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International Journal of Biological... May 2024Drug binding and interactions with plasma proteins play a crucial role in determining the efficacy of drug delivery, thus significantly impacting the overall...
Drug binding and interactions with plasma proteins play a crucial role in determining the efficacy of drug delivery, thus significantly impacting the overall pharmacological effect. AGP, the second most abundant plasma protein in blood circulation, has the unique capability to bind drugs and transport various compounds. In our present study, for the first time, we investigated whether AGP, a major component of the acute phase lipocalin in human plasma, can bind with pentamidine derivatives known for their high activity against the fungal pathogen Pneumocystis carinii. This investigation was conducted using integrated spectroscopic techniques and computer-based approaches. According to the results, it was concluded that compounds having heteroatoms (-NCH) in the aliphatic linker and the addition of a Br atom and a methoxy substituent at the C-2 and C-6 positions on the benzene ring, exhibit strong interactions with the AGP binding site. These compounds are identified as potential candidates for recognition by this protein. MD studies indicated that the tested analogues complexed with AGPs reach an equilibrium state after 60 ns, suggesting the stability of the complexes. This observation was further corroborated by experimental results. Therefore, exploring the interaction mechanism of pentamidine derivatives with plasma proteins holds promise for the development of bis-benzamidine-designed pharmaceutically important drugs.
Topics: Humans; Pentamidine; Protein Binding; Orosomucoid; Binding Sites; Molecular Dynamics Simulation; Molecular Docking Simulation
PubMed: 38582487
DOI: 10.1016/j.ijbiomac.2024.131405 -
Medical Mycology Case Reports Mar 2024is a type of endophytic fungus that parasitizes monocotyledonous plants. Cases of humans and other mammals being infected by are very rare around the world. We report...
is a type of endophytic fungus that parasitizes monocotyledonous plants. Cases of humans and other mammals being infected by are very rare around the world. We report the first case of subcutaneous mycosis caused by in China. A kidney transplant recipient was admitted for pneumonia and subsequently developed left calf redness and swelling due to a infection. The patient was treated with sulfamethoxazole and voriconazole and underwent five surgical debridements and vacuum sealing drainage (VSD) applications with the left leg. The patient was eventually cured and discharged from the hospital.
PubMed: 38533460
DOI: 10.1016/j.mmcr.2023.100620 -
British Journal of Haematology Jun 2024Pneumocystis jirovecii can cause life-threatening pneumonia (PjP), and patients with haematological malignancies are at high risk of this infection. Prophylactic... (Randomized Controlled Trial)
Randomized Controlled Trial
Pneumocystis jirovecii can cause life-threatening pneumonia (PjP), and patients with haematological malignancies are at high risk of this infection. Prophylactic measures have significantly decreased morbidity and mortality, but there is a paucity of contemporary data on the incidence and clinical course of PjP in well-defined and homogenous patient populations, such as children suffering from acute lymphoblastic leukaemia (ALL). In the multi-international trial AIEOP-BFM ALL2009, PjP was diagnosed in six children (incidence 1/1000) and was associated with insufficient prophylaxis in five of them. Although none of the patients died of PjP, the long-term impact of the infection is unclear.
Topics: Humans; Pneumonia, Pneumocystis; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Child; Pneumocystis carinii; Male; Female; Child, Preschool; Antineoplastic Combined Chemotherapy Protocols; Adolescent; Incidence
PubMed: 38527954
DOI: 10.1111/bjh.19382 -
Revista Do Instituto de Medicina... 2024Trimethoprim-sulfamethoxazole (TMP-SMX) is the primary therapeutic option for Pneumocystis jirovecii pneumonia (PCP). Gastrointestinal symptoms and cutaneous rash are...
Myelotoxicity and kidney dysfunction related to the use of trimethoprim-sulfamethoxazole for the treatment of Pneumocystis jirovecii pneumonia: a case report of severe adverse events with a common drug.
Trimethoprim-sulfamethoxazole (TMP-SMX) is the primary therapeutic option for Pneumocystis jirovecii pneumonia (PCP). Gastrointestinal symptoms and cutaneous rash are common side effects, with hyperkalemia being uncommon in patients without kidney dysfunction, and myelotoxicity being even rarer. We present the case of a male patient with hypertension and a recent diagnosis of non-Hodgkin lymphoma, undergoing rituximab treatment for two months. He was admitted to the intensive care unit due to dyspnea, tachypnea, and pleuritic pain, requiring mechanical ventilation. Chest computed tomography showed bilateral and multilobed ground-glass opacities, compromising more than 80% of the lung parenchyma. Pulmonary tuberculosis and COVID-19 were ruled out. An angiotomography and Doppler ultrasound revealed an extensive pulmonary thrombus and deep venous thrombosis. Empiric treatment with TMP-SMX for PCP was initiated, but within four days, the patient experienced metabolic acidosis and severe hyperkalemia, necessitating hemodialysis. He also presented with progressive pancytopenia and critical levels of leukopenia and thrombocytopenia. The hypothesis of TMP-SMX-induced myelotoxicity was suspected. Considering the unavailability of an alternative treatment, it was opted to continue TMP-SMX and initiate a granulocyte-colony-stimulating factor. However, the patient maintained medullary deterioration, becoming refractory to the transfusion of blood derivates. On the 17th day of treatment, a clinical decision was made to suspend TMP-SMX, leading to improvements within 48 hours in marrow and kidney functions, metabolic acidosis, and hyperkalemia. Despite all efforts, the patient died after 35 days of hospitalization due to hospital-acquired infections. This case highlights the importance of clinicians recognizing potential myelotoxicity with TMP-SMX and promptly discontinuing the drug if necessary.
Topics: Humans; Male; Trimethoprim, Sulfamethoxazole Drug Combination; Pneumonia, Pneumocystis; Hyperkalemia; Pneumocystis carinii; Acidosis; Kidney; Retrospective Studies
PubMed: 38511807
DOI: 10.1590/S1678-9946202466018 -
International Journal of Antimicrobial... May 2024American guidelines recommend trimethoprim-sulphamethoxazole (TMP-SMX) for preventing Pneumocystis jirovecii pneumonia (PJP) in paediatric patients at doses of 5-10...
Evaluation of effectiveness, hyperkalaemia, and hepatotoxicity of trimethoprim-sulphamethoxazole prophylaxis for Pneumocystis jirovecii pneumonia in paediatric patients: A single-centre retrospective study.
BACKGROUND
American guidelines recommend trimethoprim-sulphamethoxazole (TMP-SMX) for preventing Pneumocystis jirovecii pneumonia (PJP) in paediatric patients at doses of 5-10 mg/kg/d of the TMP component, administered either daily, three times weekly, or twice weekly. However, limited studies describe the effectiveness and safety of these prophylactic regimens. Our study aimed to assess the clinical effectiveness and incidence of adverse events associated with each TMP-SMX regimen in paediatric patients, and to identify risk factors for adverse events.
METHODS
We collected data regarding the onset of PJP, hyperkalaemia, and hepatotoxicity in patients aged 0-18 years who underwent prophylaxis with TMP-SMX from July 2018 to June 2023.
RESULTS
A total of 215 paediatric patients met the inclusion criteria. No patients developed PJP. Hyperkalaemia occurred in 14.7%, patients receiving TMP-SMX daily, 15.4% receiving it three times weekly, and 15.5% receiving it twice weekly. Hepatotoxicity was most frequent in patients receiving TMP-SMX twice weekly (19%), followed by those receiving it three times weekly (7.7%), and daily (5.9%). Younger patients were significantly more prone to developing hyperkalaemia or hepatotoxicity. Patients aged <1 year had the highest incidences of hyperkalaemia (56.5%), and those aged 1-2 years had the highest incidence of hepatotoxicity (25%).
CONCLUSIONS
No patient developed PJP under various dosage prophylactic regimens of TMP-SMX. However, our findings suggest the need to monitor potassium levels and hepatic function in patients undergoing any of the three TMP-SMX regimens. In particular, patients aged <1 year old and 1-2 years old face a higher risk of hyperkalaemia and hepatotoxicity, respectively.
Topics: Humans; Pneumonia, Pneumocystis; Trimethoprim, Sulfamethoxazole Drug Combination; Hyperkalemia; Child; Child, Preschool; Retrospective Studies; Infant; Male; Female; Adolescent; Pneumocystis carinii; Infant, Newborn; Chemical and Drug Induced Liver Injury; Anti-Bacterial Agents; Antibiotic Prophylaxis
PubMed: 38508538
DOI: 10.1016/j.ijantimicag.2024.107151 -
Chemotherapy 2024With the increasing use of blinatumomab in relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL), including minimal residual disease (MRD)-positive...
INTRODUCTION
With the increasing use of blinatumomab in relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL), including minimal residual disease (MRD)-positive cases, awareness of its adverse effects has gradually improved. Pneumocystis jirovecii pneumonia (PCP) associated with blinatumomab therapy is rare.
CASE PRESENTATION
We present a case of PCP in a patient undergoing blinatumomab therapy. A 70-year-old female diagnosed with Philadelphia-like CRLF2 overexpression B-cell precursor ALL received blinatumomab as consolidation therapy after achieving complete remission with prior induction chemotherapy. On the second day of blinatumomab infusion, she developed intermittent low-grade fever, and chest computed tomography (CT) revealed subtle infiltrates and nodules. Despite empiric trimethoprim-sulfamethoxazole (TMP-SMX) prophylaxis, she progressed to significant shortness of breath and type I respiratory failure, with increased lactate dehydrogenase and β-D-glucan assays. Chest CT showed diffuse ground-glass opacities with scattered small nodules. The dry cough prompted next-generation sequencing of peripheral blood, which tested positive for pneumocystis jirovecii without evidence of other pathogens. Consequently, the patient was diagnosed with PCP. The first cycle of blinatumomab had to be discontinued, and therapeutic dosages of TMP-SMX and dexamethasone were administered, resulting in full recovery and stable condition during follow-ups.
CONCLUSION
PCP is rare in B-cell precursor ALL patients receiving blinatumomab therapy but manifests with early onset and rapid disease progression. Despite prophylaxis, PCP infection cannot be ignored during blinatumomab therapy. Therefore, heightened attention is warranted when using blinatumomab therapy.
Topics: Humans; Female; Pneumonia, Pneumocystis; Aged; Antibodies, Bispecific; Pneumocystis carinii; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; Tomography, X-Ray Computed; Trimethoprim, Sulfamethoxazole Drug Combination
PubMed: 38508148
DOI: 10.1159/000538256 -
Respiratory Research Mar 2024Increasing evidence revealed that lung microbiota dysbiosis was associated with pulmonary infection in lung transplant recipients (LTRs). Pneumocystis jirovecii (P.... (Observational Study)
Observational Study
BACKGROUND
Increasing evidence revealed that lung microbiota dysbiosis was associated with pulmonary infection in lung transplant recipients (LTRs). Pneumocystis jirovecii (P. jirovecii) is an opportunistic fungal pathogen that frequently causes lethal pneumonia in LTRs. However, the lung microbiota in LTRs with P. jirovecii pneumonia (PJP) remains unknow.
METHODS
In this prospective observational study, we performed metagenomic next-generation sequencing (mNGS) on 72 bronchoalveolar lavage fluid (BALF) samples from 61 LTRs (20 with PJP, 22 with PJC, 19 time-matched stable LTRs, and 11 from LTRs after PJP recovery). We compared the lung microbiota composition of LTRs with and without P. jirovecii, and analyzed the related clinical variables.
RESULTS
BALFs collected at the episode of PJP showed a more discrete distribution with a lower species diversity, and microbiota composition differed significantly compared to P. jirovecii colonization (PJC) and control group. Human gammaherpesvirus 4, Phreatobacter oligotrophus, and Pseudomonas balearica were the differential microbiota species between the PJP and the other two groups. The network analysis revealed that most species had a positive correlation, while P. jirovecii was correlated negatively with 10 species including Acinetobacter venetianus, Pseudomonas guariconensis, Paracandidimonas soli, Acinetobacter colistiniresistens, and Castellaniella defragrans, which were enriched in the control group. The microbiota composition and diversity of BALF after PJP recovery were also different from the PJP and control groups, while the main components of the PJP recovery similar to control group. Clinical variables including age, creatinine, total protein, albumin, IgG, neutrophil, lymphocyte, CD3CD45, CD3CD4 and CD3CD8 T cells were deeply implicated in the alterations of lung microbiota in LTRs.
CONCLUSIONS
This study suggests that LTRs with PJP had altered lung microbiota compared to PJC, control, and after recovery groups. Furthermore, lung microbiota is related to age, renal function, nutritional and immune status in LTRs.
Topics: Humans; Pneumonia, Pneumocystis; Transplant Recipients; CD8-Positive T-Lymphocytes; Pneumocystis carinii; Microbiota; Lung
PubMed: 38486264
DOI: 10.1186/s12931-024-02755-9 -
Journal of Clinical Microbiology Apr 2024pneumonia (PJP) is a serious and sometimes fatal infection occurring in immunocompromised individuals. High-risk patients include those with low CD4 counts due to human...
UNLABELLED
pneumonia (PJP) is a serious and sometimes fatal infection occurring in immunocompromised individuals. High-risk patients include those with low CD4 counts due to human immunodeficiency virus infection and transplant recipients. The incidence of PJP is increasing, and rapid detection of PJP is needed to effectively target treatment and improve patient outcomes. A common method used is an immunofluorescent assay (IFA), which has limitations, including labor costs, low sensitivity, and requirement for expert interpretation. This study evaluates the performance of the DiaSorin Molecular analyte-specific reagent (ASR) in a laboratory-developed test (LDT) for the direct detection of DNA without prior nucleic acid extraction. Respiratory samples ( = 135) previously tested by IFA from 111 patients were included. Using a composite standard of in-house IFA and reference lab PJP PCR, the percent positive agreement for the LDT using the DiaSorin ASR was 97.8% (90/92). The negative percent agreement was 97.7% (42/43). The lower limit of detection of the assay was determined to be 1,200 copies/mL in bronchoalveolar lavage fluid. Analytical specificity was assessed using cultures of oropharyngeal flora and common respiratory bacterial and fungal pathogens. No cross-reactivity was observed. Our study suggests that the DiaSorin ASR accurately detects DNA and demonstrates improved sensitivity compared to the IFA method.
IMPORTANCE
Our study is unique compared to other previously published studies on the DiaSorin analyte-specific reagent (ASR) because we focused on microbiological diagnostic methods commonly used (immunofluorescent assay) as opposed to pathology findings or reference PCR. In addition, in our materials and methods, we describe the protocol for the use of the DiaSorin ASR as a singleplex assay, which will allow other users to evaluate the ASR for clinical use in their lab.
Topics: Humans; Pneumocystis carinii; Indicators and Reagents; Sensitivity and Specificity; Pneumonia, Pneumocystis; Bronchoalveolar Lavage Fluid; Immunocompromised Host; DNA
PubMed: 38477535
DOI: 10.1128/jcm.00045-24 -
Biomedicines Feb 2024This study aimed to develop a simple predictive model for early identification of the risk of adverse outcomes in kidney transplant-associated pneumonia (PCP) patients.
BACKGROUND
This study aimed to develop a simple predictive model for early identification of the risk of adverse outcomes in kidney transplant-associated pneumonia (PCP) patients.
METHODS
This study encompassed 103 patients diagnosed with PCP, who received treatment at our hospital between 2018 and 2023. Among these participants, 20 were categorized as suffering from severe PCP, and, regrettably, 13 among them succumbed. Through the application of machine learning techniques and multivariate logistic regression analysis, two pivotal variables were discerned and subsequently integrated into a nomogram. The efficacy of the model was assessed via receiver operating characteristic (ROC) curves and calibration curves. Additionally, decision curve analysis (DCA) and a clinical impact curve (CIC) were employed to evaluate the clinical utility of the model. The Kaplan-Meier (KM) survival curves were utilized to ascertain the model's aptitude for risk stratification.
RESULTS
Hematological markers, namely Procalcitonin (PCT) and C-reactive protein (CRP)-to-albumin ratio (CAR), were identified through machine learning and multivariate logistic regression. These variables were subsequently utilized to formulate a predictive model, presented in the form of a nomogram. The ROC curve exhibited commendable predictive accuracy in both internal validation (AUC = 0.861) and external validation (AUC = 0.896). Within a specific threshold probability range, both DCA and CIC demonstrated notable performance. Moreover, the KM survival curve further substantiated the nomogram's efficacy in risk stratification.
CONCLUSIONS
Based on hematological parameters, especially CAR and PCT, a simple nomogram was established to stratify prognostic risk in patients with renal transplant-related PCP.
PubMed: 38397968
DOI: 10.3390/biomedicines12020366