Prevention Of Pneumocystis Carinii Pneumonia Research Articles

Efficacy and safety of a low-dose sulfamethoxazole/trimethoprim regimen in preventing pneumocystis pneumonia: A retrospective study using a large-scale electronic medical record database

IntroductionSulfamethoxazole/trimethoprim (ST) is a first-line drug for preventing pneumocystis pneumonia (PCP). Several small-scale studies have suggested the usefulness of the low-dose regimen of ST (200/40 mg/day) over the standard-dose one (400/80 mg/day). Thus, this study aimed to investigate the efficacy and safety of low-dose and standard-dose regimens of ST in preventing PCP in patients with non human immunodeficiency virus infection using a large-scale electronic medical record database. MethodsThis retrospective study included patients who received ST prophylaxis for PCP registered in the RWD database between June 2007 and February 2023. Patients received either standard-dose (400/80 mg/day) or low-dose (200/40 mg/day) regimen groups. The incidence of cases initiated PCP therapeutic dose (ci-PCPTD) (ST ≥ 3600/720 mg/day) and adverse events (AEs) was evaluated, and risk factors for ci-PCPTD were investigated. ResultsA total of 11,384 patients received the standard-dose, whereas 7973 received the low-dose regimen groups. No significant difference in the cumulative incidence of ci-PCPTD was observed between the standard-dose (0.67%) and low-dose regimen group (0.47%). Lung disease was a significant risk factor for ci-PCPTD. The cumulative incidence of ci-PCPTD in patients with acute exacerbation of interstitial pneumonia was 1.3% in both groups, and no significant difference was observed between the two groups. The low-dose regimen group had a lower incidence of all AEs than the standard-dose regimen group. ConclusionThese results based on a large-scale electronic medical record database provide important evidence supporting the clinical significance of low-dose regimen of ST.

Liquid Chromatography-Tandem Mass Spectrometry-Based Therapeutic Monitoring of Plasma Atovaquone Concentrations in Pediatric Patients.

Atovaquone is an FDA-approved antiparasitic and antifungal therapeutic that is currently used as a prophylactic agent to prevent Pneumocystis carinii pneumonia (PCP) infections in acute myeloid leukemia (AML) patients after receiving hematopoietic stem cell transplantation (HSCT). Recent studies have shown that atovaquone has shown potential as an anticancer agent. The high variability in atovaquone bioavailability prompts the need for therapeutic drug monitoring, especially in pediatric patients. The goal of our study was to develop and validate the performance of an assay to quantify atovaquone plasma concentrations collected from pediatric cancer patients. Briefly, an organic-based solvent system is used to precipitate protein and extract the atovaquone content from each patient-derived plasma sample. After completing a second stage of sample dilution (5000-fold overall), a 2 μL volumeof the plasma extract is analyzed using the liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based bioanalytical method described.

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

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. 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. 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. In hematological disease patients with relatively low risk of PJP, low-dose atovaquone may prevent the onset of PJP.

A therapeutic vaccine strategy to prevent Pneumocystis pneumonia in an immunocompromised host in a non-human primate model of HIV and Pneumocystis co-infection.

Pneumocystis is a ubiquitous fungal pathogen that causes pneumonia (PCP) and pulmonary sequelae in HIV-infected individuals and other immunocompromised populations. With the success of anti-retroviral therapy for HIV-infected individuals the frequency of PCP in that population has decreased, however, PCP remains a significant cause of morbidity and mortality in individuals with hematologic and solid malignancies, and in individuals treated with immunosuppressive therapies for autoimmune diseases, and following bone marrow and solid organ transplantation. Despite the clinical need, there is no approved vaccine to prevent PCP in vulnerable populations. The ultimate goal of the field is to develop an effective vaccine that can overcome immune deficits in at risk populations and induce long-lasting protective immunity to Pneumocystis. Toward this goal, our laboratory has established a model of PCP co-infection in simian immunodeficiency virus (SIV)-infected non-human primates (NHP) and identified a recombinant protein sub-unit vaccine, KEX1, that induces robust anti-Pneumocystis immunity in immune-competent macaques that is durable and prevents PCP following simian immunodeficiency virus (SIV)-induced immunosuppression. Type I, or invariant natural killer T (iNKT) cells have the potential to provide B cell help under conditions of reduced CD4+ T cell help. In the present study, we used the SIV model of HIV infection to address whether therapeutic vaccination with the iNKT cell-activating adjuvant α-galactosylceramide (α-GC) and KEX1 (α-GC+KEX1) can effectively boost anti-Pneumocystis humoral immunity following virus-induced immunosuppression. Immunization of antigen-experienced NHPs with α-GC+KEX1 during the early chronic phase of SIV-infection significantly boosted anti-Pneumocystis humoral immunity by increasing memory B cells and antibody titers, and enhanced titer durability during SIV-induced immunosuppression. This therapeutic vaccination strategy boosted anti-Pneumocystis immune responses during SIV-infection and contributed to protection against Pneumocystis co-infection in KEX1-vaccinated macaques. These studies present a novel strategy for stimulating durable anti-Pneumocystis humoral immunity in the context of complex, chronic SIV-induced immunosuppression and may be further applied to immunization of other immunosuppressed populations, and toward other common recall antigens.

Prophylaxis against pneumocystis pneumonia in rheumatoid arthritis patients treated with b/tsDMARDs: insights from 3787 cases in the FIRST registry.

ObjectivesThe use of biologic and targeted synthetic (b/ts) DMARDs in the treatment of RA is increasing. Therefore, prevention of b/tsDMARDs-induced infection is important. Here we describe a prophylaxis protocol for preventing pneumocystis pneumonia (PCP) in RA patients treated with b/tsDMARDs.MethodsThe study subjects were 3787 RA patients from the FIRST registry. They were divided into cohort 1 (n = 807, requiring prophylaxis against PCP based on physicians’ assessment at the point of new treatment with or switch to b/tsDMARDs) and cohort 2 (n = 2980, receiving strategic PCP prophylaxis). The incidence and risk factors for PCP were investigated.ResultsTwenty-six PCP cases were observed throughout the study. After the introduction of strategic PCP prophylaxis, PCP incidence diminished from 0.51/100 person-years (PYs) to 0.21/100 PYs (risk ratio = 0.42). Sulfamethoxazole and trimethoprim in combination (SMX–TMP) showed greater efficacy in the prevention of PCP than pentamidine inhalation (P <0.0001). The prophylaxis rate increased chronologically despite the falls in the average SMX–TMP dose and in the incidence of PCP. Subanalysis of the data for 929 patients from both groups who did not receive prophylaxis showed that old age, high BMI, coexisting lung diseases, low lymphocyte count, and low serum IgG levels increased the risk of PCP development. Development of PCP could be predicted (using an equation based on these variables) in patients not treated with glucocorticoids [area under the curve (AUC) = 0.910)], but less accurately in those on glucocorticoids (AUC = 0.746).ConclusionsOur study clarified the risk factors for PCP in RA patients on b/tsDMARDs treatment and highlighted and defined the criteria for effective prophylaxis against PCP.

Mechanisms and management of drug-induced hyperkalemia in kidney transplant patients.

Hyperkalemia is a common and potentially life-threatening complication following kidney transplantation that can be caused by a composite of factors such as medications, delayed graft function, and possibly potassium intake. Managing hyperkalemia after kidney transplantation is associated with increased morbidity and healthcare costs, and can be a cause of multiple hospital admissions and barriers to patient discharge. Medications used routinely after kidney transplantation are considered the most frequent culprit for post-transplant hyperkalemia in recipients with a well-functioning graft. These include calcineurin inhibitors (CNIs), pneumocystis pneumonia (PCP) prophylactic agents, and antihypertensives (angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, beta blockers). CNIs can cause hyperkalemic renal tubular acidosis. When hyperkalemia develops following transplantation, the potential offending medication may be discontinued, switched to another agent, or dose-reduced. Belatacept and mTOR inhibitors offer an alternative to calcineurin inhibitors in the event of hyperkalemia, however should be prescribed in the appropriate patient. While trimethoprim/sulfamethoxazole (TMP/SMX) remains the gold standard for prevention of PCP, alternative agents (e.g. dapsone, atovaquone) have been studied and can be recommend in place of TMP/SMX. Antihypertensives that act on the Renin-Angiotensin-Aldosterone System are generally avoided early after transplant but may be indicated later in the transplant course for patients with comorbidities. In cases of mild to moderate hyperkalemia, medical management can be used to normalize serum potassium levels and allow the transplant team additional time to evaluate the function of the graft. In the immediate post-operative setting following kidney transplantation, a rapidly rising potassium refractory to medical therapy can be an indication for dialysis. Patiromer and sodium zirconium cyclosilicate (ZS-9) may play an important role in the management of chronic hyperkalemia in kidney transplant patients, although additional long-term studies are necessary to confirm these effects.

Pneumocystis Pneumonia: Immunity, Vaccines, and Treatments.

For individuals who are immunocompromised, the opportunistic fungal pathogen Pneumocystis jirovecii is capable of causing life-threatening pneumonia as the causative agent of Pneumocystis pneumonia (PCP). PCP remains an acquired immunodeficiency disease (AIDS)-defining illness in the era of antiretroviral therapy. In addition, a rise in non-human immunodeficiency virus (HIV)-associated PCP has been observed due to increased usage of immunosuppressive and immunomodulating therapies. With the persistence of HIV-related PCP cases and associated morbidity and mortality, as well as difficult to diagnose non-HIV-related PCP cases, an improvement over current treatment and prevention standards is warranted. Current therapeutic strategies have primarily focused on the administration of trimethoprim-sulfamethoxazole, which is effective at disease prevention. However, current treatments are inadequate for treatment of PCP and prevention of PCP-related death, as evidenced by consistently high mortality rates for those hospitalized with PCP. There are no vaccines in clinical trials for the prevention of PCP, and significant obstacles exist that have slowed development, including host range specificity, and the inability to culture Pneumocystis spp. in vitro. In this review, we overview the immune response to Pneumocystis spp., and discuss current progress on novel vaccines and therapies currently in the preclinical and clinical pipeline.

A Novel Encochleated Formulation Improves Atovaquone Activity in a Murine Model of Pneumocystis Pneumonia.

Although atovaquone is effective in treating and preventing Pneumocystis pneumonia (PCP), its use is limited by nonlinear absorption and adverse events. The current study was undertaken to examine the activity of encochleated atovaquone (eATQ), a novel lipid-crystal nanoparticle formulation, in a mouse model of PCP. eATQ 100-200 mg was superior to commercially available atovaquone at 14 days in decreasing total Pneumocystis nuclei and asci. eATQ plus anidulafungin reduced nuclei significantly better than commercial atovaquone plus anidulafungin. eATQ is a novel formulation of atovaquone that warrants further evaluation for treatment and prevention of PCP.

Pneumocystis jirovecii pneumonia in diffuse large B-cell Lymphoma treated with R-CHOP.

The aim of this study was to estimate the incidence of and risk factors for Pneumocystis pneumonia (PCP) infection in diffuse large B-cell lymphoma (DLBCL) patients treated with rituximab plus cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP). The medical records of 739 DLBCL patients who received R-CHOP between May 2004 and January 2019 were retrospectively evaluated. Patients were divided into two groups: those who received primary PCP prophylaxis (prophylaxis group) and those who did not (control group). The incidence rate of PCP in each group was calculated, and risk factors for PCP were evaluated in the control group. Baseline characteristics were significantly different between the two groups. Compared to the 602 patients who did not receive prophylaxis, the prophylaxis group (n=137) had poor prognostic factors of older age, high lactate dehydrogenase (LDH) levels, advanced Ann Arbour stage, and high International Prognostic Index (IPI) risk scores. None of the patients receiving PCP prophylaxis developed PCP, while the incidence of PCP in the control group was 8.1% (definite cases 5.5% and probable cases 2.7%). Out of the 49 patients who developed PCP, 10 patients (20.4%) were admitted to the intensive care unit, and the PCP-related death rate was 16.3% (8/49). This study showed that PCP prophylaxis is highly effective against PCP infection and may help guide prevention of PCP during R-CHOP treatment in DLBCL patients.

Abstract B14: Atovaquone targets STAT3 in ovarian cancer spheroids

Abstract Ovarian cancer remains a deadly disease for countless women. Recent evidence demonstrates that ovarian cancer cell clusters, spheroids, are important in promoting ovarian recurrence and metastasis. Often these spheroids are resistant to therapy. Therefore, we were interested in identifying drugs that could target ovarian cancer spheroids. To do this, we wanted to identify pathways that were activated in cells growing in three-dimensional (3D) clusters. Analysis of gene expression from 2D and 3D growing cells identified STAT3 as a pathway enriched in 3D growing cells. STAT3 is a transcription factor that is activated by tyrosine phosphorylation. In ovarian cancer cells, activation usually occurs from interleukin 6 (IL-6) binding to the IL-6 receptor and recruiting the signal transducer molecule (GP130, IL6ST). This activates Jak kinases that then tyrosine phosphorylates STAT3. Once activated, STAT3 dimerizes, translocates into the nucleus, and regulates the expression of target genes. Using shRNA targeting STAT3 and the upstream signaling molecule, GP130, we found that reduction of both STAT3 and its upstream signaling molecule GP130 reduced the growth of spheroids. This suggested that targeting STAT3 or an upstream signaling molecule might be a viable treatment option. Atovaquone, used normally for the treatment of malaria or the prevention of pneumocystis pneumonia, inhibits STAT3 activation by inhibiting the expression of GP130 on the cell surface. Therefore, we hypothesized that atovaquone would have efficacy in ovarian cancer spheroids. Treatment of ovarian spheroids with atovaquone reduced their growth and viability. Importantly, atovaquone inhibited STAT3 tyrosine phosphorylation and target gene expression, demonstrating that atovaquone is inhibiting STAT3 in ovarian spheroids. Preliminary data suggest that overexpression of STAT3 partially rescues the effects of atovaquone on spheroid growth. As spheroids are also involved in ovarian cancer metastasis, we are currently assessing the effects of atovaquone on spheroid-mediated ovarian cancer metastasis. Taken together, our data suggest that atovaquone may be a beneficial treatment for ovarian cancer patients. Citation Format: Kayli E. Neil, Sarah J. Lacroix, David F. Walker, Suhu Liu, David A. Frank, Sarah R. Walker. Atovaquone targets STAT3 in ovarian cancer spheroids [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr B14.

An open-label, randomized controlled trial of sulfamethoxazole-trimethoprim for Pneumocystis prophylaxis: results of 52-week follow-up.

ObjectivesThe aim was to investigate the long-term prophylactic efficacy, drug retention and safety of low-dose sulfamethoxazole–trimethoprim (SMX/TMP) prophylaxis against Pneumocystis pneumonia (PCP).MethodsAdult patients with rheumatic diseases receiving prednisolone ≥0.6 mg/kg/day were randomized into the single-strength group (SS; SMX/TMP 400/80 mg daily), the half-strength group (HS; 200/40 mg daily) or the escalation group (ES; starting at 40/8 mg and increasing incrementally to 200/40 mg daily) and treated for 24 weeks, then observed for 52 weeks. The primary endpoint, the PCP non-incidence rate (non-IR) at week 24, has been reported previously. The secondary endpoints were the PCP non-IR at week 52, treatment discontinuation rate and adverse events.ResultsFifty-eight, 59 and 55 patients in the SS, HS and ES, respectively, received SMX/TMP. PCP did not develop in any of the patients by week 52. The estimated PCP non-IR in patients receiving SMX/TMP 200/40 mg daily (HS and ES) was 96.8–100%. Throughout the 52-week observation period, the overall discontinuation rate was significantly lower in HS than in SS (22.7 vs 47.2%, P = 0.004). The discontinuation rates attributable to adverse events were significantly lower in HS (19.1%, P = 0.007) and ES (20.3%, P = 0.007) than in SS (41.8%). The IRs of adverse events requiring SMX/TMP dose reduction before week 52 differed among the three groups, with a significantly higher IR in SS than in HS or ES (P = 0.007).ConclusionSMX/TMP 200/40 mg had a high PCP prevention rate and was superior to SMX/TMP 400/80 mg in terms of drug retention and safety.Trial registrationUniversity Hospital Medical Information Network Clinical Trials Registry, UMIN000007727.

Effect of renal function on the fluctuations in serum creatinine and potassium levels due to sulfamethoxazole-trimethoprim combination for preventing Pneumocystis pneumonia

Effect of renal function on the fluctuations in serum creatinine and potassium levels due to sulfamethoxazole-trimethoprim combination for preventing Pneumocystis pneumonia

Incidence and Outcomes of Pneumocystis pneumonia When Utilizing PCR-Based Diagnosis in Patients with Hodgkin Lymphoma Receiving Intensive Chemotherapy

Background: The overall incidence of Pneumocystis Pneumonia (PJP) in lymphoma varies according to diagnosis, host factors and treatment rendered.(Carmona, et al. 2011) A meta-analysis suggested that prophylaxis is appropriate when the chance of incurring PJP is 3.5% or greater.(Green, et al. 2007) Accurately characterizing the incidence of PJP is further complicated by a transition in diagnostic methods from direct immunofluorescence assay (DFA) to a DNA-based polymerase chain reaction (PCR) technique.(Caliendo et al., 1998, Wilson JW, et al., 2011) The incidence of PCR-based diagnosis of PJP and the need for anti-Pneumocystis prophylaxis in patients diagnosed with Hodgkin lymphoma receiving chemotherapy requires further investigation. Methods: This single center, retrospective, observational study was approved by the Mayo Clinic Institutional Review Board and performed in accordance with the ethical standards of the 1964 Declaration of Helsinki. Consecutive adult patients with a diagnosis of Hodgkin lymphoma receiving chemotherapy between January 2006 and August 2018 were evaluated. Patients with history of bone marrow transplant were excluded. Kaplan-Meier estimation was used to calculate the cumulative incidence of PJP with a 95% confidence interval. Cox proportional hazard models were used to demonstrate the strength of association between the independent variables and PJP rate. Results: The 506 included patients had a median (IQR) age of 40.3 (28.6, 59.7) years, 287 (56.7%) were male, and 470 (92.9%) were Caucasian. Further baseline demographics and clinical characteristics are described in table 1 with no significant differences between those diagnosed and those free from PJP. Chemotherapy combined with radiation therapy was prescribed for 163 (32.3%) patients while 342 (67.7%) patients received chemotherapy alone. Chemotherapy regimen distribution included 356 patients (70.4%) receiving bleomycin-containing chemotherapy. Median (IQR) total Bleomycin dose was 122 (IQR: 78, 178) Units. Bleomycin-containing combination chemotherapy regimen was not significantly associated with a higher risk for PJP when compared to other combination regimens (HR=1.59, 95% CI 0.55-4.62 p=0.40). Bleomycin-related lung compromise was suspected in 130 (25.7%) patients. Anti-pneumocystis prophylaxis was provided for 97 patients (n=39 a priori, 58 after chemotherapy initiation) and this was not significantly associated with a decreased incidence of PJP (HR=0.51, 95% CI 0.15-1.71, p=0.28). The cumulative incidence of PJP 1 year after start of chemotherapy was 6.2% (95% CI 3.8%-8.5%) and is shown in figure 1. Diagnosis of PJP occurred most commonly during the 2nd (n=8, 30.7%), 3rd (n=8, 30.7%), and 4th (n=7, 26.9%) cycles of chemotherapy. Trimethoprim-sulfamethoxazole was the only agent prescribed as PJP management. There were 10 (38%) patients with PCP that required ICU admission with 9 needing mechanical ventilation, 4 necessitating vasopressor support, and none requiring dialysis. Mortality 30-days from PJP diagnosis was 8% (n=2) with one death attributable to PJP infection. Conclusion: Cumulative incidence of PJP was 6.2% in patients receiving intensive chemotherapy for Hodgkin lymphoma. As the incidence is above the 3.5% threshold previously described, the clinician should consider the potential value of prophylaxis. Defining the overall utility of universal vs. targeted anti-pneumocystis prophylaxis requires further prospective, randomized investigation. Disclosures No relevant conflicts of interest to declare. OffLabel Disclosure: Trimethoprim/Sulfamethoxazole, Pentamidine isethionate, and dapsone will be discussed as prevention of Pneumocystis Pneumonia in the HIV-negative population

Relation between dexamethasone (DEX) usage, preventive trimetprim/sulfametoxazole (ST), and pneumocystis pneumonia (PCP) for patients with breast cancer receiving dose-dense AC followed by dose-dense paclitaxel (ddAC-ddP): Preplanned analysis of WJOG9016B.

e12022 Background: PCP is rare complication of ddAC-ddP. DEX is plausible risk factor for PCP. Dose and duration of DEX against CINV is changing over time as other anti-emetic drugs (5HT3 RA, NK1 RA, and olanzapin) became available. Then DEX usage varies widely in each hospitals. ASCO/IDSA guideline recommends preventive ST for patients receiving 20 mg or more predonisone equivalents daily for more than one month, although evidence is lacking in patients receiving ddAC-ddP. This study is to investigate relation between DEX usage, preventive ST, and risk of PCP for patients receiving ddAC-ddP. Methods: This study is preplanned analysis of WJOG9016B (UMIN000024992) which investigated relative dose intensity of ddAC-ddP supported by 3.6 mg (approved dose in Japan) of pegfilgrastim. Eligible pts were HER2 negative PBC with stage I to IIIc, going to start ddAC-ddP and younger than 65 y.o.. DEX usage and preventive ST usage were discrete to treating physicians. Results: From Jan. 2017 to Jan. 2018, 92 pts were registered and 91 pts were in the FAS set, because one patients turned out be ineligible after registration. All patients received DEX for prevention of delayed CINV. Median total dose of DEX during ddAC was 112 mg (range; 80 to 212 mg), which was equal to 13.3 mg (9.52 mg–24.76 mg) predonisone equivalents daily. Only five of them (5.4%) received more than 20 mg predonisone equivalents daily. Twenty patients received preventive ST. Three patients developed PCP. None of them with preventive ST developed PCP (0%), whereas three of patients without ST developed PCP (4.2%). These three patients received total DEX dose during ddAC at 80 mg, 112 mg, and 112 mg, respectively. Conclusions: ST was highly effective for PCP prevention for patients receiving ddAC-ddP, if DEX used against delayed CINV. Without ST prevention, the risk of PCP was 4.2 %, which was higher than threshold (3.5%) proposed in ASCO/ IDSA guidelines. The threshold of steroid dose leading to the risk of PCP might be lower than 20 mg or more predonisone equivalents daily in patients receiving ddAC-ddP. Clinical trial information: UMIN000024992.

Pneumocystis pneumonia in HIV-1-infected patients.

Pneumocystis pneumonia (PCP) is an opportunistic disease that mainly affects patients with a deficiency of cell-mediated immunity, especially acquired immunodeficiency syndrome (AIDS). The incidence of PCP in these patients has declined substantially owing to the widespread use of antiretroviral therapy and PCP prophylaxis. However, PCP is still a major AIDS-related opportunistic infection, particularly in patients with advanced immunosuppression in whom human immunodeficiency virus type 1 (HIV-1) infection remains undiagnosed or untreated. The clinical manifestations, diagnosis, treatment, and prevention of PCP in patients with HIV-1 infection are addressed in this review.

Conventional-dose Versus Half-dose Sulfamethoxazole-trimethoprim for the Prophylaxis of Pneumocystis Pneumonia in Patients with Systemic Rheumatic Disease: A Non-blind, Randomized Controlled Trial.

Pneumocystis pneumonia (PCP) due to Pneumocystis jirovecii infection is the leading cause of fatal opportunistic infections in immunocompromised patients. We will determine whether a daily sulfamethoxazole-trimethoprim (SMX/TMP) dose of 200/40 mg was non-inferior to 400/80 mg for PCP prevention in patients with systemic rheumatic disease under immunosuppressive therapy. This is a randomized, open-label, multicenter controlled trial. The primary outcome is the rate of PCP prevention at 52 weeks. The secondary outcome is the discontinuation rate of SMX/TMP. The trial will evaluate the optimal dose of SMX/TMP for PCP prevention in patients with systemic rheumatic disease under immunosuppressive therapy.

Optimizing the use of trimethoprim-sulfamethoxazole for prevention of PCP and opportunistic infections in allogeneic hematopoietic cell transplant recipients.

138 Background: Trimethoprim-sulfamethoxazole (TMP-SMX) is preferred for prevention of Pneumocystis pneumonia (PCP), toxoplasmosis and other opportunistic infections after allogeneic hematopoietic cell transplantation (HCT), but it is often withheld due to potential adverse events (AE). From July 2016-June 2017 we observed that 31% of allogeneic HCT recipients at our hospital were prescribed TMP-SMX throughout the high risk period (day +30-180). Therefore, we developed an intervention to explore reasons for such a low prescription rate and to optimize TMP-SMX use. Methods: Our institution’s HCT practice guidelines were revised to include indications for TMP-SMX and alternative agents for PCP and Toxoplasma prophylaxis and specific clinical and laboratory criteria for withholding TMP-SMX. Education on the guidelines was provided to transplant clinicians. Outpatient encounters were prospectively audited from January to April 2018. Providers received real-time feedback with recommendations in accordance with our guidelines prior to patients’ visits. Results: We reviewed 321 outpatient encounters among 112 patients. Seventy-six (68%) patients were on TMP-SMX prophylaxis at the first reviewed encounter. Cytopenias were the most common reason for withholding TMP-SMX, occurring in 50 (57%) encounters, followed by elevated liver function tests (LFTs) (13.6%), hyperkalemia (3.4%), elevated creatinine (3.4%), rash or hypersensitivity (3.4%), and unknown/other (22%) . In 73 encounters in which patients received alternative or no PCP prophylaxis, we recommended changing to TMP-SMX. This intervention was accepted in 15 patients, 11(73%) of whom tolerated TMP-SMX well. In the remaining four patients, TMP-SMX was subsequently discontinued due to unrelated AE (N = 3) and possible TMP-SMX-associated elevated LFTs (N = 1). Conclusions: Provider education and real-time feedback led to increased utilization of TMP-SMX for prevention of PCP and other opportunistic infections in HCT recipients without an increase in TMP-SMX-related adverse effects. Further study is needed to understand the low clinician acceptance rate of the intervention.

Healthcare related transmission of Pneumocystis pneumonia: From key insights toward comprehensive prevention.

In at risk populations, Pneumocystis pneumonia (PCP) may occur as a solitary event as well as in a cluster- or outbreak setting due to interpatient transmission of Pneumocystis jirovecii. Despite the data and insights obtained from studies of outbreaks of PCP, the development and implementation of comprehensive recommendations for the prevention of healthcare related transmission of P.jirovecii have been delayed. Both optimization of chemoprophylaxis strategies as well as combination with prudent use of isolation precautions are warranted to achieve this goal. The rationale of the available measures for the prevention of PCP should be viewed in the context of what is currently known about the complex biology and epidemiology of P.jirovecii. From there, phased but practical prevention strategies can be deducted to balance the efforts, costs and negative consequences of chemoprophylaxis and isolation precautions with the beneficial effect of preventing healthcare related transmission of P.jirovecii and development of PCP.

Efficacy of CD101, a Novel Echinocandin, in Prevention of Pneumocystis Pneumonia (PCP): Thwarting the Biphasic Life Cycle of Pneumocystis

Background:Pneumocystis spp. are the obligate pathogenic fungi that cause PCP in immunocompromised mammalian hosts. The life cycle of Pneumocystis is thought to be biphasic with asexual replication by trophic forms and sexual production leading to formation of asci/cysts. There is evidence to suggest that infection is initiated by cyst inhalation and asci formation may be essential for the Pneumocystis life cycle. We have previously reported (Cushion, et al. 2010; 5:e8524) that currently available echinocandins are not suitable for monotherapy as large numbers of trophic forms remained after 3 weeks of treatment and asci re-appeared and replication resumed after treatment discontinuation. We evaluated the effects of CD101, a novel long-acting echinocandin, on trophic and cyst forms of Pneumocystis murina and its efficacy in preventing infection in a mouse model of PCP.Methods: Mice (C3H/HeN) were immunosuppressed throughout this 6-week study by dexamethasone (4 mg/L) in acidified drinking water. Infection with P. murina was by intranasal inoculation (2 x 106/50 µL). Mice were divided into groups to receive either vehicle (untreated control), trimethoprim/sulfamethoxazole (TMP/SMX 50/250 mg/kg x 3 per week), or CD101 (20, 2, or 0.2 mg/kg once or 3x per week) intraperitoneally at the time mice were inoculated. After 6 weeks, mice were humanely euthanized and lungs were processed for analysis by homogenization. Slides made from the lung homogenates were prepared for quantification of trophic forms by rapid Wright-Giemsa stain and of asci by cresyl echt violet staining. The reduction in P. murina burden (nuclei of trophic forms and asci) in treatment and untreated control groups was evaluated. The nuclei and asci counts for each lung were log transformed and analyzed by ANOVA. Individual groups were compared by Dunn’s test for multiple comparisons (GraphPadPrismv.6).Results: The reduction in nuclei and asci counts for all groups are shown in the Figure. Statistically significant reductions in nuclei levels compared with untreated controls were demonstrated with all CD101-treated groups except for the 0.2 mg/kg once weekly group. CD101 efficacy was comparable to that of TMP/SMX for 3 of the CD101 dose groups; no nuclei were observed by microscopic evaluation following CD101 dosages of 2 or 20 mg/kg 3x per week or 20 mg/kg once weekly. In terms of asci reduction, all CD101 groups demonstrated statistically significant reductions compared with untreated controls. CD101 efficacy was comparable to that of TMP/SMX for 5 of the CD101 dose groups (all but the 0.2 mg/kg once weekly group), with no asci observed by microscopic evaluation.Conclusion: Asci/cysts appear to be critical for replication as well as transmission of Pneumocystis. CD101 inhibited the formation of both trophic forms and asci of P. murina in thismouse model of PCP in immunocompromised mice. These data demonstrate that CD101 is a viable candidate for prophylactic therapy of PCP. [Display omitted] DisclosuresCushion:Univ. of Cincinnati: Employment; Cincinnati VAMC: Research Funding; Cidara Therapeutics, Inc.: Research Funding. Bartizal:Cidara Therapeutics, Inc.: Employment, Other: Stockholder.

Cytomegalovirus pneumonia after living-related donor kidney transplantation : the experiences of one single center within 10 years

Objective To report one-center experience on diagnosis and treatment of cytomegalovirus (CMV) pneumonia in recipients after living-related donor kidney transplantation (LDKT). Methods The clinical and follow-up data of 168 recipients after LDKT from April 2005 to September 2014 were analyzed retrospectively. We analyzed the general information, clinical manifestation, treatment and outcomes of 34 recipients who were diagnosed as CMV pneumonia. Of the 34 patients, 26 were male and 8 were female. The average age were 32.0 years old. Thirty-four patients developed CMV pneumonia between 12 to 402 days with an average of (91.7±60.8) days post-transplant. It was (6.4±3.7) d(range 1-14 d) from the onset of illness to seeking medical intervention. All cases presented with fever, 18 cases with dyspnea, 11 cases with cough and 6 cases with myalgia or fatigue. The highest temperature was (38.8±0.5)℃ (range 38.0-40.0℃). Leukocyte count was (10.5±4.4)×109/L, elevated in 18 cases, normal in 14 cases, reduced in 2 cases. Quantitative polymerase chain reaction(PCR) assay for CMV DNA was (9.3-15.8)×103 copies/ml for active CMV infection. Chest X ray or CT of all cases demonstrated patchy shadow or interstitial pneumonia. The etiological examination showed that 12 cases were complicated with other microorganism, including 8 cases with Pneumocystis carinii, 3 cases with Streptococcus A, 3 cases with Neisseria, 3 cases with candida albicans, 2 cases with klebsiella pneumoniae, Staphylococcus aureus, enterococcus faecium, Pseudomonas aeruginosa varied 1 case. Results In antiviral therapy, patients were treated by introvenous ganciclovir 5 mg/kg every 12 h for 14-21d and then 5 mg/kg every day. Glucocorticoid treatment included intravenous methylprednisolone 200 mg/kg for 3-5 d, then gradually reduced to 160 mg/kg for 3-5 d, 120 mg/kg for 3 d, 80 mg/kg for 3 d, 40 mg/kg for 3-5 d, until to the original oral dose. Early application of broad-spectrum antibiotics was to prevent bacterial infection, and routine application of compound sulfamethoxazole to prevent Pneumocystis carinii pneumonia. Treatment options were adjusted according to periodic bacteria and fungal culture in blood, urine or sputum, and effective anti bacterial, viral or fungal treatment was selected. After administration of antiviral therapy, methylprednisolone, treatment for other microorganism, as well as adjusted immunosuppressive drugs, 30 cases were cured. The total course of the pneumonia lasted for (28.5±9.4) days on average. However, 4 patients complicated with other microorganism died of severe pneumonia and acute respiratory distress syndrome(ARDS). Conclusion CMV infection was a common complication of living-related donor kidney transplantation. CMV infection often complicated with other microbial infections, and became one of the causes of death after renal transplantation. Early diagnosis, early antiviral therapy combined with effective anti bacterial, fungal treatment would improve the survival of kidney transplant recipients. Key words: Cytomegalovirus; Kidney transplantation; Living donors; Pneumonia