalized linear regression and Cox hazards models., Results: Implementation of the programme resulted in a decrease in anti-MRSA (-1.44 DOT, P = 0.007) and anti-pseudomonal (-2.03 DOT, P < 0.001) antibiotic utilization, but was not associated with a significant difference in the odds of readmissions (OR 0.64, 95% CI 0.16-2.57) or in time to clinical improvement (HR 1.19, 95% CI 0.62-2.21)., Conclusions: An individualized MDR organism risk assessment strategy using a clinical prediction score for community-onset pneumonia can decrease the utilization of broad-spectrum antibiotics without an increase in adverse outcomes.

Bacterial cell division involves the dynamic assembly of a diverse set of proteins that coordinate the invagination of the cell membrane and synthesis of cell wall material to create the new cell poles of the separated daughter cells. Penicillin-binding protein PBP 2B is a key cell division protein in Bacillus subtilis proposed to have a specific catalytic role in septal wall synthesis. Unexpectedly, we find that a catalytically inactive mutant of PBP 2B supports cell division, but in this background the normally dispensable PBP 3 becomes essential. Phenotypic analysis of pbpC mutants (encoding PBP 3) shows that PBP 2B has a crucial structural role in assembly of the division complex, independent of catalysis, and that its biochemical activity in septum formation can be provided by PBP 3. Bioinformatic analysis revealed a close sequence relationship between PBP 3 and Staphylococcus aureus PBP 2A, which is responsible for methicillin resistance. These findings suggest that mechanisms for rescuing cell division when the biochemical activity of PBP 2B is perturbed evolved prior to the clinical use of β-lactams., (© 2017 The Authors. Molecular Microbiology published by John Wiley & Sons Ltd.)

Bacteria surround their cytoplasmic membrane with an essential, stress-bearing peptidoglycan (PG) layer. Growing and dividing cells expand their PG layer by using membrane-anchored PG synthases, which are guided by dynamic cytoskeletal elements. In Escherichia coli, growth of the mainly single-layered PG is also regulated by outer membrane-anchored lipoproteins. The lipoprotein LpoB is required for the activation of penicillin-binding protein (PBP) 1B, which is a major, bifunctional PG synthase with glycan chain polymerizing (glycosyltransferase) and peptide cross-linking (transpeptidase) activities. Here, we report the structure of LpoB, determined by NMR spectroscopy, showing an N-terminal, 54-aa-long flexible stretch followed by a globular domain with similarity to the N-terminal domain of the prevalent periplasmic protein TolB. We have identified the interaction interface between the globular domain of LpoB and the noncatalytic UvrB domain 2 homolog domain of PBP1B and modeled the complex. Amino acid exchanges within this interface weaken the PBP1B-LpoB interaction, decrease the PBP1B stimulation in vitro, and impair its function in vivo. On the contrary, the N-terminal flexible stretch of LpoB is required to stimulate PBP1B in vivo, but is dispensable in vitro. This supports a model in which LpoB spans the periplasm to interact with PBP1B and stimulate PG synthesis.

Daphnids are fresh water microcrustaceans, many of which follow a cyclically parthenogenetic life cycle. Daphnia species have been well studied in the context of ecology, toxicology, and evolution, but their epigenetics remain largely unexamined even though sex determination, the production of sexual females and males, and distinct adult morphological phenotypes, are determined epigenetically. Here, we report on the characterization of histone modifications in Daphnia. We show that a number of histone H3 and H4 modifications are present in Daphnia embryos and histone H3 dimethylated at lysine 4 (H3K4me2) is present nonuniformly in the nucleus in a cell cycle-dependent manner. In addition, this histone modification, while present in blastula and gastrula cells as well as the somatic cells of adults, is absent or reduced in oocytes and nurse cells. Thus, the epigenetic repertoire of Daphnia includes modified histones and as these epigenetic forces act on a genetically homogeneous clonal population Daphnia offers an exceptional tool to investigate the mechanism and role of epigenetics in the life cycle and development of an ecologically important species.