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PLoS Genetics Apr 2024Pneumocystis jirovecii is a fungal pathogen that causes pneumocystis pneumonia, a disease that mainly affects immunocompromised individuals. This fungus has historically...
Pneumocystis jirovecii is a fungal pathogen that causes pneumocystis pneumonia, a disease that mainly affects immunocompromised individuals. This fungus has historically been hard to study because of our inability to grow it in vitro. One of the main drug targets in P. jirovecii is its dihydrofolate reductase (PjDHFR). Here, by using functional complementation of the baker's yeast ortholog, we show that PjDHFR can be inhibited by the antifolate methotrexate in a dose-dependent manner. Using deep mutational scanning of PjDHFR, we identify mutations conferring resistance to methotrexate. Thirty-one sites spanning the protein have at least one mutation that leads to resistance, for a total of 355 high-confidence resistance mutations. Most resistance-inducing mutations are found inside the active site, and many are structurally equivalent to mutations known to lead to resistance to different antifolates in other organisms. Some sites show specific resistance mutations, where only a single substitution confers resistance, whereas others are more permissive, as several substitutions at these sites confer resistance. Surprisingly, one of the permissive sites (F199) is without direct contact to either ligand or cofactor, suggesting that it acts through an allosteric mechanism. Modeling changes in binding energy between F199 mutants and drug shows that most mutations destabilize interactions between the protein and the drug. This evidence points towards a more important role of this position in resistance than previously estimated and highlights potential unknown allosteric mechanisms of resistance to antifolate in DHFRs. Our results offer unprecedented resources for the interpretation of mutation effects in the main drug target of an uncultivable fungal pathogen.
Topics: Tetrahydrofolate Dehydrogenase; Pneumocystis carinii; Folic Acid Antagonists; Drug Resistance, Fungal; Mutation; Methotrexate; Allosteric Regulation; Saccharomyces cerevisiae; Humans; Fungal Proteins; Catalytic Domain
PubMed: 38683847
DOI: 10.1371/journal.pgen.1011252 -
Infection and Drug Resistance 2024Lymphoma is complicated by intricate infections, notably pneumonia (PJP), marked by rapid progression, respiratory failure, and high mortality. Rapid diagnosis of PJP...
BACKGROUND
Lymphoma is complicated by intricate infections, notably pneumonia (PJP), marked by rapid progression, respiratory failure, and high mortality. Rapid diagnosis of PJP and effective administration of the first-line treatment trimethoprim-sulfamethoxazole (TMP-SMX) are important. For patients intolerant to TMP-SMX, selecting appropriate alternatives is challenging, necessitating careful decisions to optimize diagnosis and treatment. We present a lymphoma case complicated by PJP, illustrating medication adjustment until a positive response was observed.
CASE DESCRIPTION
A 41-year-old male patient with lymphoma presented with a week-long history of fever, fatigue, cough, sputum, chest tightness, and exertional dyspnea, unresponsive to treatment. Routine laboratory examinations revealed no pathogenic bacteria. PJ and (MTB) were detected in bronchoalveolar lavage fluid (BALF) using metagenomic next-generation sequencing (mNGS). On Day 1 of admission, meropenem, TMP-SMX, and rifampicin+isoniazid+levofloxacin were administered. However, the patient developed drug-induced hepatotoxicity and gastrointestinal adverse reactions after six days of treatment. After a multidisciplinary team discussion, anti-tuberculosis therapy was stopped because of insufficient evidence of tuberculosis infection. A reduced dose of TMP-SMX with micafungin was used for PJP; however, symptoms persisted and repeated computed tomography showed extensive deterioration of bilateral pulmonary plaques. The PJP regimen was modified to include a combination of TMP-SMX and caspofungin. Due to the high fever and elevated infection indices, the patient was treated with teicoplanin to enhance the anti-infection effects. By Day 13, the patient's temperature had normalized, and infection control was achieved by Day 30. CT revealed that the infection in both lung lobes fully resolved. Subsequently, lymphoma treatment commenced.
CONCLUSION
BALF-NGS facilitates early and rapid diagnosis of PJP. mNGS reads of MTB bacillus <5 may indicate a bacterial carrier state, warranting other detection techniques to support it. There is insufficient evidence for using TMP-SMX with micafungin to treat PJP; however, TMP-SMX combined with caspofungin is suitable.
PubMed: 38681899
DOI: 10.2147/IDR.S461607 -
Archives of Dermatological Research Apr 2024This study investigates the frequency of infections in autoimmune blistering disease (AIBD) patients treated with rituximab and evaluates the difference in infectious...
This study investigates the frequency of infections in autoimmune blistering disease (AIBD) patients treated with rituximab and evaluates the difference in infectious complications in patients on concomitant antibiotic and/or antiviral prophylaxis. The study retrospectively reviewed 43 AIBD patients who received rituximab over a five-year interval. The patients were categorized based on prophylaxis type (antibiotic, antiviral, or both) and concomitant immunosuppression status, which we defined as treatment with an immunosuppressive medication during the time frame they were given Rituximab. Our findings suggest that concomitant immunosuppression alongside rituximab did not significantly increase the risk of developing infectious complications compared to rituximab monotherapy. Results revealed that 34.4% of patients with concomitant immunosuppression had a secondary bacterial infection, defined as bacterial complications requiring hospitalization, consistent with prior studies. Moreover, antibiotic prophylaxis did not significantly reduce infection risk in patients on rituximab, with 45.1% of these patients experiencing bacterial complications. There was an absence of pneumocystis pneumonia in the study population. Despite the small sample size and limited timeline, this study suggests that antibiotic prophylaxis may not significantly mitigate the risk of infections in AIBD patients receiving rituximab, and the risk of infection with concomitant immunosuppression with rituximab requires additional investigation for definitive causal risk.
Topics: Humans; Rituximab; Retrospective Studies; Female; Male; Middle Aged; Aged; Autoimmune Diseases; Adult; Immunosuppressive Agents; Aged, 80 and over; Bacterial Infections; Antibiotic Prophylaxis; Anti-Bacterial Agents
PubMed: 38676739
DOI: 10.1007/s00403-024-02865-w -
Journal of Infection and Chemotherapy :... Apr 2024Nocardiosis in patients after allogeneic hematopoietic stem cell transplantation (HSCT) is rare, but is associated with a significant mortality risk. Although...
Successful maintenance treatment of disseminated nocardiosis with cerebral abscess in a severely immunocompromised patient allergic to trimethoprim-sulfamethoxazole using moxifloxacin and high-dose minocycline: A case report.
Nocardiosis in patients after allogeneic hematopoietic stem cell transplantation (HSCT) is rare, but is associated with a significant mortality risk. Although trimethoprim-sulfamethoxazole (TMP/SMX) remains the cornerstone of nocardiosis treatment, optimal alternative therapies for patients intolerant to TMP/SMX are not well-established. Herein, we report a case of disseminated nocardiosis with bacteremia and multiple lesions in the lungs and brain caused by Nocardia farcinica, in a 60-year-old man who had previously undergone allogeneic HSCT and was receiving immunosuppressants for severe chronic graft-versus-host disease. The patient received atovaquone for the prophylaxis of Pneumocystis pneumonia because of a previous serious allergic reaction to TMP/SMX. The patient was initially treated with imipenem/cilastatin and amikacin, which were later switched to ceftriaxone and amikacin based on the results of antimicrobial susceptibility testing. After switching to oral levofloxacin and a standard dose of minocycline, the patient experienced a single recurrence of brain abscesses. However, after switching to oral moxifloxacin and high-dose minocycline, the patient did not experience any relapses during the subsequent two years and seven months of treatment. In treating nocardiosis with brain abscesses, it is crucial to select oral antibiotics based on the antimicrobial susceptibility test results and pharmacokinetics, especially when TMP/SMX is contraindicated. A combination of oral moxifloxacin and high-dose minocycline could be a promising alternative therapy.
PubMed: 38670455
DOI: 10.1016/j.jiac.2024.04.008 -
Current Rheumatology Reports Apr 2024The purpose of this review is to summarize and evaluate most recent evidence on the epidemiology of infections and associated risk factors in patients with primary... (Review)
Review
PURPOSE OF REVIEW
The purpose of this review is to summarize and evaluate most recent evidence on the epidemiology of infections and associated risk factors in patients with primary systemic vasculitides (PSV), as well as discuss mitigation strategies including the risk of antibiotic prophylaxis.
RECENT FINDINGS
Infections remain one of the leading causes of mortality in patients with PSV, with rates of severe infection ranging from 16 to 40% in different cohorts. Older age, frailty, renal and pulmonary involvement, and higher burden of comorbidities have been recognized as important patient-associated risk factors. Treatments including higher cumulative doses of glucocorticoids are associated with an increased risk of infections, and recent studies show the potential benefit of interventions such as reduced-dose glucocorticoid regimens. Existing mitigation strategies include screening, vaccination, and infection prophylaxis. The latter remains particularly important for Pneumocystis jirovecii pneumonia; however, the benefit-risk ratio seems to be less clear outside of induction phase (i.e., high dose of glucocorticoids) and optimal treatment duration remains less clear. Patients with PSV are at increased risk of infections, due to disease itself, comorbidities, and treatment side effects. Awareness of the timing and types of infection, as well as mitigation strategies are imperative to ensure treatment success and survival for patients.
PubMed: 38668813
DOI: 10.1007/s11926-024-01149-6 -
Journal of Fungi (Basel, Switzerland) Apr 2024pneumonia (PJP) has high mortality rates in immunocompromised children, even though routine prophylaxis has decreased in incidence. The aim of this case series is to...
BACKGROUND
pneumonia (PJP) has high mortality rates in immunocompromised children, even though routine prophylaxis has decreased in incidence. The aim of this case series is to present the radiological and clinical pathway of PJP in a pediatric population.
DESCRIPTION OF CASES
All PJP cases in non-HIV/AIDS patients diagnosed at Istituto Giannina Gaslini Pediatric Hospital in Genoa (Italy) from January 2012 until October 2022 were retrospectively evaluated. Nine cases were identified (median age: 8.3 years), and of these, 6/9 underwent prophylaxis with trimethoprim/sulfamethoxazole (TMP/SMX; five once-a-week schedules and one three times-a-week schedule), while 3/9 did not receive this. PJP was diagnosed by real-time PCR for -DNA in respiratory specimens in 7/9 cases and two consecutive positive detections of β-d-glucan (BDG) in the serum in 2/9 cases. Most patients (6/8) had a CT scan with features suggestive of PJP, while one patient did not undergo a scan. All patients were treated with TMP/SMX after a median time from symptoms onset of 3 days. In 7/9 cases, empirical TMP/SMX treatment was initiated after clinical suspicion and radiological evidence and later confirmed by microbiological data. Clinical improvement with the resolution of respiratory failure and 30-day survival included 100% of the study population.
DISCUSSION
Due to the difficulty in obtaining biopsy specimens, PJP diagnosis is usually considered probable in most cases. Moreover, the severity of the clinical presentation often leads physicians to start TMP/SMX treatment empirically. BDG proved to be a useful tool for diagnosis, and CT showed good accuracy in identifying typical patterns. In our center, single-day/week prophylaxis was ineffective in high-risk patients; the three-day/week schedule would, therefore, seem preferable and, in any case, should be started promptly in all patients who have an indication of pneumonia.
PubMed: 38667947
DOI: 10.3390/jof10040276 -
Diagnostics (Basel, Switzerland) Apr 2024A 54-year-old woman presented to an outpatient clinic with a recurrence of triple-negative breast cancer and multiple bone metastases. The patient had a large mass...
A 54-year-old woman presented to an outpatient clinic with a recurrence of triple-negative breast cancer and multiple bone metastases. The patient had a large mass lesion of 10 cm on the sternum. She received the immune checkpoint inhibitors pembrolizumab and taxane. Initially, the patient responded excellently to treatment, but stopped pembrolizumab for grade IV skin toxicity with multiple ulcerative wounds over the bilateral leg and trunk. The lesions abated following administration of antibiotics and oral prednisolone for two months. After that, she was referred to the radiation oncology department for further treatment. She received radiotherapy for the sternum mass but stopped radiation at 42Gy/21 fractions for severe dyspnea and fever. Blood sampling found leukocytosis with neutrophil predominance. Chest radiography showed bilateral lung infiltration. Pulmonary CT scan yielded bilateral lung patchy consolidation compatible with radiation isodose-line. Bronchial lavage showed positive Pneumocystis jiroveci PCR. Dyspnea improved after titrating methylprednisolone within two days. The patient recovered well with TMP-SMX and glucocorticoids after the initiation of therapy.
PubMed: 38667495
DOI: 10.3390/diagnostics14080850 -
BMC Pulmonary Medicine Apr 2024Pneumocystis jirovecii pneumonia (PJP) is an interstitial pneumonia caused by pneumocystis jirovecii (PJ). The diagnosis of PJP primarily relies on the detection of the... (Comparative Study)
Comparative Study
BACKGROUND
Pneumocystis jirovecii pneumonia (PJP) is an interstitial pneumonia caused by pneumocystis jirovecii (PJ). The diagnosis of PJP primarily relies on the detection of the pathogen from lower respiratory tract specimens. However, it faces challenges such as difficulty in obtaining specimens and low detection rates. In the clinical diagnosis process, it is necessary to combine clinical symptoms, serological test results, chest Computed tomography (CT) images, molecular biology techniques, and metagenomics next-generation sequencing (mNGS) for comprehensive analysis.
PURPOSE
This study aims to overcome the limitations of traditional PJP diagnosis methods and develop a non-invasive, efficient, and accurate diagnostic approach for PJP. By using this method, patients can receive early diagnosis and treatment, effectively improving their prognosis.
METHODS
We constructed an intelligent diagnostic model for PJP based on the different Convolutional Neural Networks. Firstly, we used the Convolutional Neural Network to extract CT image features from patients. Then, we fused the CT image features with clinical information features using a feature fusion function. Finally, the fused features were input into the classification network to obtain the patient's diagnosis result.
RESULTS
In this study, for the diagnosis of PJP, the accuracy of the traditional PCR diagnostic method is 77.58%, while the mean accuracy of the optimal diagnostic model based on convolutional neural networks is 88.90%.
CONCLUSION
The accuracy of the diagnostic method proposed in this paper is 11.32% higher than that of the traditional PCR diagnostic method. The method proposed in this paper is an efficient, accurate, and non-invasive early diagnosis approach for PJP.
Topics: Humans; Pneumonia, Pneumocystis; Neural Networks, Computer; Tomography, X-Ray Computed; Pneumocystis carinii; Polymerase Chain Reaction; Male; Middle Aged; Female; Early Diagnosis; Adult; Aged
PubMed: 38664747
DOI: 10.1186/s12890-024-02987-x -
Research Square Apr 2024Immune checkpoint inhibitor-related pneumonitis (ICI-P) is a condition associated with high mortality, necessitating prompt recognition and treatment initiation. This...
PURPOSE
Immune checkpoint inhibitor-related pneumonitis (ICI-P) is a condition associated with high mortality, necessitating prompt recognition and treatment initiation. This study aimed to assess the impact of implementing a clinical care pathway algorithm on reducing the time to treatment for ICI-P.
METHODS
Patients with lung cancer and suspected ICI-P were enrolled, and a multi-modal intervention promoting algorithm use was implemented in two phases. Pre- and post-intervention analyses were conducted to evaluate the primary outcome of time from ICI-P diagnosis to treatment initiation.
RESULTS
Of the 82 patients admitted with suspected ICI-P, 73.17% were confirmed to have ICI-P, predominantly associated with non-small cell lung cancer (91.67%) and stage IV disease (95%). Pembrolizumab was the most commonly used immune checkpoint inhibitor (55%). The mean times to treatment were 2.37 days in the pre-intervention phase and, 3.07 days (=0.46), and 1.27 days (=0.40) in the post-intervention phases 1 and 2, respectively. Utilization of the immunotoxicity order set significantly increased from 0% to 27.27% (p = 0.04) after phase 2. While there were no significant changes in ICU admissions or inpatient mortality, outpatient pulmonology follow-ups increased statistically significantly, demonstrating enhanced continuity of care. The overall mortality for patients with ICI-P was 22%, underscoring the urgency of optimizing management strategies. Notably, all patients discharged on high-dose corticosteroids received appropriate gastrointestinal prophylaxis and prophylaxis against Pneumocystis jirovecii pneumonia infections at the end of phase 2.
CONCLUSION
Implementing a clinical care pathway algorithm for ICI-P management standardizes care practices and enhances patient outcomes, underscoring the importance of structured approaches.
PubMed: 38659939
DOI: 10.21203/rs.3.rs-4209489/v1 -
Cureus Mar 2024Pneumocystis pneumonia (PCP) primarily affects immunosuppressed patients, with trimethoprim-sulfamethoxazole (TMP-SMX) commonly used for prophylaxis. However, there is...
Pneumocystis Pneumonia in Locally Advanced Breast Cancer Despite Prophylactic Use of Trimethoprim-Sulfamethoxazole During Prednisolone Treatment for a Pembrolizumab-Induced Immune-Related Adverse Event: A Case Report.
Pneumocystis pneumonia (PCP) primarily affects immunosuppressed patients, with trimethoprim-sulfamethoxazole (TMP-SMX) commonly used for prophylaxis. However, there is insufficient information on PCP occurrence despite TMP-SMX prophylaxis. We encountered a 57-year-old woman with locally advanced breast cancer developing PCP despite prophylactic intake of TMP-SMX, during treatment with prednisolone for Stevens-Johnson syndrome (SJS) induced by pembrolizumab. This case underscores the need to pay attention to the possibility of PCP development even during TMP-SMX prophylaxis. Dosage and duration adjustments according to the patient's condition and weight may be required.
PubMed: 38659518
DOI: 10.7759/cureus.56868