Exploring TSPAN4 promoter methylation as a diagnostic biomarker for tuberculosis.

Background: Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), is a persistent infectious disease threatening human health. The existing diagnostic methods still have significant shortcomings, including a low positivity rate in pathogen-based diagnoses and the inability of immunological diagnostics to detect active TB. Hence, it is urgent to develop new techniques to detect TB more accurate and earlier. This research aims to scrutinize and authenticate DNA methylation markers suitable for tuberculosis diagnosis. Concurrently, Providing a new approach for tuberculosis diagnosis. Methods: Blood samples from patients with newly diagnosed tuberculosis and healthy controls (HC) were utilized in this study. Examining methylation microarray data from 40 whole blood samples (22TB + 18HC), we employed two procedures: signature gene methylated position analysis and signature region methylated position analysis to pinpoint distinctive methylated positions. Based on the screening results, diagnostic classifiers are constructed through machine learning, and validation was conducted through pyrosequencing in a separate queue (22TB + 18HC). Culminating in the development of a new tuberculosis diagnostic method via quantitative real-time methylation specific PCR (qMSP). Results: The combination of the two procedures revealed a total of 10 methylated positions, all of which were located in the promoter region. These 10 signature methylated positions facilitated the construction of a diagnostic classifier, exhibiting robust diagnostic accuracy in both cross-validation and external test sets. The LDA model demonstrated the best classification performance, achieving an AUC of 0.83, specificity of 0.8, and sensitivity of 0.86 on the external test set. Furthermore, the validation of signature methylated positions through pyrosequencing demonstrated high agreement with screening outcomes. Additionally, qMSP detection of 2 potential hypomethylated positions (cg04552852 and cg12464638) exhibited promising results, yielding an AUC of 0.794, specificity of 0.720, and sensitivity of 0.816. Conclusion: Our study demonstrates that the validated signature methylated positions through pyrosequencing emerge as plausible biomarkers for tuberculosis diagnosis. The specific methylation markers in the TSPAN4 gene, identified in whole blood samples, hold promise for improving tuberculosis diagnosis. This approach could significantly enhance diagnostic accuracy and speed, offering a new avenue for early detection and treatment.

LectoScape: A Highly Multiplexed Imaging Platform for Glycome Analysis and Biomedical Diagnosis.

Glycosylation, a fundamental biological process, involves the attachment of glycans to proteins, lipids, and RNA, and it plays a crucial role in various biological pathways. It is of great significance to obtain the precise spatial distribution of glycosylation modifications at the cellular and tissue levels. Here, we introduce LectoScape, an innovative method enabling detailed imaging of tissue glycomes with up to 1 µm resolution through image mass cytometry (IMC). This method utilizes 12 distinct, nonoverlapping lectins selected via microarray technology, enabling the multiplexed detection of a wide array of glycans. Furthermore, we developed an efficient labeling strategy for these lectins. Crucially, our approach facilitates the concurrent imaging of diverse glycan motifs, including N-glycan and O-glycan, surpassing the capabilities of existing technologies. Using LectoScape, we have successfully delineated unique glycan structures in various cell types, enhancing our understanding of the glycan distribution across human tissues. Our method has identified specific glycan markers, such as α2,3-sialylated Galß1, 3GalNAc in O-glycan, and terminal GalNAc, as diagnostic indicators for cervical intraepithelial neoplasia. This highlights the potential of LectoScape in cancer diagnostics through the detection of abnormal glycosylation patterns.

Evaluation of Sulfasalazine as an Adjunctive Therapy in Treating Pulmonary Pre-XDR-TB: Efficacy, Safety, and Treatment Implication.

Background: The rising prevalence and limited efficacy of treatments for pre-extensively drug-resistant tuberculosis (pre-XDR-TB) underscore an immediate need for innovative therapeutic options. A combination of host-directed therapy (HDT) and anti-TB treatment presents a viable alternative for pre-XDR-TB management. Sulfasalazine (SASP), by targeting the amino acid transport system xc (xCT), potentially reduces the intracellular Mycobacterium tuberculosis load and mitigates lung pathology, positioning it as a promising TB HDT agent. This study aims to assess the efficacy of SASP as a supplementary therapy for pre-XDR-TB. Methods: A pilot study examined the safety and effectiveness of two 9-month short-course, all-oral regimens for pre-XDR-TB treatment: Bdq-regimen (consisting of Bdq, linezolid, cycloserine, clofazimine, and pyrazinamide) and SASP-regimen (comprising SASP, linezolid, cycloserine, clofazimine, and pyrazinamide). The primary endpoint was the incidence of unfavorable outcomes 12 months post-treatment. Results: Of the 44 participants enrolled, 43 were assessable 12 months post-treatment. Culture conversion rates stood at 73.2% by Month 2 and escalated to 95.1% by Month 6. Overall, 88.4% (38/43) of the participants exhibited favorable outcomes, 85.2% (19/23) for the Bdq-regimen and 93.8% (14/15) for the SASP-regimen. The SASP-regimen group recorded no deaths or treatment failures. Conclusion: Both 9-month short-course, all-oral regimens manifested commendable primary efficacy in treating pre-XDR-TB patients. The SASP-regimen emerged as effective, safe, well-tolerated, and cost-effective.

MSTRG3207 promotes apoptosis in zebrafish ZF4 cells via sponging dre-miR-736/bbc3/LOC101885512 axis during cold acclimation.

Long non-coding RNAs (lncRNAs) play essential roles in a variety of biological processes. It has been recently reported that lncRNAs can regulate mRNA expression by binding to microRNAs (miRNAs) as competing endogenous RNAs (ceRNAs). However, the involvement of this regulatory mechanism during cold acclimation in fish remains unclear. In this study, we constructed a ceRNA network mediated by lncRNAs in cold-acclimated zebrafish ZF4 cells through bioinformatic analysis of the mRNA, miRNA, and lncRNA profiles obtained from ZF4 cells cultured at 18 °C for 30 days. A previously uncharacterized lncRNA, MSTRG3207, was selected for further analysis. MSTRG3207 was upregulated and dre-miR-736 was downregulated during cold acclimation. MSTRG3207 was cloned by rapid amplification of cDNA ends (RACE) and functionally characterized. The binding of MSTRG3207 to dre-miR-736 was validated by dual-luciferase reporter assay. Under cold acclimation, MSTRG3207 promoted apoptosis by sponging dre-miR-736 and upregulating bbc3 and LOC101885512, two apoptotic genes targeted by dre-miR-736. Taken together, our findings indicate that MSTRG3207 upregulation promotes apoptosis by sponging dre-miR-736 during cold acclimation in fish.

Nasopharyngeal neutrophilic-retention signatures could predict disease progression in early SARS-CoV-2 infection.

The nasopharynx is the initial site of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, and neutrophils play a critical role in preventing viral transmission into the lower airways or lungs during the early phases of infection. However, neutrophil dynamics, functional signatures, and predictive roles in the nasopharynx of coronavirus disease 2019 (COVID-19) patients have not yet been elucidated. In this study, we carried out RNA sequencing of nasopharyngeal swabs from a cohort of COVID-19 patients with mild, moderate, severe outcomes and healthy donors as controls. Over 32.7% of the differentially expressed genes associated with COVID-19 severity were neutrophil-related, including those involved in migration, neutrophil extracellular traps formation, and inflammasome activation. Multicohort single-cell RNA sequencing analysis further confirmed these findings and identified a population of neutrophils expressing Vacuolar-type ATPase (V-ATPase) and the chemokine receptor CXCR4 in the nasopharynx. This population of neutrophils preferentially expressed pro-inflammatory genes relevant to phagosomal maturation as well as local reactive oxygen species and reactive nitrogen species production in the nasopharynx of patients with severe outcomes. A four-gene panel defined as a neutrophil signature associated with COVID-19 progression (NSAP) was identified as an early diagnostic predictor of severe COVID-19, which potentially distinguished severe patients from mild cases with influenza, respiratory syncytial virus, dengue virus, or hepatitis B virus infection. NSAP is mainly expressed on CXCR4high neutrophils and exhibits a significant association with the cell fraction of this neutrophil population. This study highlights novel potential therapeutic targets or diagnostic tools for predicting patients at a higher risk of severe outcomes.

Study protocol for safety and efficacy of all-oral shortened regimens for multidrug-resistant tuberculosis: a multicenter randomized withdrawal trial and a single-arm trial [SEAL-MDR].

INTRODUCTION: The urgent need for new treatments for multidrug-resistant tuberculosis (MDR-TB) and pre-extensively drug-resistant tuberculosis (pre-XDR-TB) is evident. However, the classic randomized controlled trial (RCT) approach faces ethical and practical constraints, making alternative research designs and treatment strategies necessary, such as single-arm trials and host-directed therapies (HDTs). METHODS: Our study adopts a randomized withdrawal trial design for MDR-TB to maximize resource allocation and better mimic real-world conditions. Patients' treatment regimens are initially based on drug resistance profiles and patient's preference, and later, treatment-responsive cases are randomized to different treatment durations. Alongside, a single-arm trial is being conducted to evaluate the potential of sulfasalazine (SASP) as an HDT for pre-XDR-TB, as well as another short-course regimen without HDT for pre-XDR-TB. Both approaches account for the limitations in second-line anti-TB drug resistance testing in various regions. DISCUSSION: Although our study designs may lack the internal validity commonly associated with RCTs, they offer advantages in external validity, feasibility, and ethical appropriateness. These designs align with real-world clinical settings and also open doors for exploring alternative treatments like SASP for tackling drug-resistant TB forms. Ultimately, our research aims to strike a balance between scientific rigor and practical utility, offering valuable insights into treating MDR-TB and pre-XDR-TB in a challenging global health landscape. In summary, our study employs innovative trial designs and treatment strategies to address the complexities of treating drug-resistant TB, fulfilling a critical gap between ideal clinical trials and the reality of constrained resources and ethical considerations. TRAIL REGISTRATION: Chictr.org.cn, ChiCTR2100045930. Registered on April 29, 2021.

Selecting an appropriate all-oral short-course regimen for patients with multidrug-resistant or pre-extensive drug-resistant tuberculosis in China: A multicenter prospective cohort study.

OBJECTIVES: Long, ineffective, and toxic regimens hinder the treatment of patients with multidrug-resistant tuberculosis (MDR-TB) and pre-extensive drug-resistant tuberculosis (pre-XDR-TB). METHODS: We conducted a multicenter cohort study to prospectively evaluate the safety and efficacy of three 9-month, all-oral, 5-drug regimens. Regimen A (bedaquiline [Bdq]+linezolid [Lzd]+moxifloxacin [Mfx]+cycloserine [Cs]+pyrazinamide [Pza]) and Regimen B (Lzd+Mfx+Cs+clofazimine [Cfz]+Pza) were used to treat MDR-TB patients (Groups A and B, respectively, assigned according to the patient's treatment preference), while Regimen C (Bdq+Lzd+Cs+Cfz+Pza) was used to treat pre-XDR-TB patients (Group C). The primary endpoint was the occurrence of an unfavorable outcome within 12 months of treatment completion, regardless of regimen. RESULTS: A total of 104 patients (34 in Group A, 46 in Group B, and 24 in Group C), with a median age of 35.5 (29.0-54.0) years, were included in the analysis population. At 12 months after treatment completion, five patients were deemed non-assessable. Of the remaining 99 participants, seven (7.1%) had an unfavorable outcome (including two deaths from any cause, four with treatment failure, and one loss to follow-up) and 92 (92.9%) had a favorable outcome. Culture conversion was achieved in 82.5% (80/97) of participants at month 2 and in 97.9% (94/97) of participants at month 6. Adverse events (AEs) resulting in drug adjustment occurred in 69.2% (72/104) of participants, mainly due to Lzd and Pza use. A QT interval prolongation of ≥ 500 ms occurred in 5.8% (6/104) of participants. CONCLUSION: The primary outcome of the three tailored, 9-month, all-oral, 5-drug regimens was satisfactory in the vast majority of MDR-TB and pre-XDR-TB patients, with manageable and reversible AEs.

The interaction of macrophages and CD8 T cells in bronchoalveolar lavage fluid is associated with latent tuberculosis infection.

Mycobacterium tuberculosis (Mtb) infection, including active tuberculosis (TB) and latent Mtb infection (LTBI), leads to diverse outcomes owing to different host immune responses. However, the immune mechanisms that govern the progression from LTBI to TB remain poorly defined in humans. Here, we profiled the lung immune cell populations within the bronchoalveolar lavage fluid (BALF) from patients with LTBI or TB using single-cell RNA sequencing (scRNA-seq). We found that Mtb infection substantially changed the immune cell compartments in the BALF, especially for the three subsets of macrophages, monocyte macrophage (MM)-CCL23, MM-FCN1, and MM-SPP1, which were found to be associated with the disease status of TB infection. Notably, MM-CCL23 cells derived from monocytes after stimulation with Mtb were characterized by high levels of chemokine (CCL23 and CXCL5) production and might serve as a marker for Mtb infection. The MM-CCL23 population mainly recruited CD8-CCR6 T cells through CCL20/CCR6, which was a prominent feature associated with protection immunity in LTBI. This study improves our understanding of the lung immune landscape during Mtb infection, which may inform future vaccine design for protective immunity.

Devising novel near-infrared aggregation-induced-emission luminogen labeling for point-of-care diagnosis of Mycobacterium tuberculosis.

Detecting and appropriately diagnosing a Mycobacterium tuberculosis infection remains technologically difficult because the pathogen commonly hides in macrophages in a dormant state. Described here is novel near-infrared aggregation-induced-emission luminogen (AIEgen) labeling developed by the current authors' laboratory for point-of-care (POC) diagnosis of an M. tuberculosis infection. The selectivity of AIEgen labeling, the labeling of intracellular M. tuberculosis by AIEgen, and the labeling of M. tuberculosis in sputum samples by AIEgen, along with its accuracy, sensitivity, and specificity, were preliminarily evaluated. Results indicated that this near-infrared AIEgen labeling had satisfactory selectivity and it labeled intracellular M. tuberculosis and M. tuberculosis in sputum samples. It had a satisfactory accuracy (95.7%), sensitivity (95.5%), and specificity (100%) for diagnosis of an M. tuberculosis infection in sputum samples. The current results indicated that near-infrared AIEgen labeling might be a promising novel diagnostic tool for POC diagnosis of M. tuberculosis infection, though further rigorous verification of these findings is required.

Construction of a risk model and deep learning network based on patients with active pulmonary tuberculosis and pulmonary inflammation.

Most patients with active pulmonary tuberculosis (TB) are difficult to be differentiated from pneumonia (PN), especially those with acid-fast bacillus smear-negative (AFB-) and interferon-γ release assay-positive (IGRA+) results. Thus, the aim of the present study was to develop a risk model of low-cost and rapid test for the diagnosis of AFB- IGRA+ TB from PN. A total of 41 laboratory variables of 204 AFB- IGRA+ TB and 156 PN participants were retrospectively analyzed. Candidate variables were identified by t-statistic test and univariate logistic model. The logistic regression analysis was used to construct the multivariate risk model and nomogram with internal and external validation. A total of 13 statistically differential variables were compared between AFB- IGRA+ TB and PN by false discovery rate (FDR) and odds ratio (OR). By integrating five variables, including age, uric acid (UA), albumin (ALB), hemoglobin (Hb) and white blood cell counts (WBC), a multivariate risk model with a concordance index (C-index) of 0.7 (95% CI: 0.61, 0.8) was constructed. The nomogram showed that UA and Hb acted as protective factors with an OR <1, while age, WBC and ALB were risk factors for TB occurrence. Internal and external validation revealed that nomogram prediction was consistent with the actual observations. Collectively, it was revealed that an integration of five biomarkers (age, UA, ALB, Hb and WBC) may be used to quickly predict TB in AFB- IGRA+ clinical samples from PN.

A cross-sectional study: a breathomics based pulmonary tuberculosis detection method.

BACKGROUND: Diagnostics for pulmonary tuberculosis (PTB) are usually inaccurate, expensive, or complicated. The breathomics-based method may be an attractive option for fast and noninvasive PTB detection. METHOD: Exhaled breath samples were collected from 518 PTB patients and 887 controls and tested on the real-time high-pressure photon ionization time-of-flight mass spectrometer. Machine learning algorithms were employed for breathomics analysis and PTB detection mode, whose performance was evaluated in 430 blinded clinical patients. RESULTS: The breathomics-based PTB detection model achieved an accuracy of 92.6%, a sensitivity of 91.7%, a specificity of 93.0%, and an AUC of 0.975 in the blinded test set (n = 430). Age, sex, and anti-tuberculosis treatment does not significantly impact PTB detection performance. In distinguishing PTB from other pulmonary diseases (n = 182), the VOC modes also achieve good performance with an accuracy of 91.2%, a sensitivity of 91.7%, a specificity of 88.0%, and an AUC of 0.961. CONCLUSIONS: The simple and noninvasive breathomics-based PTB detection method was demonstrated with high sensitivity and specificity, potentially valuable for clinical PTB screening and diagnosis.

Spatial mapping reveals granuloma diversity and histopathological superstructure in human tuberculosis.

The hallmark of tuberculosis (TB) is the formation of immune cell-enriched aggregates called granulomas. While granulomas are pathologically diverse, their tissue-wide heterogeneity has not been spatially resolved at the single-cell level in human tissues. By spatially mapping individual immune cells in every lesion across entire tissue sections, we report that in addition to necrotizing granulomas, the human TB lung contains abundant non-necrotizing leukocyte aggregates surrounding areas of necrotizing tissue. These cellular lesions were more diverse in composition than necrotizing lesions and could be stratified into four general classes based on cellular composition and spatial distribution of B cells and macrophages. The cellular composition of non-necrotizing structures also correlates with their proximity to necrotizing lesions, indicating these are foci of distinct immune reactions adjacent to necrotizing granulomas. Together, we show that during TB, diseased lung tissue develops a histopathological superstructure comprising at least four different types of non-necrotizing cellular aggregates organized as satellites of necrotizing granulomas.

Detecting latent tuberculosis infection with a breath test using mass spectrometer: A pilot cross-sectional study.

Mycobacterium tuberculosis (M.tb) infects a quarter of the world's population and may progress to active tuberculosis (ATB). There is no gold standard for diagnosing latent tuberculosis infection (LTBI). Some immunodiagnostic tests are recommended to detect LTBI but can not distinguish ATB from LTBI. The breath test is useful for diagnosing ATB compared to healthy subjects but was never studied for LTBI. This proof-of-concept study (Chinese Clinical Trials Registry number: ChiCTR2200058346) was the first to explore a novel, rapid, and simple LTBI detection method via breath test on high-pressure photon ionization time-of-flight mass spectrometry (HPPI-TOFMS). The case group of LTBI subjects (n = 185) and the control group (n = 250), which included ATB subgroup (n = 121) and healthy control (HC) subgroup (n = 129), were enrolled. The LTBI detection model indicated that a breath test via HPPI-TOFMS could distinguish LTBI from the control with a sensitivity of 80.0% (95% CI: 67.6%, 92.4%) and a specificity of 80.8% (95% CI: 71.8%, 89.9%). Nevertheless, further intensive studies with a larger sample size are required for clinical application.

The recommended dosage regimen for caspofungin in patients with higher body weight or hypoalbuminaemia will result in low exposure: Five years of data based on a population pharmacokinetic model and Monte-Carlo simulations.

Background: To develop a population pharmacokinetic (PPK) model for caspofungin, identify parameters influencing caspofungin pharmacokinetics, and assess the required probability of target attainment (PTA) and cumulative fraction of response (CFR) for various dosing regimens of caspofungin in all patients and intensive care unit (ICU)-subgroup patients. Method: The general PPK model was developed based on data sets from all patients (299 patients). A ICU-subgroup PPK model based on data sets from 136 patients was then analyzed. The effects of demographics, clinical data, laboratory data, and concomitant medications were tested. Monte-Carlo simulations (MCS) were used to evaluate the effectiveness of different caspofungin dosage regimens. Results: One-compartment model best described the data of all patients and ICU patients. Clearances (CL) were 0.32 L/h and 0.40 L/h and volumes of distribution (V) were 13.31 L and 10.20 L for the general and ICU-subgroup PPK models, respectively. In the general model, CL and V were significantly associated with albumin (ALB) concentration and body weight (WT). In the ICU-subgroup model, CL was associated with WT. The simulated exposure in ICU patients was lower than that in all patients (p < 0.05). MCS indicated that higher caspofungin maintenance doses of 70-150 mg may achieve target CFR of >90% for patients with higher WT (>70 kg) or with C. albicans or C. parapsilosis infections, and especially for ICU patients with hypoalbuminaemia. Conclusion: The PPK model and MCS presented in the study demonstrated that the recommended dosage regimen for caspofungin in patients with higher body weight or hypoalbuminaemia will result in low exposure.

Whole transcriptome sequencing reveals neutrophils' transcriptional landscape associated with active tuberculosis.

Neutrophils have been recognized to play an important role in the pathogenesis of tuberculosis in recent years. Interferon-induced blood transcriptional signatures in ATB are predominantly driven by neutrophils. In this study, we performed global RNA-seq on peripheral blood neutrophils from active tuberculosis patients (ATB, n=15); latent tuberculosis infections (LTBI, n=22); and healthy controls (HC, n=21). The results showed that greater perturbations of gene expression patterns happened in neutrophils from ATB individuals than HC or those with LTBI, and a total of 344 differentially expressed genes (DEGs) were observed. Functional enrichment analysis showed that besides the interferon signaling pathway, multiple pattern recognition receptor pathways were significantly activated in ATB, such as NOD-like receptors and Toll-like receptors. Meanwhile, we also observed that the expression of genes related to endocytosis, secretory granules, and neutrophils degranulation were downregulated. Our data also showed that the NF-κB signaling pathway might be inhibited in patients with ATB, which could increase Mycobacterium tuberculosis survival and lead to active tuberculosis status. Furthermore, we validated the accuracy of some differentially expressed genes in an independent cohort using quantitative PCR, and obtained three novel genes (RBM3, CSRNP1, SRSF5) with the ability to discriminate active tuberculosis from LTBI and HC.

Efficacy and Safety of Combination Antifungals as Empirical, Preemptive, and Targeted Therapies for Invasive Fungal Infections in Intensive-Care Units.

Purpose: To determine whether combinations of antifungal drugs are effective and safe for patients in intensive-care units. Methods: This study compared the efficacy and safety of caspofungin (CAS), voriconazole (VOR), amphotericin B liposome (L-AmB), CAS+VOR, and CAS+L-AmB as empirical, preemptive, and targeted therapies for invasive fungal infection (IFI). Results: Comparing the CAS, VOR, and CAS+VOR groups revealed that there were no differences in response rates between all therapy types, IFI-associated death within 90 days was less common in the CAS+VOR group (1.8%) than the VOR group (14.3%), and there were more adverse events in the VOR group than in the CAS group (P < 0.05). For empirical or preemptive therapy, the CAS group had a better response rate (80.0%) than the CAS+VOR group (47.1%), and there were more adverse events in the VOR group than in the CAS group (P < 0.05). For targeted therapy, no differences were found for efficacy and safety. There were no differences among the CAS, L-AmB, and CAS+L-AmB groups in efficacy and safety. Conclusion: Patients who received CAS monotherapy as an empirical or preemptive therapy could achieve good outcomes. Patients who received CAS+VOR or CAS+L-AmB achieved almost the same outcomes when compared with those who received CAS, VOR, and L-AmB monotherapy as targeted therapies, but those who received CAS+VOR had a lower IFI mortality rate than did those who received VOR monotherapy.

In vitro synergistic antifungal activities of caspofungin in combination with fluconazole or voriconazole against Candida species determined by the Etest method.

OBJECTIVES: Increased resistance of Candida species, especially Candida. glabrata is problematic. Combination antifungal therapies were studied to solve the problem. METHODS: In this study, combinations of caspofungin with fluconazole and voriconazole were evaluated in 28 Candida species (including 15 C. glabrata and 12 with FKS mutation) at 24 and 48 hours using two Etest methods (direct cover method and MIC/MIC method). RESULTS: For Candida isolates, direct cover method showed synergy of caspofungin-fluconazole and caspofungin-voriconazole against 12/28 (43%) isolates at 24 hours, and against 16/28 (57%) isolates at 48 hours. The MIC/MIC method showed synergy of caspofungin-fluconazole and caspofungin-voriconazole against 11/28 (39%) and 12/28 (43%) isolates at 24 hours, and against 16/28 (57%) and 17/28 (61%) isolates at 48 hours, respectively. For C. glabrata, direct cover method showed synergy of caspofungin-fluconazole and caspofungin-voriconazole against 11/15 (73%) and 10/15 (67%) isolates at 24 hours, and 11/15 (73%) and 13/15 (87%) isolates at 48 hours, respectively. The MIC/MIC method showed synergy of caspofungin-fluconazole and caspofungin-voriconazole against both 11/15 (73%) isolates at 24 hours, and 10/15 (67%) and 14/15 (93%) isolates at 48 hours, respectively. CONCLUSION: A combination of caspofungin and fluconazole or voriconazole might be effective against infections caused by Candida species, especially C. glabrata with FKS mutation.

Pharmacokinetic/Pharmacodynamic Target Attainment of Different Antifungal Agents in De-escalation Treatment in Critically Ill Patients: a Step toward Dose Optimization Using Monte Carlo Simulation.

Differences in pharmacokinetics/pharmacodynamics (PK/PD) target attainment are rarely considered when antifungals are switched in critically ill patients. This study intends to explore whether the antifungal de-escalation treatment strategy and the new intermittent dosing strategy of echinocandins in critically ill patients are able to achieve the corresponding PK/PD targets. The published population PK models of antifungals in critically ill patients and a public data set from the MIMIC-III database (n = 662) were employed to evaluate PK/PD target attainment of different dosing regimens of antifungals. Cumulative fraction of response (CFR) was calculated for each dosing regimen. Most guideline-recommended dosing regimens of fluconazole and voriconazole could achieve target exposure as de-escalation treatment in critically ill patients. For initial echinocandin treatment, achievement of the target exposure decreased as body weight increased, and the intermittent dosing strategy had a slightly higher CFR value in most simulations compared to conventional dosing strategy. For Candida albicans and Candida glabrata infection, caspofungin at the lowest dose achieved a CFR of >90%, while micafungin or anidulafungin required almost the highest doses simulated in this study to achieve the same effect. None of the echinocandins other than 150 mg every 24 h (q24h) or 200 mg q48h of caspofungin achieved the target CFR for Candida parapsilosis infection. These findings support the guideline-recommended dose of triazoles for antifungal de-escalation treatment and confirm the insufficient dosage of echinocandins in critically ill patients, indicating that a dosing regimen based on body weight or intermittent dosing of echinocandins may be required.

Potentially Hazardous Drug-Drug Interactions Associated With Oral Antineoplastic Agents Prescribed in Chinese Tertiary Care Teaching Hospital Settings: A Multicenter Cross-Sectional Study.

Background: Oral administration increases the risk of interactions, because most oral antineoplastic agents (OAAs) are taken on a daily basis. Interactions can increase exposure to antitumoral agents or cause treatment failure. Potential drug-drug interactions (DDIs) are commonly observed in patients with cancer, while the extent to which OAAs related hazardous DDIs remains unclear. Methods: We studied the contraindication patterns between oral antineoplastic agents and other medications among cancer patients in two tertiary care teaching hospitals in China. A total of 20 clinically significant hazardous DDI pairs that involved 30 OAAs were identified based on the predetermined criteria. Patient medications were checked for DDIs by using the US Food and Drug Administration approved labeling. Descriptive statistics and uni- and multivariate logistic regression analyses were carried out. Results: In this study, 13,917 patients were included and a total of 297 DDIs were identified. The results revealed that proton pump inhibitors (PPIs), dexamethasone and fluoroquinolones were the most often involved hazardous DDIs with OAAs. The most prevalent contraindication is the simultaneous use of certain molecular targeted agents and PPIs. In the result of the multivariate analysis, younger age (0-20 group), increasing number of drugs and patient treated with targeted therapy had a higher risk for DDIs. Conclusion: The prevalence of OAAs related hazardous DDIs appears to be low in the cancer patients. However, physicians and clinical pharmacologists should be aware of the potential hazardous DDIs when prescribing OAAs, especially certain pH-dependent molecular targeted agents and potential QTc prolonging drugs.