A retrospective study of intravenous pentamidine for Pneumocystis jirovecii pneumonia prophylaxis in adult patients with hematologic malignancies-its utility during respiratory virus pandemics.

OBJECTIVES: In hematology, prophylaxis for Pneumocystis jirovecii pneumonia (PCP) is recommended for patients undergoing hematopoietic stem cell transplantation and in selected categories of intensive chemotherapy for hematologic malignancies. Trimethoprim-sulfamethoxazole (TMP-SMX) is the recommended first-line agent; however, its use is not straightforward. Inhaled pentamidine is the recommended second-line agent; however, aerosolized medications were discouraged during respiratory virus outbreaks, especially during the COVID-19 pandemic, in view of potential contamination risks. Intravenous (IV) pentamidine is a potential alternative agent. We evaluated the effectiveness and tolerability of IV pentamidine use for PCP prophylaxis in adult allogeneic hematopoietic stem cell transplantation recipients and patients with hematologic malignancies during COVID-19. RESULTS: A total of 202 unique patients who received 239 courses of IV pentamidine, with a median of three doses received (1-29). The largest group of the patients (49.5%) who received IV pentamidine were undergoing or had received a hematopoietic stem cell transplant. The most common reason for not using TMP-SMX prophylaxis was cytopenia (34.7%). We have no patients who had breakthrough PCP infection while on IV pentamidine. None of the patients developed an infusion reaction or experienced adverse effects from IV pentamidine. CONCLUSIONS: Pentamidine administered IV monthly is safe and effective.

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.

Effect of Pneumocystis jirovecii pneumonia prophylaxis on hematologic toxicity in patients receiving chemoradiation for primary brain tumors.

PURPOSE: Diffuse gliomas are managed with radiation and temozolomide; however, this therapy often results in hematologic toxicities. Patients undergoing chemoradiation also risk contracting Pneumocystis jirovecii pneumonia (PJP), and frequently receive prophylaxis against PJP during treatment. Independent of chemoradiation, some PJP prophylaxis drugs have the potential to cause myelosuppression, which could require cessation of chemotherapy. Here, we evaluate differences in the frequency of hematologic toxicities during chemoradiation when patients receive PJP prophylaxis. METHODS: This retrospective chart review evaluated patients with primary brain tumors treated with radiation and concurrent temozolomide. Analyses were performed to assess the effect of the type of PJP prophylaxis on risk for neutropenia, lymphopenia, or thrombocytopenia and the severity of these adverse effects as defined using the Common Terminology Criteria for Adverse Events. RESULTS: Of the 217 patients included in this analysis, 144 received trimethoprim-sulfamethoxazole (TMP/SMX) and 69 received pentamidine. Of the patients who received TMP/SMX, 15.3% developed an absolute neutrophil count < 1500 cells/µL compared with 7.2% of patients receiving pentamidine (p = 0.10). Platelet count < 100,000/µL occurred in 18.1% of patients who received TMP/SMX and 20.3% of patients who received pentamidine (p = 0.70). No significant differences in lymphocyte counts between therapies were seen. Severity of hematologic toxicities were similar between PJP prophylaxis groups. CONCLUSION: These findings suggest that the type of PJP prophylaxis does not significantly affect the risk for hematologic toxicity in brain tumor patients receiving radiation and temozolomide. Additional studies are merited to evaluate the higher rate of neutropenia in patients on TMP/SMX observed in this study.

Pneumocystis jirovecii pneumonia in people living with HIV: a review.

Pneumocystis jirovecii is a ubiquitous opportunistic fungus that can cause life-threatening pneumonia. People with HIV (PWH) who have low CD4 counts are one of the populations at the greatest risk of Pneumocystis jirovecii pneumonia (PCP). While guidelines have approached the diagnosis, prophylaxis, and management of PCP, the numerous studies of PCP in PWH are dominated by the 1980s and 1990s. As such, most studies have included younger male populations, despite PCP affecting both sexes and a broad age range. Many studies have been small and observational in nature, with an overall lack of randomized controlled trials. In many jurisdictions, and especially in low- and middle-income countries, the diagnosis can be challenging due to lack of access to advanced and/or invasive diagnostics. Worldwide, most patients will be treated with 21 days of high-dose trimethoprim sulfamethoxazole, although both the dose and the duration are primarily based on historical practice. Whether treatment with a lower dose is as effective and less toxic is gaining interest based on observational studies. Similarly, a 21-day tapering regimen of prednisone is used for patients with more severe disease, yet other doses, other steroids, or shorter durations of treatment with corticosteroids have not been evaluated. Now with the widespread availability of antiretroviral therapy, improved and less invasive PCP diagnostic techniques, and interest in novel treatment strategies, this review consolidates the scientific body of literature on the diagnosis and management of PCP in PWH, as well as identifies areas in need of more study and thoughtfully designed clinical trials.

Late-onset Pneumocystis jirovecii pneumonia post-allogeneic stem cell transplantation after time-dependent discontinuation of prophylaxis.

INTRODUCTION: Pneumocystis jirovecii pneumonia (PJP) is a rare complication of hematopoietic stem cell transplantation (HSCT). Primary prophylaxis for 6-12 months post-HSCT is the standard approach. However, there is no consensus regarding the optimal duration of prophylaxis. METHODS: We identified patients who developed PJP more than 1-year post-HSCT. All patients had previously received 12 months of PJP prophylaxis. PJP was diagnosed based on clinical findings and the detection of P. jirovecii in bronchoalveolar lavage (BAL) using polymerase chain reaction (PCR). The CD4+ T-cell percentage was determined using flow cytometry. Data expressed as median (interquartile range). RESULTS: Ten patients developed PJP at 17.5 months (16-24 months) post-HSCT. PJP diagnosis occurred 5.5 months (3-15 months) after discontinuing prophylaxis. Eight patients received anti-thymocyte globulin (ATG) as graft versus host disease (GVHD) prophylaxis. At diagnosis, only one patient had lymphopenia; all patients had CD4+ T-lymphocyte counts ≥0.2 × 109 /L (median 0.337 × 109 /L). Three patients had concomitant bacterial infections. The clinical presentation was mild; only three required hospitalization, none of them required intensive care and there were no deaths. CONCLUSION: There is a need to develop risk-adapted prophylactic strategies in the contemporary era using ATG-based GVHD prophylaxis.

Sulfamethoxazole-trimethoprim for pneumocystis pneumonia prophylaxis, causes of discontinuation and thrombocytopenia observed during administration: A single-center retrospective study.

INTRODUCTION: The development of pneumocystis pneumonia (PCP) has recently become a growing concern; thus, its prevention has become increasingly important. Sulfamethoxazole-trimethoprim (ST) is a cost-effective first-line and prophylactic treatment for PCP. However, ST administration criteria for PCP prophylaxis remain unclear and are often discontinued because of adverse events (AEs). In this study, we aimed to investigate the causes of ST discontinuation and the associated AEs using objective data. METHODS: We retrospectively analyzed the data of 162 patients admitted to Kansai Medical University Hospital between January 2018 and December 2020, who received ST for PCP prophylaxis. We compared clinical characteristics, laboratory data, and incidence of AEs between ST non-discontinuation and ST discontinuation groups. Additionally, we divided the patients into non-developing and developing thrombocytopenia (≥ Grade 1) groups based on the investigation results. RESULTS: No patients developed PCP while receiving ST. The most common causes of ST discontinuation were thrombocytopenia (37%), liver dysfunction (20%), and rash (18%). Multivariate analysis revealed thrombocytopenia (≥ Grade 1) as a factor significantly associated with ST discontinuation. Furthermore, we identified three factors correlated with thrombocytopenia (≥ Grade 1): age ≥50 years, lymphocyte count <1000/µL, and platelet count <180,000/µL. CONCLUSIONS: Patients with the aforementioned factors are at higher risk of developing thrombocytopenia (≥ Grade 1) during ST administration for PCP prophylaxis. Therefore, platelet count monitoring is essential to enhance safety and efficacy of ST treatment. Nonetheless, further research is warranted to explore additional implications and interventions.

The 'pulmonary diseases spectrum' in HIV infected children.

Despite advances in diagnostic, therapeutic and preventive strategies for HIV, pulmonary diseases continue to be the major cause of morbidity and mortality in infants and children infected with HIV. With effective programs to prevent perinatal HIV-1 transmission to early diagnosis in infants, we have seen a substantial decline in paediatric HIV incidence. Early initiation of Highly Active Anti-Retroviral Therapy (HAART) in all HIV infected children coupled with consistent use of Pneumocystis prophylaxis in all HIV exposed/infected children under 5 years of age has considerably reduced associated infections overall and respiratory infections in particular. In developing countries already burdened with poverty, malnutrition, suboptimal immunization coverage and limited access to health care and treatment, acute and chronic HIV-associated respiratory disease remain a major cause for concern. Prevention of severe respiratory infections in advanced HIV disease among children consists mostly of rapid and optimal HAART initiation & continuation, preventing severe TB disease with BCG and TB preventive treatment, preventing Pneumocystis jirovecii pneumonia with cotrimoxazole prophylaxis and administering age-appropriate vaccinations and catch-up vaccines as per National Immunization schedule.

Indication for a Pneumocystis Prophylaxis Therapy in Patients with Vascular Anomalies Treated with PIK3/AKT/mTOR Pathway Inhibitors: Experts' Opinion and Systematic Review from the Literature.

BACKGROUND: Vascular anomalies (VAs) are increasingly being treated with PI3K/AKT/mTOR pathway inhibitors. These drugs have immunosuppressive properties and thus theoretically overexpose patients to opportunistic infections, especially Pneumocystis jirovecii pneumonia (PJP). PJP prophylaxis use lacks consensus. We aimed to investigate the prevalence of PJP in patients receiving mTOR/PI3K/AKT inhibitors for VAs and determine any indication for pneumocystis prophylaxis in this population. METHODS: The study was conducted in 2 parts: (1) we sent a survey to a panel of international experts of VAs asking about their use of pneumocystis prophylaxis drugs and (2) we performed a systematic review of the literature of all published cases of patients receiving these drugs for VA to estimate the prevalence of PJP in this population. RESULTS: Answers from 68 experts were analyzed: 21 (30.9%) answered they always add PJP prophylaxis when prescribing mTOR inhibitors, 20 (29.4%) case-by-case, and 27 (39.7%) never. For the systematic review, among 3,053 reports screened, 217 were included involving 1,189 patients (1,143 received sirolimus, 38 everolimus, 4 alpelisib, 4 miransertib). Among the 1,189 cases, 2 (0.2%) PJP were reported: one under sirolimus and one under everolimus. Thus, the prevalence of PJP was estimated at 0.88 cases/1,000 patients under sirolimus (95% CI: -0.84 to 2.59) and 26.31 cases/1,000 under everolimus (95% CI: -24.58 to 77.18). Patients with PJP never received prophylaxis drugs. We found no PJP cases under alpelisib and miransertib. PJP prophylaxis was given in 218 (18.3%) cases, more frequently for children (91.3 vs. 77.2% in the non-prophylaxis group, p = 0.012), mostly trimethoprim-sulfamethoxazole (186 patients, 85.3%). CONCLUSION: Our study shows that even if PJP is a rare event, it may occur in patients with VAs treated with an mTOR inhibitor. Although our results cannot allow for revising guidelines, prophylaxis with TMP-SMX might be appropriate for a subgroup of patients with risk factors for PJP.

Prevalence of Trimethoprim-Sulfamethoxazole Adverse Reaction Mislabelling in Australia.

INTRODUCTION: Trimethoprim-sulfamethoxazole (TMP-SMX) is an important antibiotic, with the most compelling indications for Pneumocystis jirovecii pneumonia prophylaxis and methicillin-resistant Staphylococcus aureus treatment. Previous adverse reactions (AR) to TMP-SMX may limit the usability of TMP-SMX. Electronic medical record (EMR) of AR for other antibiotics has previously been shown to be inaccurate; however, the extent to which this occurs for TMP-SMX is unknown. METHODS: A multi-centre retrospective observational study was conducted for consecutive inpatient admissions over a 2.5-year period commencing 2020. Adverse reactions to TMP-SMX recorded in the EMR were collected and reviewed by two independent medical officers using pre-defined expert criteria for the classification of allergies and intolerances. RESULTS: TMP-SMX AR were present in the EMR of 759 individuals (prevalence 0.6%). The majority were labelled as allergy (725, 95.5%) rather than intolerance (34, 4.5%). Most common AR were rash, vomiting, and swelling. When classified against the gold-standard expert criteria, there were 437 allergies (57.6%) and 159 intolerances (21.0%). Overall, the number of incorrect EMR AR labels was 133/759 (17.5%). Both medical and surgical specialties had significant numbers of patients with TMP-SMX AR labels and incorrectly classified EMR AR labels. CONCLUSION: TMP-SMX AR labels affect inpatients admitted under multiple specialty units. The user-entered categorization as allergy or intolerance labels in EMRs are frequently used incorrectly. These incorrect labels may inappropriately contraindicate the use of TMP-SMX, and formal evaluation of TMP-SMX ARs with immunological assessment and relabelling where appropriate may increase the use of this agent.

Prevention of pneumocystis pneumonia in patients with hematological diseases: Efficacy of low-dose atovaquone.

OBJECTIVE: At our institution, patients with hematological disease who require Pneumocystis jirovecii pneumonia (PJP) prophylaxis were administered atovaquone at a low dose (750 mg/day). However, there have been few reports on the efficacy of low-dose atovaquone administration, and the purpose of this study is, therefore, to investigate its effectiveness. MATERIALS AND METHODS: We investigated the expression of PJP in patients with hematological disease who received atovaquone administration. Atovaquone was administered at a low dose of 750 mg once daily, and the follow-up time was the period of PJP prophylaxis that included atovaquone administration. RESULTS: 85 patients were included in the study. The median age of the study population was 72 years (range: 33 - 97). The duration of atovaquone treatment and follow-up time were 150 days (22 - 1,018) and 258 days (22 - 1,457), respectively. In hematologic diseases, multiple myeloma was high in 31 patients and malignant lymphoma in 28 patients. No patients exhibited PJP during the observation period. CONCLUSION: In hematological disease patients with relatively low risk of PJP, low-dose atovaquone may prevent the onset of PJP.

Trimethoprim-sulfamethoxazole prevents interstitial pneumonitis in B-cell lymphoma patients receiving chemotherapy: a propensity score matching analysis.

B-cell lymphoma is the most prevalent type of non-Hodgkin lymphoma, for which the standard treatment regimen includes rituximab combined with CHOP. However, some patients may develop interstitial pneumonitis (IP), which can be caused by various factors; one of the most important factors is Pneumocystis jirovecii. It is crucial to investigate the pathophysiology of IP and implement preventive measures since IP can be fatal for some people. The data were collected from the First Affiliated Hospital, Zhejiang University School of Medicine, where patients with B-cell lymphoma received the R-CHOP/R-CDOP regimen with or without prophylactic use of trimethoprim-sulfamethoxazole (TMP-SMX). Multivariable logistic regression and propensity score matching (PSM) were used to investigate any potential association. Eight hundred thirty-one patients with B-cell lymphoma were classified into two groups: the non-prophylaxis group without TMP-SMX (n=699) and the prophylaxis group with TMP-SMX (n = 132). IP occurred in 66 patients (9.4%, all in the non-prophylaxis group), with an onset median of three cycles of chemotherapy. Multiple logistic regression analysis demonstrated that IP incidence was associated with pegylated liposome doxorubicin (OR=3.29, 95% CI 1.84-5.90, P<0.001). After utilizing a 1:1 matching algorithm for PSM, 90 patients from each group were obtained. There was a statistical difference between the two cohorts in the IP incidence (non-prophylaxis 12.2% vs prophylaxis 0.0%, P <0.001). The prophylactic use of TMP-SMX could prevent the occurrence of IP whose risk factor was pegylated liposome doxorubicin after chemotherapy for B-cell lymphoma.

Prophylaxis Against Pneumocystis jirovecii Pneumonia in Adults.

This JAMA Insights Clinical Update discusses current recommendations regarding prevention of Pneumocystis pneumonia in patients who are immunocompromised.

Current Concepts in the Diagnosis and Management of Pneumocystis Pneumonia in Solid Organ Transplantation.

Pneumocystis infection manifests predominantly as an interstitial pneumonia in immunocompromised patients. Diagnostic testing in the appropriate clinical context can be highly sensitive and specific and involves radiographic imaging, fungal biomarkers, nucleic acid amplification, histopathology, and lung fluid or tissue sampling. Trimethoprim-sulfamethoxazole remains the first-choice agent for treatment and prophylaxis. Investigation continues to promote a deeper understanding of the pathogen's ecology, epidemiology, host susceptibility, and optimal treatment and prevention strategies in solid organ transplant recipients.

Risk-Benefit Analysis of Primary Prophylaxis Against Pneumocystis Jirovecii Pneumonia in Patients With Rheumatic Diseases Receiving Rituximab.

OBJECTIVE: To identify a specific population of patients with rheumatic diseases receiving rituximab treatment for whom the benefit from primary prophylaxis against Pneumocystis jirovecii pneumonia (PJP) outweighs the risk of adverse events (AEs). METHODS: This study included 818 patients treated with rituximab for rheumatic diseases, among whom 419 received prophylactic trimethoprim/sulfamethoxazole (TMP/SMX) with rituximab, while the remainder did not. Differences in 1-year PJP incidence between the groups were estimated using Cox proportional hazards regression. Risk-benefit assessment was performed in subgroups stratified according to risk factors based on the number needed to treat (NNT) to prevent 1 case of PJP and the number needed to harm (NNH) due to severe AEs. Inverse probability of treatment weighting was applied to minimize the confounding by indication. RESULTS: During the 663.1 person-years, there were 11 PJP cases, with a mortality rate of 63.6%. Concomitant use of high-dose glucocorticoids (≥30 mg/day of prednisone or equivalent during 4 weeks after rituximab administration) was the most important risk factor. The PJP incidence (per 100 person-years) was 7.93 (95% confidence interval [95% CI] 2.91-17.25) in the subgroup receiving high-dose glucocorticoids compared with 0.40 (95% CI 0.01-2.25) in the subgroup without high-dose glucocorticoid use. Although prophylactic TMP/SMX significantly reduced the overall PJP incidence (HR 0.11 [95% CI 0.03-0.43]), the NNT to prevent 1 case of PJP (146) was higher than the NNH (86). In contrast, the NNT fell to 20 (95% CI 10.7-65.7) in patients receiving concomitant high-dose glucocorticoids. CONCLUSION: The benefit associated with primary PJP prophylaxis outweighs the risk of severe AEs in patients with rheumatic diseases receiving rituximab and concomitant high-dose glucocorticoid treatment.