Trimethoprim-sulfamethoxazole Prophylaxis Research Articles

Typical pneumonia among human immunodeficiency virus-infected patients in public hospitals in southern Ethiopia.

Typical pneumonia is a pressing issue in the treatment of human immunodeficiency virus (HIV) patients, especially in Sub-Saharan Africa, where it remains a significant menace. Addressing this problem is crucial in improving health outcomes and the reduction of the burden of diseases in this vulnerable category of patients. To determine the prevalence of community-acquired typical pneumonia among HIV patients in Public Hospitals in southern Ethiopia. A cross-sectional study was done among 386 HIV patients clinically suspected of typical pneumonia attending the anti-retroviral therapy (ART) clinics of two hospitals from March to September 2022. A pretested structured questionnaire was employed to collect the demographic, clinical, and behavioral data. Sputum samples were collected and inspected for bacteria following standard procedures, and antimicrobial susceptibility testing was performed employing the Kirby-Bauer disk diffusion method. Besides, extended-spectrum β-lactamase (ESβL) and carbapenemase-producing Gram-negative bacteria were inspected by the double disk synergy test and modified carbapenem inactivation method. Descriptive and inferential statistical analyses were also done. Overall, 39.1% (151/386) of sputum cultures (95% Confidence Interval: 32.4-44) were bacteriologically positive. A total of 151 bacteria were identified, comprising 72.8% (n = 110) of Gram-negative bacteria. The predominant isolate was Klebsiella pneumoniae (25.8%, n = 39), followed by Staphylococcus aureus (17.9%, n = 27); 59.6% (n = 90) of the entire isolates were multidrug-resistant (MDR). Forty percent (11/27) of S. aureus were methicillin-resistant S. aureus (MRSA), and 28.1% (n = 31) and 20.9% (n = 23) of Gram-negative bacteria were extended-spectrum beta-lactamases (ESBL) and carbapenemase producers, respectively. Occupational status, alcohol consumption, cluster of differentiation4 (CD4) Thymocyte cell count < 350, interruption of trimethoprim-sulfamethoxazole prophylaxis and antiretroviral treatment, and recent viral load ≥ 150 were found statistically significant. The higher rates of MDR, MRSA, ESBL, and carbapenem-resistant Enterobacterales (CRE) indicate that bacterial pneumonia is a vexing problem among HIV patients and therefore it is advisable to implement an antimicrobial stewardship program in the study area.

Infection prophylaxis among patients with antineutrophil cytoplasmic antibody (ANCA) vasculitis: a scoping review.

Severe infections associated with the use of strong immunosuppressive medication are a leading cause of morbidity and mortality in patients with ANCA vasculitis (AV). While guidelines conditionally recommend trimethoprim-sulfamethoxazole (TMP-SMX) prophylaxis for Pneumocystis jirovecii pneumonia in AV patients, robust evidence on prophylaxis strategies is lacking. This scoping review aimed to assess the existing evidence on infection prophylaxis in AV patients, identify knowledge gaps, and guide future study design. A comprehensive search of six databases and relevant references identified original studies in English from January 1, 2000, to July 31, 2020. Inclusion criteria encompassed studies evaluating the impact of any antimicrobial prophylaxis strategy on infection-related outcomes in AV patients receiving immunosuppressive treatment. Studies were screened by four researchers using a blinded approach. Data was extracted by two reviewers, with differences resolved via consensus in consultation with a third reviewer. Nineteen studies met inclusion criteria, including two randomized trials and 17 cohort studies, with TMP-SMX being the most commonly assessed prophylactic strategy. The studies varied in sample sizes, outcomes measured, prophylactic strategies employed, and proportion of patients who received the regimen. Most cohort studies included no or limited control of potential confounding factors. This scoping review suggests significant variation in AV patients' receipt of TMP-SMX and alternative infection prophylaxis approaches. Observational studies using large secondary healthcare databases with rigorous designs are needed to provide high-quality evidence of the real-world effectiveness of antimicrobial prophylactic regimens, to improve clinical decision-making and quality of care for AV patients receiving immunosuppressive treatment.

Trimethoprim sulfamethoxazole prophylaxis and serious infections in granulomatosis with polyangiitis treated with rituximab.

To assess the association of trimethoprim sulfamethoxazole (TMP-SMX) prophylaxis with serious infections in rituximab-treated patients with granulomatosis with polyangiitis (GPA). This retrospective cohort study included adults with GPA (2011-2020) within the United States Merative™ Marketscan® Research Databases with ≥6 months enrolment prior to first (index) rituximab treatment. We defined TMP-SMX prophylaxis as a ≥28-day prescription dispensed after or overlapping the index date. Serious infection was a hospital primary diagnosis for infection (excluding viral or mycobacterial codes). Secondary outcomes were outpatient infection, PJP, and adverse events potentially attributable to TMP-SMX. Cox proportional hazards regression assessed the association of time-varying TMP-SMX with outcomes of interest, adjusting for potential confounders. Individuals were followed until the outcome of interest, end of database enrolment, or Dec 31, 2020. Among 919 rituximab-treated individuals (53% female), mean age was 52.1 years (SD 16) and 281 (31%) were dispensed TMP-SMX within 30 days of index date. Over a median of 496 (IQR 138, 979) days, 130 serious infections occurred among 104 individuals (incidence 6.1 [95% CI 5.0-7.4] per 100 person-years). Time-varying TMP-SMX was negatively associated with serious infection (adjusted HR 0.5; 95% CI 0.3-0.9). The aHR for outpatient infections was 0.8 (95% CI 0.6-1.1). The estimate for PJP was imprecise (13 events, unadjusted HR 0.2; 95% CI 0.03-1.8). TMP-SMX was potentially associated with adverse events (aHR 1.3; 95% CI 0.9-1.9). TMP-SMX prophylaxis was associated with reduced serious infections in rituximab-treated GPA, but may increase adverse events, warranting further study of optimal prophylaxis strategies.

Nocardiosis in Solid Organ Transplant Recipients: 10-Year Single Center Experience and Review of Literature.

Solid organ transplant recipients (SOTRs) are at an increased risk of nocardiosis, a rare but life-threatening opportunistic infection. Universal PCP prophylaxis with trimethoprim-sulfamethoxazole (TMP-SMX) is used at our center, which is active in vitro against most species of the Nocardia genus and may have a role in preventing early infections. This is a single-center retrospective cohort study of nocardiosis in adult SOTRs at a large transplant center between January 2012 and June 2022, with comprehensive review of literature. Out of 6179 consecutive cases, 13 (0.2%) were diagnosed with nocardiosis. The patients were predominantly male (76.9%) and kidney transplant recipients (62%). Infection was diagnosed at median of 8.8 months (range, 3.7-98) after transplant. Patients were followed for a median of 457 days (range 8-3367). Overall mortality within one year after diagnosis was 46% (6/13), of which 17% (1/6) of deaths was attributable to Nocardia infection. No recurrence was reported. Nocardia infections were noted in a small proportion of our SOTRs and carried significant morbidity and mortality. TMP-SMX prophylaxis may be protective in some cases given low incidence of cases.

Risk factors for Nocardia infection among allogeneic hematopoietic cell transplant recipients: A case-control study of the Infectious Diseases Working Party of the European Society for Blood and Marrow Transplantation

Nocardiosis is a rare but life-threatening infection after hematopoietic cell transplantation (HCT). We aimed at identifying risk factors for nocardiosis after allogeneic HCT and clarifying the effect of trimethoprim-sulfamethoxazole prophylaxis on its occurrence. We performed a retrospective multicenter case-control study of patients diagnosed with nocardiosis after allogeneic HCT between January 2000 and December 2018. For each case, two controls were matched by center, transplant date, and age group. Multivariable analysis was conducted using conditional logistic regression to identify potential risk factors for nocardiosis. Kaplan-Meier survival curves of cases and controls were compared using log-rank tests. Sixty-four cases and 128 controls were included. Nocardiosis occurred at a median of 9 months after allogeneic HCT (interquartile range: 5-18). After adjustment for potential confounders in a multivariable model, Nocardia infection was associated with tacrolimus use (adjusted odds ratio [aOR] 9.9, 95% confidence interval [95% CI]: 1.6-62.7), lymphocyte count <500/µL (aOR 8.9, 95% CI: 2.3-34.7), male sex (aOR 8.1, 95% CI: 2.1-31.5), recent use of systemic corticosteroids (aOR 7.9, 95% CI: 2.2-28.2), and recent CMV infection (aOR 4.3, 95% CI: 1.2-15.9). Conversely, use of trimethoprim-sulfamethoxazole prophylaxis was associated with a significantly decreased risk of nocardiosis (aOR 0.2, 95% CI: 0.1-0.8). HCT recipients who developed nocardiosis had a significantly decreased survival, as compared with controls (12-month survival: 58% and 90%, respectively; p<0.0001). We identified six factors independently associated with the occurrence of nocardiosis among allogeneic HCT recipients. In particular, trimethoprim-sulfamethoxazole prophylaxis was found to protect against nocardiosis.

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

ObjectivesIn 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. ResultsA 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. ConclusionsPentamidine administered IV monthly is safe and effective.

Clinical Characteristics and Epidemiological Analysis of Pneumocystis Jirovecii Pneumonia Infection in Kidney Transplant Patients with Trimethoprim-Sulfamethoxazole Dose Reduction Prophylaxis Strategy.

The administration of trimethoprim-sulfamethoxazole (TMP-SMX) for the prophylaxis of Pneumocystis jirovecii pneumonia (PJP) has proven to be highly efficacious in individuals who have undergone kidney transplantation. Nevertheless, the potential for severe adverse reactions associated with this treatment cannot be overlooked, and the determination of an optimal dosage regimen continues to be a matter of investigation. The current study evaluated the effectiveness of low-dose TMP-SMX for PJP prophylaxis in kidney transplant patients and conducted an analysis of the clinical characteristics and epidemiological trends in patients with PJP infection. This retrospective analysis studied electronic medical records of 1763 kidney transplant recipients from 2017 to 2020. These patients were initially prescribed a daily half-strength TMP-SMX (40 mg/200 mg), and the efficacy of this regimen was assessed during a follow-up period of 3-51 months. Under our PJP prevention and adjustment strategy, 24 patients were infected with PJP. The overall morbidity of PJP infection in our study was 1.36%, corroborates with findings from previously published studies. Among these 24 patients, up to 87.5% had their dosage adjusted due to increased creatinine or other adverse reactions, the most frequent dose was daily quarter-strength TMP-SMX (20 mg/100 mg). TMP-SMX prophylaxis successfully postponed and distributed the onset of PJP, with the mean duration from transplantation to the occurrence of PJP being 13.50±7.11 months. Daily administration of half-strength TMP-SMX can effectively prevent PJP, and prolonging prophylaxis with this medication may potentially reduce the incidence of infection.

Flat Dose Intravenous Immunoglobulin Primary Infection Prophylaxis in Multiple Myeloma Patients on Bispecific Antibody Therapy: Vanderbilt Experience

BACKGROUND Bispecific antibodies (BsAbs) are novel immunotherapeutic agents with prolific anti-multiple myeloma (MM) efficacy in highly relapsed/refractory disease (RRMM). They have been associated with profound and prolonged hypogammaglobinemia which represents a unique challenge regarding increased risk of serious (sometimes fatal) infections. Though IVIG has historically been dosed at 0.4g/kg for secondary prophylaxis, there is still uncertainty in optimal timing, schedule and frequency of supplementation in MM patients. At Vanderbilt University Medical Center, we have adopted a flat dose 10g IVIG prophylaxis schedule, which on average delivers ~36% of historical, weight-based dosing. At present, expert recommendations advise IVIG replacement every 4 weeks in recipients of BsAb starting the second month of therapy and continuing until the end of therapy or until serum IgG levels reach &amp;gt; 400 mg/dL, whichever is longer ( Mohan M et al. Br J Haematol.2023;00:1-11). Considering that MM BsAbs are currently used with continued dosing schedule, adoption and anticipated new BsAb approvals are increasing, IVIG has previously been on national/global shortage (occasionally unavailable), IVIG replacement during hypogammaglobulinemia represents a crucial aspect of adequate infection prophylaxis in MM, we explored the impact of our institutional 10g IVIG prophylaxis on infection rates in RRMM patients receiving BsAbs. Prior studies with comparable BsAbs reported Grade (G) ≥3 infection rate of 32-45% and 18%, in anti-BCMA and anti-GPRC5D BsAbs, respectively. In these trials, overall, 14-53% of patients received IVIG prophylaxis. METHODS We performed a retrospective review using electronic medical record of RRMM patients receiving anti-BCMA or anti-GPRC5D BsAbs from Jan 2019 to Dec 2022, either on clinical trials or as a standard of care at our institution. The inclusion criteria were minimum of two months of BsAb therapy, and the use of at least one month of monthly IVIG prophylaxis for serum IgG &amp;lt; 400 mg/dL. All patients were also on baseline valacyclovir, trimethoprim-sulfamethoxazole and levofloxacin prophylaxis. Routine disease and treatment specifics as well as infection rates and grades were collected. Infections were defined as mild (infections treated outpatient), moderate (required hospital admission) or severe (hospital admission with intensive care unit level of care), next to also being graded by CTCAE v5 with the rest of hematologic and non-hematologic adverse events (AEs). RESULTS A total of 30 patients with RRMM were identified. Table 1 illustrates the demographic and disease specifics: 79% received a median (range) of 4 (2-7) lines of prior therapy, over half were penta-class exposed, 27% were triple and quad refractory, 67% received a prior autologous stem cell transplant and 17% underwent prior treatment with BCMA targeting CAR-T therapy. All except 2 patients received BsAb therapy on clinical trials. Anti-GPRC5D BsAb was used to treat 60% of patients, while the rest (40%) received anti-BCMA BsAb, all of which were given for a median of 27 (12-45) months (Table 1). Overall, 30% of patients had one infectious episode, while 43% had ≥2. Viral infections (57%) were twice as common as bacterial (30%) (Table 2). Infections were mild in 60%, moderate in 23%, and severe in 6.6% of patients. We observed 27% rate of G ≥3 infectious complications. Patients had a median (range) IgG at diagnosis of 1284(196-5431), and 499(210-2246) at the time of onset of first infection (IgG values at the start of BsAb therapy, at first and at ≥2 infections are outlined in Table 2). The rate of G ≥3 neutropenia and lymphopenia was 6.6% and 30% respectively. There were 2 (6.6%) sepsis related deaths, one each with anti-BCMA and anti-GPRC5D BsAbs. Table 2 also describes severity and the rates of cytokine release syndrome and neurotoxicity. CONCLUSIONS We observed relatively lower rate of severe or ≥ G3 infectious events with 10g flat IVIG dosing schedule. While our results represent a small, single-institutional cohort of predominantly anti-GPRC5D treated RRMM patients and require prospective validation in a randomized (IVIG 10g vs 0.4g/kg body weight) fashion, they demonstrate feasibility of reduced level dosing of a critical resource such as IVIG, in the fast expanding, national/global BsAb-based MM armamentarium.

2738. Two-step sulfonamide antibiotic challenges in patients who require treatment with trimethoprim-sulfamethoxazole at an academic medical center: Outcomes in a largely immunocompromised population

Abstract Background Sulfonamide antibiotic allergy is the second most reported medication allergy. The allergy label limits the use of trimethoprim-sulfamethoxazole (TMP-SMX), the antibiotic of choice for pneumocystis jirovecii pneumonia (PJP), Toxoplasma, and many types of urinary tract infections. Immunocompromised patients, including solid organ transplant recipients, are considered to be at a higher risk for developing an infection. While penicillin allergies are commonly tested and patients delabeled, sulfonamide challenges are not as prevalent. Patients who are tested following a transplant may be on medications that lower the negative predictive value of the challenge, raising questions about whether they truly passed the challenge or whether mild reactions were masked. Methods: Thirty-seven patients labeled with a sulfonamide allergy who were evaluated and challenged with two doses of TMP-SMX were included. Adults (≥18 years) with a sulfonamide antibiotic allergy were evaluated and challenged between June 2020 and May 2023. Data collection included the number of patients challenged and delabeled, number of patients who had reactions and what type of reaction, and proportion of patients who completed the treatment or prophylaxis course for which TMP-SMX was the first-line antibiotic. Results Thirty-seven patients were challenged, of which twenty-seven patients were immunocompromised (73%). Thirty-four (92%) passed the sulfonamide challenge and were delabeled, and thirty-two (86%) completed the full course of TMP-SMX prophylaxis or treatment. Nineteen patients (51%) were tested following immunosuppression or antihistamine treatment due to a new transplant. Five patients were not able to be delabeled due to mild or delayed reactions to the challenge or treatment, including two patients that passed the sulfonamide challenge and were delabeled but had a mild reaction during SMX-TMP therapy and were relabeled. Conclusion The benefits of sulfonamide antibiotic allergy testing can have great effects in immunocompromised patients in preventing the use of second-line antibiotics. Sulfonamide challenges were shown to be safe and effective in immunocompromised patients in delabeling the sulfonamide antibiotic allergy and leading to the completion of treatment with TMP-SMX. Disclosures Shyam Joshi, MD, Cogent: Honoraria|Leo Pharma: Honoraria|Nectar Allergy: Advisor/Consultant|Nectar Allergy: Stocks/Bonds|Sanofi/Regeneron: Advisor/Consultant|Sanofi/Regeneron: Honoraria|Takeda: Honoraria

Abstract 13379: Guideline Directed Medical Therapy Treatment Patterns and Outcomes in Cardiac Sarcoidosis Patients With Systolic Heart Failure

Introduction: Cardiac sarcoidosis (CS) results in HFrEF, but its natural history and response to GDMT remains uncertain. Methods: We queried a registry of 631 CS patients evaluated at our institution to identify those with LVEF &lt; 35% on TTE within 30 d of diagnosis and a follow-up TTE 12-18 months later (external CS diagnoses were excluded). Demographics, LVEF, NT-proBNP, GDMT, immunosuppression, CIED, and outcomes (hyperkalemia, LVAD/transplant, CV hospitalization, death) were recorded. Results: Overall, 25/631 (4%) of CS patients had an LVEF &lt;35% at initial presentation (36% female, 84% white; median age of 58 y; probable/not biopsy-proven CS in 52%). Mean baseline LVEF was 27% (σ=7%), NT-proBNP 1736 pg/mL (n=11), potassium 4.3 mEq/L (n=18), and median NYHA Class II (54%). Patients were on a mean 1.7 GDMT agents at CS diagnosis (Figure). Most were treated with immunosuppression (88%) for mean 0.75 y, usually prednisone (88%, mean 16 mg daily) and fewer with mycophenolate (32%, mean 1875 mg daily), methotrexate (28%, mean 18mg weekly), or TNF-α inhibitor (4%). 64% were on trimethoprim-sulfamethoxazole prophylaxis. At follow-up (median 317 d), 3 patients (12%) required LVAD and 1 (4%) required heart transplant. Mean LVEF improved to 37% (excluding LVAD/transplant, σ=11%, p=0.001). CIED prevalence increased from 48 to 81% (p=0.03). Overall GDMT did not change (mean 2.0 agents, p=0.2) and only beta-blocker dose changed (64 to 138 mg mean daily metoprolol equivalents). Potassium did not change (p=0.4) and hyperkalemic events were infrequent (16%). No patients died, but unplanned hospitalization occurred in 36% of patients. Conclusions: CS patients with HFrEF are usually on partial GDMT at diagnosis, presumably due to earlier recognition of HFrEF, but intensification of GDMT may be limited. Despite improved LVEF which may be due to GDMT, immunosuppression, and/or CIED, over 1/3 patients were hospitalized within 18 mo, highlighting the high-risk profile of HFrEF in CS.

A Clinical Model to Predict the Occurrence of Select High-risk Infections in the First Year Following Heart Transplantation.

Invasive infection remains a dangerous complication of heart transplantation (HT). No objectively defined set of clinical risk factors has been established to reliably predict infection in HT. The aim of this study was to develop a clinical prediction model for use at 1 mo post-HT to predict serious infection by 1 y. A retrospective cohort study of HT recipients (2000-2018) was performed. The composite endpoint included cytomegalovirus (CMV), herpes simplex or varicella zoster virus infection, blood stream infection, invasive fungal, or nocardial infection occurring 1 mo to 1 y post-HT. A least absolute shrinkage and selection operator regression model was constructed using 10 candidate variables. A concordance statistic, calibration curve, and mean calibration error were calculated. A scoring system was derived for ease of clinical application. Three hundred seventy-five patients were analyzed; 93 patients experienced an outcome event. All variables remained in the final model: aged 55 y or above, history of diabetes, need for renal replacement therapy in first month, CMV risk derived from donor and recipient serology, use of induction and/or early lymphodepleting therapy in the first month, use of trimethoprim-sulfamethoxazole prophylaxis at 1 mo, lymphocyte count under 0.75 × 103cells/µL at 1 mo, and inpatient status at 1 mo. Good discrimination (C-index 0.80) and calibration (mean absolute calibration error 3.6%) were demonstrated. This model synthesizes multiple highly relevant clinical parameters, available at 1 mo post-HT, into a unified, objective, and clinically useful prediction tool for occurrence of serious infection by 1 y post-HT.

Trimethoprim-sulfamethoxazole prophylaxis during treatment of granulomatosis with polyangiitis with rituximab in the United States of America: a retrospective cohort study

BackgroundAntibiotic prophylaxis is recommended during ANCA-associated vasculitis (AAV) induction. We aimed to describe the frequency, persistence, and factors associated with trimethoprim-sulfamethoxazole (TMP-SMX) use in an adult population sample with granulomatosis with polyangiitis (GPA) treated with rituximab (RTX).MethodsWe identified adults with GPA treated with RTX within the Merative™ Marketscan® Research Databases (2011–2020). TMP-SMX prophylaxis was defined as a ge 28-day prescription dispensed within a month of starting RTX. We estimated TMP-SMX persistence, allowing prescription refill gaps of 30 days. Multivariable logistic regression and Cox proportional hazards regression assessed the factors associated with baseline TMP-SMX use and persistence, respectively. Covariates included age, sex, calendar year, insurance type, immunosuppressant use, hospitalization, and co-morbidities.ResultsAmong 1877 RTX-treated GPA patients, the mean age was 50.9, and 54% were female. A minority (n = 426, 23%) received TMP-SMX with a median persistence of 141 (IQR 83–248) days. In multivariable analyses, prophylaxis was associated with prednisone use in the month prior to RTX (ge 20 mg/day vs none, OR 3.96; 95% CI 3.0–5.2; 1–19 mg/day vs none, OR 2.63; 95% CI 1.8–3.8), and methotrexate use (OR 1.48, 95% CI 1.04–2.1), intensive care (OR 1.95; 95% CI 1.4–2.7), and non-intensive care hospitalization (OR 1.56; 95% CI 1.2–2.1) in the 6 months prior to RTX. Female sex (OR 0.63; 95% CI 0.5–0.8) was negatively associated with TMP-SMX use.ConclusionsTMP-SMX was dispensed to a minority of RTX-treated GPA patients, more often to those on glucocorticoids and with recent hospitalization. Further research is needed to determine the optimal use and duration of TMP-SMX prophylaxis following RTX in AAV.

An Atypical Presentation of X-linked Lymphoproliferative Disease type 1 Presenting with Seronegative Coccidioidomycosis

X-linked lymphoproliferative disease (XLP-1), an inborn error of immunity (IEI) caused by pathogenic variants in SH2D1A encoding signaling lymphocyte activation molecule-associated protein (SAP), is characterized by hemophagocytic lymphohistiocytosis (HLH), lymphoma, and hypogammaglobulinemia. We report the first known case of XLP-1 presenting with seronegative coccidioidomycosis. CaseA 13-year-old boy with persistent asthma, recurrent otitis media requiring four sets of tympanostomy tubes, chronic sinusitis, and Common Variable Immunodeficiency (CVID) presented with acute-on-chronic hypoxic respiratory failure. He had been off subcutaneous immunoglobulin (SCIg) replacement for 2 years. Sputum culture was positive for H. influenzae, treated with cefepime and azithromycin and supplemental oxygen for acute hypoxic respiratory failure. Fever persisted despite 48 hours of antibiotics. CT chest showed bronchiectasis with mediastinal, subcarinal and hilar adenopathy. Coccidioides immitis IgG and IgM were negative, but urine antigen was positive. There was no radiologic or cerebrospinal fluid evidence of disseminated coccidioidomycosis.Immunologic workup revealed undetectable IgG, IgA, IgM, and IgE (table 1). Lymphocyte subsets showed severe T and NK cell lymphopenia. Total B cell count was normal, but he had decreased CD19+27+ and transitional B cells, with absent switched memory B cells and no plasmablasts (table 1). Lymphocyte proliferation to mitogens/antigens was decreased. Serum ferritin was normal, and EBV PCR was negative. A targeted 429-gene panel identified a hemizygous variant of uncertain significance (VUS) in SH2D1A, c.82_102dup (p.Ser28_Ser34dup). SAP expression was absent in CD4+ T cells and NK cells with a bimodal expression in CD8+ T cells, suggesting possible mosaicism in this subset. He was diagnosed with X-linked lymphoproliferative disease 1 (XLP-1) and treated with fluconazole, trimethoprim-sulfamethoxazole prophylaxis, and IgG replacement (1 g/kg intravenous initially, then transitioned to weekly SCIg targeting an IgG >1000 mg/dL), with clinical improvement, resolution of fevers and acute hypoxia. He was referred for hematopoietic cell transplant evaluation.Coccidioidomycosis has not been described in a new diagnosis of XLP-1 and should be considered in this IEI. Coccidioidomycosis susceptibility has been reported in other IEIs including impaired interleukin-12/interferon-gamma axis signaling, STAT3 loss of function, chronic granulomatous disease, and recently cytidine triphosphate synthase 1 (CTPS1) deficiency.Table 1Patient’s immunologic variables compared to reference range. Absolute values are shownImmunologic VariablePatient ValuesReference RangeIgG<70 (L)<70 mg/dLIgA<15 (L)<15 mg/dLIgM<8 (L)<8 mg/dLIgE<1.5 (L)<1.5 IU/uLTotal CD4+ T Cells11 (L)570–2400 cells/uLTotal CD8+ T Cells63 (L)210–1200 cells/uLTotal CD19+ B cells173165–1154 cells/uLCD19+ CD24++ CD38++ (Transitional B Cells)0 (L)8–392 cells/uLCD19+CD24+CD38+ (Naïve B Cells)12159–1146 cells/uLCD19+CD27-(Naïve B cells)169140–2269 cells/uLCD19+ CD27+ CD38+ IgM- (Plasmablasts)0<30 cells/uLCD19+CD27+IgD-IgM- (Switched-memory B cells)0 (L)6–190 cells/uLCD16+ CD56+ (NK Cells)32 (L)78–470 cells/uLL – low

High prevalence and mortality of Pneumocystis jirovecii pneumonia in anti-MDA5 antibody-positive dermatomyositis.

To identify potential risk factors and prognostic factors of Pneumocystis jirovecii pneumonia (PJP) infection in anti-melanoma differentiation-associated gene 5 antibody-positive DM (anti-MDA5+ DM) patients, and to evaluate the diagnostic performance of metagenomic next-generation sequencing (mNGS). Anti-MDA5+ DM patients who underwent mNGS or real-time PCR for PJP detection were recruited. The potential risk factors for PJP occurrence and death were analysed via Logistic regression and Cox proportional hazards regression, respectively. The diagnostic efficacy of mNGS was compared with the conventional methods. 91 patients were enrolled and 44 were assigned to PJP+ group. The PJP detection rate was 48.4%. PJP often occurred in the first 3 months (68.2%) of the disease; this period also showed the highest mortality rate (20.5%). Fever and increased lactate dehydrogenase (LDH) were independent risk factors for PJP occurrence, while trimethoprim-sulfamethoxazole (TMP/SMZ) prophylaxis was an independent protective factor (all P < 0.05). Older age and increased LDH were predictors for mortality in patients with anti-MDA5+ DM and PJP (all P < 0.05). In addition, we found that mNGS had a sensitivity of 100.0% and specificity of 90.0% in diagnosing PJP, with the highest area under the curve of 0.95 (P < 0.001). PJP has high prevalence and mortality in anti-MDA5+ DM. It is crucial for clinicians to identify high-risk patients and promptly institute TMP/SMZ to prevent PJP. mNGS is the preferred approach for pathogen detection in anti-MDA5+ DM when PJP is suspected.

Risk Factors and Outcomes of Nocardiosis in Hematopoietic Stem Cell Transplantation Recipients

Nocardiosis occurs in up to 1.7% of hematopoietic stem cell transplantation (HSCT) recipients. Risk factors for its development and subsequent outcomes have been incompletely studied. The present study evaluated risk factors for nocardiosis in HSCT recipients and an association with 12-month mortality following Nocardia infection. We performed a nested case-control study of HSCT recipients at 3 transplantation centers between 2011 and 2021. Allogeneic HSCT recipients were matched 1:4 to controls based on age, sex, date of transplantation, and transplantation site. Because of theorized differences in the risk for nocardiosis between allogeneic HSCT recipients and autologous HSCT recipients and a low number of infected autologous HSCT recipients, only allogeneic HSCT recipients were matched to controls. Associations with nocardiosis in the allogeneic group were assessed by multivariable conditional logistic regression. Outcomes of all HSCT recipients with nocardiosis included 12-month mortality and post-treatment recurrence. Twenty-seven HSCT recipients were diagnosed with nocardiosis, including 20 allogeneic HSCT recipients and 7 autologous HSCT recipients. Twenty (74.1%) had localized pulmonary infection, 4 (14.8%) had disseminated infection, and 3 (11.1%) had localized skin infection. The allogeneic recipients were diagnosed at a median of 12.2 months after transplantation, compared with 41 months for the autologous recipients. All autologous HSCT recipients had alternative reasons for ongoing immunosuppression at diagnosis, most frequently therapy for relapsed hematologic disease. No infected patients were receiving trimethoprim-sulfamethoxazole (TMP-SMX) prophylaxis. In multivariable analysis of 20 allogeneic patients and 80 matched controls, graft-versus-host disease (GVHD) requiring current immunosuppression and lack of prophylaxis were associated with nocardiosis. Nocardiosis was significantly associated with subsequent mortality, with a 12-month mortality rate of 29.6%; however, no patients who completed treatment experienced Nocardia recurrence. OUR DATA INDICATE THAT: intensified immunosuppression following allogeneic HSCT, such as treatment for GVHD, is associated with the development of nocardiosis. Nocardiosis occurs more distantly from transplantation in autologous recipients, possibly driven by therapy for relapsed hematologic disease. No patients receiving TMP-SMX prophylaxis developed nocardiosis. Nocardia infection is associated with high mortality, and further strategies for prevention and treatment are needed.

Impact of Drug Exposure on Resistance Selection Following Artemether-Lumefantrine Treatment for Malaria in Children With and Without HIV in Uganda.

Artemisinin-based combination therapies (ACTs) are the primary treatment for malaria. It is essential to characterize the pharmacokinetics (PKs) and pharmacodynamics (PDs) of ACTs in vulnerable populations at risk of suboptimal dosing. We developed a population PK/PD model using data from our previous study of artemether-lumefantrine in HIV-uninfected and HIV-infected children living in a high-transmission region of Uganda. HIV-infected children were on efavirenz-, nevirapine-, or lopinavir-ritonavir-based antiretroviral regimens, with daily trimethoprim-sulfamethoxazole prophylaxis. We assessed selection for resistance in two key parasite transporters, pfcrt and pfmdr1, over 42-day follow-up and incorporated genotyping into a time-to-event model to ascertain how resistance genotype in relation to drug exposure impacts recurrence risk. Two hundred seventy-seven children contributed 364 episodes to the model (186 HIV-uninfected and 178 HIV-infected), with recurrent microscopy-detectable parasitemia detected in 176 episodes by day 42. The final model was a two-compartment model with first-order absorption and an estimated age effect on bioavailability. Systemic lumefantrine exposure was highest with lopinavir-ritonavir, lowest with efavirenz, and equivalent with nevirapine and HIV-uninfected children. HIV status and lumefantrine concentration were significant factors associated with recurrence risk. Significant selection was demonstrated for pfmdr1 N86 and pfcrt K76 in recurrent infections, with no evidence of selection for pfmdr1 Y184F. Less sensitive parasites were able to tolerate lumefantrine concentrations ~ 3.5-fold higher than more sensitive parasites. This is the first population PK model of lumefantrine in HIV-infected children and demonstrates selection for reduced lumefantrine susceptibility, a concern as we confront the threat to ACTs posed by emerging artemisinin resistance in Africa.

Association between different infection profiles and one-year outcomes in ANCA-associated vasculitis: a retrospective study with monthly infection screening

ObjectivesThis study aimed to explore clinical features of early infection in patients with antineutrophil cytoplasmic antibody-associated vasculitis (AAV) and to identify the association between the infection profile of patients with...

Nocardial Infection in the Early Period after Kidney Transplantation

Patients with solid organ transplant have weaker immune system and can develop opportunistic infections. Prophylactic antimicrobials can help lower that risk but do not prevent it completely. High index of suspicion increases the chance of diagnosing rare opportunistic infections in immunocompromised patients and helps early and effective treatment. We present a unique case of a patient who developed pneumonia from Nocardia early after kidney transplant despite being on trimethoprim-sulfamethoxazole (TMP-SMX) prophylaxis. He was diagnosed and treated early which helped improving his outcome. We discuss incidence, risk factors, and treatment of nocardiosis post kidney transplant.

Extended Spectrum β-Lactamase Producing Lactose Fermenting Bacteria Colonizing Children with Human Immunodeficiency Virus, Sickle Cell Disease and Diabetes Mellitus in Mwanza City, Tanzania: A Cross-Sectional Study.

Rectal carriage of extended spectrum β-lactamase-lactose fermenters (ESBL-LF) is the major risk factor for the development of subsequent endogenous infections. This study determined the patterns and factors associated with the rectal carriage of ESBL-LF among children with Human Immunodeficiency Virus (HIV), Diabetes Mellitus (DM), and Sickle Cell Disease (SCD) attending clinics at different health care facilities in the city of Mwanza, Tanzania. A cross-sectional study was conducted among children living with HIV (n = 236), DM (n = 42) and SCD (n = 126) between July and September 2021. Socio-demographic and clinical data were collected using a structured questionnaire. Rectal swabs/stool samples were collected and processed to detect the rectal carriage of ESBL-LF following laboratory standard operating procedures (SOPs). Descriptive statistical analysis was conducted using STATA 13.0. The overall prevalence of ESBL-LF carriage was 94/404 (23.3%). Significantly higher resistance was observed to ampicillin, trimethoprim-sulfamethoxazole, and tetracycline among Enterobacteriaceae isolated from HIV infected children than in non-HIV infected children (p < 0.05). The commonest ESBL allele 45/62 (72.6%) detected was blaCTX-M. Generally, a parent’s low education level was found to be associated with ESBL-LF colonization among children living with HIV; (OR 4.60 [95%CI] [1.04–20], p = 0.044). A higher proportion of ESBL-LF from DM 10/10 (100%) carried ESBL genes than ESBL-LF from HIV 37/56 (66.1%) and SCD 15/28 (53.6%), p = 0.02. There is a need to collect more data regarding trimethoprim-sulfamethoxazole (SXT) prophylaxis and antibiotic resistance to guide the decision of providing SXT prophylaxis in HIV-infected children especially at this time, when testing and treatment is carried out.

Multifocal Trichosporon asahii Infection in a Patient With Chronic Granulomatous Disease

A 20-year-old female with chronic granulomatous disease (CGD) presented with a 10-day history of left hip pain and intermittent fever to an outpatient clinic in the Midwestern United States. She reported constant, moderate to severe pain over the posterior aspect of the left hip with distal radiation that improved with movement. She denied any joint swelling, decrease in range of motion, discoloration, rash, or edema. A review of systems was significant for a nonproductive cough without dyspnea and a 3-kg weight loss during the last 4 months. The patient’s CGD resulted from biallelic pathogenic variants in the neutrophil cytosolic factor 1 (NCF1) gene, an autosomal-recessive form of CGD. She was originally from the United Arab Emirates (UAE) and had arrived in the United States 30 days before presentation for allogeneic hematopoietic stem cell transplantation (HSCT) evaluation. Previous history was notable for Streptococcus intermedius liver abscess treated 4 years before presentation. She denied any significant animal exposure or known exposure to individuals with active tuberculosis infection. She had poor adherence to her previously prescribed itraconazole and trimethoprim-sulfamethoxazole (TMP-SMX) prophylaxis regimen.