Low-dose Trimethoprim-sulfamethoxazole Research Articles

Low-dose trimethoprim-sulfamethoxazole treatment for Pneumocystis pneumonia: a systematic review and meta-analysis

BackgroundThe recommended standard treatment for Pneumocystis jirovecii pneumonia (PJP) is high-dose trimethoprim-sulfamethoxazole (TMP-SMX) (15–20 mg/kg/d TMP). However, the standard regimen may cause a high incidence of dose-related adverse events (AEs). Therefore, we aimed to conduct a systematic review and meta-analysis to evaluate the efficacy and safety of low-dose TMP-SMX regimens (<15 mg/kg/d of TMP) compared with the standard regimen in patients with PJP.MethodsWe searched PubMed, Embase, and the Cochrane database for relevant articles from inception to 10 March 2024. Studies were included if they focused on PJP patients receiving a low-dose TMP-SMX regimen compared with a standard regimen. The primary outcome was mortality. We assessed study quality and performed subgroup analysis and sensitivity analysis to explore potential heterogeneity among the included studies.ResultsSeven studies were included. Overall, the low-dose regimen significantly reduced the risk of mortality (odds ratio [OR] = 0.49; 95% CI, 0.30–0.80; I2 = 16%; P = 004). This finding was confirmed in further sensitivity and subgroup analyses. The low-dose regimen also significantly reduced total AEs (OR = 0.43; 95% CI, 0.29–0.62; I2 = 0%; P < 0.0001), and improved the incidence of most specific AEs (ORs ranged from 0.13 to 0.89). In addition, the low-dose regimen had significantly more patients completing the initial regimen (P = 0.002), fewer patients requiring dose reductions (P = 0.04), and almost significantly fewer patients requiring a switch to a second-line regimen (P = 0.06).ConclusionThe limited available evidence suggests that a low-dose TMP-SMX regimen significantly reduced mortality and total AEs in PJP patients. Thus, it is one of the potentially promising therapies to PJP and more high-quality and multi-center randomized trials should be conducted in the future.

Outcomes of low-dose trimethoprim-sulfamethoxazole treatment in patients with non-HIV pneumocystis pneumonia: A nationwide Japanese retrospective cohort study

ObjectivesLow-dose trimethoprim-sulfamethoxazole (TMP-SMX) may be a treatment option for patients with Pneumocystis jirovecii pneumonia (PCP). However, its effectiveness in patients without human immunodeficiency virus (HIV) infection has yet to be thoroughly investigated. MethodsThis retrospective cohort study used data extracted from the Japanese Diagnosis Procedure Combination inpatient database. We included immunocompromised patients without HIV having been diagnosed with PCP and had started TMP-SMX treatment between July 2010 and March 2022. We divided eligible patients into conventional-dose (15.0–20.0 mg/kg/d) and low-dose (7.5–15.0 mg/kg/d) groups and performed propensity-score overlap-weighting analysis. The primary outcome was in-hospital mortality rate. Secondary outcomes were completion of the initial treatment and use of alternatives to TMP-SMX for PCP treatment during hospitalization. ResultsAmong 4449 eligible patients, 1682 (37.8 %) and 2767 (62.2 %) received conventional- and low-dose TMP-SMX treatments, respectively. No significant difference was observed in in-hospital mortality (risk difference, −1.4 %; 95 % CI, −4.5–1.7 %; P = 0.388). Low-dose TMP-SMX was associated with increased completion of initial treatment (risk difference, 4.6 %; 95 % CI, 2.3–6.9 %; P < 0.001), and reduced use of alternative agents (risk difference, −4.0 %; 95 % CI, −7.4 to −0.6 %; P = 0.020). ConclusionLow-dose TMP-SMX may be a treatment option for patients with non-HIV PCP.

Comparison of High-Dose versus Low-Dose Trimethoprim-Sulfamethoxazole for Treating Pneumocystis jirovecii Pneumonia among Hemodialysis Patients: A Nationwide Database Study in Japan.

Background: Hemodialysis patients are at high risk for developing Pneumocystis jirovecii pneumonia (PJP), and trimethoprim-sulfamethoxazole (TMP-SMX) is the first-line agent for treating this disease. However, there is a lack of consensus on the required dosage of TMP-SMX for hemodialysis patients. Methods: This study used the nationwide Japanese Diagnosis Procedure Combination database to review hemodialysis patients hospitalized for PJP from April 2014 to March 2022. Eligible patients were divided into high-dose and low-dose groups based on the median daily dose per body weight of TMP. The 90-day mortality and adverse events after propensity score matching were compared between the groups. Results: A total of 126 hemodialysis patients with PJP were included, and the median daily dose per body weight of TMP was 5.74 mg/kg/day (interquartile range: 4.33-8.18 mg/kg/day). Thirty-two pairs were analyzed after the propensity score matching. No significant differences in the 90-day mortality and proportion of adverse events were observed between the high-dose and low-dose groups. Conclusions: A high dose of TMP-SMX is unlikely to decrease the in-hospital mortality and adverse events among hemodialysis patients with PJP. However, the results should be interpreted with caution, given the lack of power and lack of long-term follow-up. Additional prospective interventional studies are required to validate these results.

Trimethoprim-sulfamethoxazole dosing and outcomes of pulmonary nocardiosis.

Nocardia often causes pulmonary infection among those with chronic pulmonary disease or immunocompromising conditions. Trimethoprim-sulfamethoxazole (TMP-SMX) is recommended as first-line treatment, though little data exists regarding outcomes of different dosing regimens. We performed a multicenter retrospective cohort study of adult patients with non-disseminated pulmonary nocardiosis initially treated with TMP-SMX monotherapy. Patients' initial TMP-SMX dosing was categorized as high- (> 10mg/kg/day), intermediate- (5-10mg/kg/day) or low-dose (< 5mg/kg/day). Outcomes included one-year mortality, post-treatment recurrence, and dose adjustment or early discontinuation of TMP-SMX. SMX serum concentrations and their effect on management were also assessed. Inverse probability of treatment weighting was applied to Cox regression analyses. Ninety-one patients were included with 24 (26.4%), 37 (40.7%), and 30 (33.0%) treated with high-, intermediate-, and low-dose TMP-SMX, respectively. Patients who initially received low-dose (HR 0.07, 95% CI 0.01-0.68) and intermediate-dose TMP-SMX (HR 0.27, 95% CI 0.07-1.04) had lower risk of one-year mortality than the high-dose group. Risk of recurrence was similar between groups. Nineteen patients had peak SMX serum concentrations measured which resulted in 7 (36.8%) dose changes and was not associated with one-year mortality or recurrence. However, 66.7% of the high-dose group required TMP-SMX dose adjustment/discontinuation compared to 24.3% of the intermediate-dose and 26.7% of the low-dose groups (p = 0.001). Low- and intermediate-dose TMP-SMX for non-disseminated pulmonary nocardiosis were not associated with poor outcomes compared to high-dose therapy, which had a higher rate of dose adjustment/early discontinuation. Historically used high-dose TMP-SMX may not be necessary for management of isolated pulmonary nocardiosis.

A Case of Listeria Monocytogenes Brain Abscess with a Clinical Presentation Mimicking Stroke

Purpose: Kidney transplant recipients are at a high risk of both stroke and infection. We report this case to inform readers of the possibility of the occurrence of Listeria monocytogenes brain abscess despite treatment with low dose trimethoprim–sulfamethoxazole (TMP/SMX). Case Report: A 62-year-old man presented to our hospital with right facial palsy, left arm and leg weakness, and mild fever; he was diagnosed with a stroke in the emergency room. The patient had a history of cadaveric renal transplantation 2 years prior, for which he was prescribed tacrolimus- based immunosuppressive drugs. Multiple myeloma was diagnosed 18 months after renal transplant. He was treated with bortezomib and steroids for the multiple myeloma, and low-dose TMP/SMX for pneumocystis prophylaxis. A listeria brain abscess was diagnosed based on a comprehensive medical history, magnetic resonance images, positive blood culture, and brain biopsy. He underwent ampicillin therapy and achieved full recovery after a 3-month follow-up period. Conclusion: Physicians should monitor unusual stroke symptoms and consider Listeria brain abscess as a differential diagnosis. This case suggests that listeria brain abscesses can potentially cause temporary neurological deficits akin to a stroke, despite TMP/SMX prophylaxis, but these symptoms resolve without necessitating surgical intervention.

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.

Low-Dose vs Conventional-Dose Trimethoprim-Sulfamethoxazole Treatment for Pneumocystis Pneumonia in Patients Not Infected With HIV: A Multicenter, Retrospective Observational Cohort Study

Trimethoprim-sulfamethoxazole (TMP-SMX) is an effective treatment for Pneumocystis jirovecii pneumonia (PCP) in immunocompromised patients with and without HIV infection; however, a high incidence of adverse events has been observed. Low-dose TMP-SMX is a potentially effective treatment with fewer adverse events; however, evidence is limited. What is the efficacy and safety of low-dose TMP-SMX for non-HIV PCP compared with conventional-dose TMP-SMX after adjusting for patient background characteristics? In this multicenter retrospective cohort study, we included patients diagnosed with non-HIV PCP and treated with TMP-SMX between June 2006 and March 2021 at three institutions. The patients were classified into low-dose (TMP< 12.5mg/kg/d) and conventional-dose (TMP 12.5-20mg/kg/d) groups. The primary end point was 30-day mortality, and the secondary end points were 180-day mortality, adverse events grade 3 or higher per the Common Terminology Criteria for Adverse Events v5.0, and initial treatment completion rates. Background characteristics were adjusted using the overlap weighting method with propensity scores. Fifty-five patients in the low-dose group and 81 in the conventional-dose group were evaluated. In the overall cohort, the average age was 70.7 years, and the proportion of women was 55.1%. The average dose of TMP-SMX was 8.71mg/kg/d in the low-dose group and 17.78mg/kg/d in the conventional-dose group. There was no significant difference in 30-day mortality (6.7%vs18.4%, respectively; P= .080) or 180-day mortality (14.6%vs26.1%, respectively; P= .141) after adjusting for patient background characteristics. The incidence of adverse events, especially nausea and hyponatremia, was significantly lower in the low-dose group (29.8%vs59.0%, respectively; P= .005). The initial treatment completion rates were 43.3%and 29.6%in the low-dose and conventional-dose groups (P= .158), respectively. Survival was similar between the low-dose and conventional-dose TMP-SMX groups, and low-dose TMP-SMX was associated with reduced adverse events in patients with non-HIV PCP.

Low-Dose TMP-SMX for Pneumocystis jirovecii Pneumonia Prophylaxis in Pediatric Solid Organ Transplant Recipients.

Pneumocystis jirovecii pneumonia (PJP) is an opportunistic infection that adversely affects solid organ transplant (SOT) recipients. Published guidelines endorse 5 to 10 mg/kg/day (trimethoprim component) trimethoprim-sulfamethoxazole (TMP-SMX) as the recommended regimen for PJP prevention, often resulting in drug-related adverse effects. We investigated the use of a low-dose TMP-SMX regimen given at 2.5 mg/kg/dose once daily every Monday, Wednesday, and Friday at a large pediatric transplantation center. A retrospective chart review was conducted, including patients ages 0 to 21 years who underwent SOT from January 1, 2012, to May 1, 2020, and who were subsequently started on PJP prophylaxis with low-dose TMP-SMX for a minimum of 6 months. The primary end point was the incidence of breakthrough PJP infection on the low-dose TMP-SMX regimen. Secondary end points include the prevalence of adverse effects characteristic of TMP-SMX. A total of 234 patients were included in this study, and 6 of 234 patients (2.6%) were empirically transitioned to treatment dosing of TMP-SMX given a clinical concern for PJP, although none received a diagnosis of PJP. There were 7 patients (2.6%) who experienced hyperkalemia, 36 (13.3%) had neutropenia, and 22 (8.1%) had thrombocytopenia (all grade 4). Clinically significant serum creatinine elevations were seen in 43 of 271 patients (15.9%). Elevations of liver enzymes were seen in 16 of 271 patients (5.9%). Rash was documented in 4 of 271 patients (1.5%). In our patient cohort, low-dose TMP-SMX preserves the efficacy of PJP prophylaxis while providing an acceptable adverse effect profile.

Prophylactic effect of low-dose trimethoprim-sulfamethoxazole for Pneumocystis jirovecii pneumonia in adult recipients of kidney transplantation: a real-world data study

ObjectivesTo evaluate the efficacy and safety of low-dose trimethoprim (TMP)-sulfamethoxazole (SMX) (TMP-SMX) as the primary prophylaxis for Pneumocystis jirovecii pneumonia (PJP) in adult recipients of kidney transplantation. MethodsThree kinds of prescriptions in kidney recipients were documented, including 20 mg TMP/100 mg SMX oral daily, 20 mg TMP/100 mg SMX oral every other day, and nonprophylaxis. The primary outcome was the incidence of PJP in the first 180 days of follow-up after kidney transplantation. The secondary outcomes were changes in renal and liver function. ResultsAmong the 1469 recipients, 1066 (72.56%) received 20 mg TMP/100 mg SMX daily, 127 (8.65%) received 20 mg TMP/100 mg SMX every other day, and 276 (18.79%) did not have prophylaxis prescription. The 276 recipients in the nonprophylaxis group had 124.92 person-years of follow-up, during which PJP occurred in 29 patients, for an incidence rate of 23.21 (95% confidence interval 15.76-32.72) per 100 person-years. The TMP-SMX daily group and the TMP-SMX every other day group had 524.89 and 62.07 person-years of follow-up, respectively, with no occurrence of PJP. There was no significant difference among the three groups in changes in renal and liver function (P >0.05, respectively). A total of 111 recipients in each group were enrolled in the propensity score matching analysis. It was revealed that the 111 nonprophylaxis recipients had 51.27 person-years of follow-up and 10 PJP cases. Prophylaxis was considered effective because there was a significant difference between the three groups (P <0.001). ConclusionLow-dose TMP-SMX prophylaxis significantly reduces the incidence of PJP within 6 months after kidney transplantation and has a favorable safety profile.

Low-dose trimethoprim-sulfamethoxazole for the treatment of Pneumocystis jirovecii pneumonia (LOW-TMP): protocol for a phase III randomised, placebo-controlled, dose-comparison trial

IntroductionPneumocystis jirovecii pneumonia (PJP) is an opportunistic infection of immunocompromised hosts with significant morbidity and mortality. The current standard of care, trimethoprim-sulfamethoxazole (TMP-SMX) at a dose of 15–20 mg/kg/day, is...

Preliminary Study on the Combination Effect of Clindamycin and Low Dose Trimethoprim-Sulfamethoxazole on Severe Pneumocystis Pneumonia After Renal Transplantation.

ObjectiveEvaluate the effect of the combination of clindamycin with low-dose trimethoprim-sulfamethoxazole (TMP/SMX) regimen on sever Pneumocystis pneumonia (PCP) after renal transplantation.Method20 severe PCP patients after renal transplantation were included in this historical-control, retrospective study. A 10 patients were treated with the standard dose of TMP/SMX (T group), the other 10 patients were treated with the combination of clindamycin and low dose TMP/SMX (CT group).ResultsAlthough there was no significant difference in the hospital survival between the two groups, the CT protocol improved the PaO2/FiO2 ratio more significantly and rapidly after the 6th ICU day (1.51 vs. 0.38, P = 0.014). CT protocol also ameliorated the pulmonary infiltration and the lactate dehydrogenase level more effectively. Moreover, the CT protocol reduced the incidence of pneumomediastinum (0 vs. 50%, P = 0.008), the length of hospital staying (26.5 vs. 39.0 days, P = 0.011) and ICU staying (12.5 vs. 22.5 days, P = 0.008). Furthermore, more thrombocytopenia (9/10 vs. 3/10, P = 0.020) was emerged in the T group than in the CT group. The total adverse reaction rate was much lower in the CT group than in the T group (8/80 vs. 27/80, P < 0.001). Consequently, the dosage of TMP/SMX was reduced in 8 patients, while only 2 patients in the CT group received TMP/SMX decrement (P = 0.023).ConclusionThe current study proposed that clindamycin combined with low-dose TMP/SMX was more effective and safer the than single use of TMP/SMX for severe PCP patients after renal transplantation (NCT 04328688).

Trimethoprim-Sulfamethoxazole (Bactrim) Dose Optimization in Pneumocystis jirovecii Pneumonia (PCP) Management: A Systematic Review.

(1) Background: Pneumocystis jirovecii pneumonia (PCP) has a substantial impact on the morbidity and mortality of patients, especially those with autoimmune disorders, thus requiring optimal dosing strategies of Trimethoprim–Sulfamethoxazole (TMP-SMX). Therefore, to ensure the safety of TMP-SMX, there is a high demand to review current evidence in PCP patients with a focus on dose optimization strategies; (2) Methods: Various databases were searched from January 2000 to December 2021 for articles in English, focusing on the dose optimization of TMP-SMX. The data were collected in a specific form with predefined inclusion and exclusion criteria. The quality of each article was evaluated using a Newcastle–Ottawa Scale (NOS) for retrospective studies, Joanna Briggs Institute (JBI) critical checklist for case reports, and Cochrane bias tool for randomized clinical trials (RCTs); (3) Results: Thirteen studies met the inclusion criteria for final analysis. Of the 13 selected studies, nine were retrospective cohort studies, two case reports, and two randomized controlled trials (RCT). Most of the studies compared the high-dose with low-dose TMP-SMX therapy for PCP. We have found that a low dose of TMP-SMX provides satisfactory outcomes while reducing the mortality rate and PCP-associated adverse events. This strategy reduces the economic burden of illness and enhances patients’ compliance to daily regimen plan; (4) Conclusions: The large-scale RCTs and cohort studies are required to improve dosing strategies to prevent initial occurrence of PCP or to prevent recurrence of PCP in immune compromised patients.

Recurrent Toxoplasma Retinitis Treated with Long-Term Oral Antibiotics

Purpose: The purpose of this case was to report the inhibition of toxoplasma retinitis reactivation with long-term, low-dose antibiotics.Case summary: A 76-year-old woman complained of poor vision and floaters in her right eye. The corrected visual acuity (LogMAR) of the right eye was 0.5, and there was an area of yellow infiltration and dye leakage on the retinal fluorescein angiography images. Toxoplasma IgG were detected in the serum, the patient was diagnosed with toxoplasma retinitis, and the patient was advised oral trimethoprim-sulfamethoxazole, clindamycin, and steroids. Her visual acuity improved and the inflammation resolved. However, she again had decreased visual activity and retinal inflammation in her right eye after 5 months. The inflammation improved with oral steroids, but she was shifted to intravitreal dexamethasone because of the side effects of systemic steroids. Although the inflammation improved initially, there was worsening of inflammation (evidenced by vitreous opacity) after 2 months, which was treated with oral antibiotics. After vitrectomy for the removal of residual vitreous opacity, antibiotics were stopped because of the stable disease course. After discontinuation of the antibiotics, inflammation was noted again, and low-dose trimethoprim-sulfamethoxazole was administered. Low-dose antibiotics were continued for 5 months and the disease remained stable without any retinal inflammation.Conclusions: Long-term, low-dose oral antibiotics may prevent reactivation of recurrent toxoplasma retinitis.

Efficacy of Low-Dose Trimethoprim/Sulfamethoxazole for the Treatment of Pneumocystis jirovecii Pneumonia in Deceased Donor Kidney Recipients.

BackgroundTrimethoprim/sulfamethoxazole (TMP-SMX) is considered the first-choice treatment for Pneumocystis jirovecii pneumonia (PJP) in recipients of solid organ transplantation. However, this treatment is associated with various severe adverse events that might not be tolerable for some renal transplant recipients, and the optimal dose remains elusive. The present study assessed the efficacy of low-dose TMP-SMX in recipients of a deceased donor kidney.MethodsA total of 37 adult deceased donor kidney recipients who suffered PJP between January 2015 and June 2020 were included. The survival rates of the patients and grafts, the rate of invasive ventilation, and adverse events, including gastrointestinal discomfort, hematologic side effects, hyperkalemia, and renal function impairments, were assessed.ResultsThe patient and graft survival rates were both 100%. Two patients (5.4%) required invasive ventilation. Eight patients (21.6%) reported gastrointestinal discomfort, but none required dose reduction or discontinued treatment. The frequencies of hematologic side effects, hyperkalemia and impaired kidney function were 5.4% (2/37), 2.7% (1/37), and 2.7% (1/37), respectively.ConclusionOptimization of TMP-SMX dose may reduce the risk of adverse events without compromising efficacy for the treatment of PJP in deceased donor kidney recipients.

Safety and efficacy evaluation of low-dose trimethoprim-sulfamethoxazole for prophylaxis of Pneumocystis pneumonia in HIV uninfected patients undergoing hemodialysis: a retrospective observational study

BackgroundPneumocystis pneumonia (PCP) is a potentially life-threatening infection. Trimethoprim-sulfamethoxazole (TMP-SMX) is considered as the first regimen for PCP prophylaxis according to several guidelines. The recommended prophylactic dose of TMP-SMX has been determined based on patients with normal renal function, but the appropriate dosage for patients undergoing hemodialysis is unknown. The aim of this study was to investigate the efficacy and safety of low-dose TMP-SMX in patients undergoing hemodialysis.MethodsHIV-uninfected adult patients who were undergoing hemodialysis and administered TMP-SMX for PCP prophylaxis, were included, and divided into standard-dose (≥6 single strength (SS, TMP-SMX 80 mg/400 mg tablets/week) and low-dose groups (< 6 SS tablets/week). The endpoints were cumulative incidence of PCP and cumulative discontinuation rate of TMP-SMX due to adverse events. For comparison of the groups, we employed the chi-squared test for categorical variables and the Mann-Whitney U test for continuous variables. Risk factors for the endpoints were evaluated using the Cox Fine and Gray method.ResultsThe median age of the 81 patients included in the study was 67 years (IQR: 60–76 years), and 52 patients (64.2%) were men. No patients in either group developed PCP during the observation period. The yearly cumulative incidence of discontinuation was 12.1% (95% confidence interval [CI]: 0.027–0.29) in the low-dose group and 35.6% (95% CI: 0.20–0.52) in the standard-dose group (P = 0.019). The adjusted hazard ratio of the low-dose group compared to standard-dose group was 0.18 (95% CI: 0.04–0.86, P = 0.032).ConclusionsNone of the study patients developed PCP, and the cumulative discontinuation rate of TMP-SMX due to adverse events was significantly lower in the low-dose group compared to that in the standard-dose group (P = 0.032). These results indicate that low-dose TMP-SMX is an appropriate regimen to maintain a balance between PCP prophylaxis and prevention of adverse events due to TMP-SMX administration. These findings can guide health care professionals to determine TMP-SMX dosage when considering PCP prophylaxis for patients undergoing hemodialysis.

Low-Dose TMP-SMX in the Treatment of Pneumocystis jirovecii Pneumonia: A Systematic Review and Meta-analysis.

Background Pneumocystis jirovecii pneumonia (PJP) remains a common and highly morbid infection for immunocompromised patients. Trimethoprim-sulfamethoxazole (TMP-SMX) is the antimicrobial treatment of choice. However, treatment with TMP-SMX can lead to significant dose-dependent renal and hematologic adverse events. Although TMP-SMX is conventionally dosed at 15–20 mg/kg/d of trimethoprim for the treatment of PJP, reduced doses may be effective and carry an improved safety profile.MethodsWe conducted a systematic search in the Medline, Embase, and Cochrane Library databases from inception through March 2019 for peer-reviewed studies reporting on reduced doses of TMP-SMX (15 mg/kg/d of trimethoprim or less) for the treatment of PJP. PRISMA, MOOSE, and Cochrane guidelines were followed. Gray literature was excluded.ResultsTen studies were identified, and 6 were included in the meta-analysis. When comparing standard doses with reduced doses of TMP-SMX, there was no statistically significant difference in mortality (absolute risk difference, –9% in favor of reduced dose; 95% confidence interval [CI], –27% to 8%). When compared with standard doses, reduced doses of TMP-SMX were associated with an 18% (95% CI, –31% to –5%) absolute risk reduction of grade ≥3 adverse events.ConclusionsIn this systematic review, treatment of PJP with doses of ≤10 mg/kg/d of trimethoprim was associated with similar rates of mortality when compared with standard doses and with significantly fewer treatment-emergent severe adverse events. Although limited by the observational nature of the studies included, this review provides the most current available evidence for the optimal dosing of TMP-SMX in the treatment of PJP.

A Four-Center Retrospective Study of the Efficacy and Toxicity of Low-Dose Trimethoprim-Sulfamethoxazole for the Treatment of Pneumocystis Pneumonia in Patients without HIV Infection

The dose of trimethoprim-sulfamethoxazole (TMP-SMX) for the treatment of Pneumocystis pneumonia (PCP) in patients without human immunodeficiency virus (HIV) infection has not been verified. The aim of this study was to investigate the efficacy and toxicity of a low-dose TMP-SMX regimen in such patients. A retrospective study was conducted in four hospitals. We reviewed the medical records of patients with PCP but not HIV (non-HIV-PCP) who were treated with TMP-SMX between 2003 and 2016. The patients were divided into conventional-dose (TMP, 15 to 20 mg/kg/day) and low-dose (TMP, <15 mg/kg/day) groups after patients who received high-dose (TMP, >20 mg/kg/day) treatment were excluded. Grouping was done according to a correction dose, which was based on renal function. Eighty-two patients had non-HIV-PCP. The numbers of patients who received high-, conventional-, and low-dose treatments were 5, 36, and 41, respectively. Kaplan-Meier analysis for death associated with PCP showed no statistically significant difference in survival rates between the conventional- and low-dose groups. Ninety-day cause-specific mortality rates were 25.0% and 19.5% in the conventional-dose and low-dose groups (P = 0.76), respectively. Adverse events that were graded as ≥3 according to the Common Terminology Criteria for Adverse Events (version 4.0) (National Cancer Institute, 2010) were 41.7% and 17.1% in the conventional-dose and low-dose groups (P = 0.02), respectively. Moreover, vomiting (P = 0.03) and a decrease in platelet count (P = 0.03) occurred more frequently in the conventional-dose group. Treatment of non-HIV-PCP with low-dose or conventional-dose TMP-SMX produces comparable survival rates; however, the low-dose regimen is better tolerated and associated with fewer adverse effects.

Low-dose trimethoprim-sulfamethoxazole treatment for pneumocystis pneumonia in non-human immunodeficiency virus-infected immunocompromised patients: A single-center retrospective observational cohort study

The efficacy of low-dose trimethoprim-sulfamethoxazole (TMP-SMX) may be acceptable for the treatment of pneumocystis pneumonia (PCP) in non-human immunodeficiency virus (HIV)-infected patients, with a low incidence of adverse reactions. This study is aimed to evaluate the efficacy and safety of such a regimen for the treatment of non-HIV PCP. We retrospectively enrolled 24 consecutive patients diagnosed with non-HIV PCP who were treated with low-dose TMP-SMX (TMP, 4-10mg/kg/day; SMX, 20-50mg/kg/day). Data of the conventional-dose treatment were used as reference. The primary endpoints were the 30- and 180-day survival rates from the day of treatment, and secondary endpoints were the incidence of each adverse reaction and dropout rate from the initial TMP-SMX regimen. The survival rate was estimated using the Kaplan-Meier method with 95% confidence interval (CI). The median age of patients was 72 years (54.2% men), and connective tissue disease was the most frequent underlying disease (66.7%) in the low-dose group. The 30- and 180-day survival rates were 95.8% (95% CI: 88.2-100.0%) and 91.0% (95% CI: 79.9%-100.0%), respectively, in the low-dose group and 69.0% (95% CI: 54.0%-88.0%) and 51.5% (95% CI: 36.1%-73.4%), respectively, in the conventional-dose group. The total adverse reaction rate was 58.3% in the low-dose group and 72.4% in the conventional-dose group. A total of 75.0% of patients in the low-dose group and 31.0% in the conventional-dose group completed treatment with the initial regimen. Low-dose TMP-SMX may be a treatment option for patients with non-HIV PCP.

1455P - The primary prophylaxis of pneumocystis pneumonia by low-dose trimethoprim-sulfamethoxazole during R-CHOP therapy

Pneumocystis pneumonia (PCP) is frequently observed in immunocompromised patients. Currently, oral administration of trimethoprim-sulfamethoxazole (TMP-SMX) at a dose of 1 tablet daily (7 tablets/week) or 2 tablets twice a day, twice a week (8 tablets/week) is considered as standard for prophylaxis. However, they sometimes induce unpleasant toxicities such as rash, leukopenia and renal dysfunction. To avoid them, dose reduction of TMP-SMX could be considerable. Rituximab plus CHOP therapy (R-CHOP) is a standard treatment for B-cell lymphoma. Since rituximab is immunosuppressive, prophylaxis of PCP is widely introduced. In our institute, low-dose TMP-SMX has been employed in such situations. To assess the efficacy and tolerability of the regimen, retrospective analysis was performed. We reviewed patients with newly diagnosed B-cell lymphoma who completed 6 to 8 cycles of R-CHOP in our institute. In all patients, low-dose TMP-SMX consisting of 1 tablet twice a day, twice a week (4 tablets/week) was started simultaneously with R-CHOP. To improve medication adherence, administration day was fixed on Tuesday and Friday. From January 2009 to September 2014, 292 patients with a median age of 67 (21-89) were treated. They included diffuse large B-cell lymphoma (n = 213), follicular lymphoma (n = 65), mantle cell lymphoma (n = 6) and others (n = 8). The median length of prophylaxis from the last day of R-CHOP was 5.7 (0.6-16.6) months. The median lymphocyte count decreased from 1.1 (0.07-19.2) to 0.4 (0.03-1.4) x 109/L during treatment. Of 292 patients, 291 showed no evidence of PCP. Although 1 patient developed PCP, the diagnosis was given on day 12 of the first cycle indicating that the patient already had PCP before the initiation of prophylaxis. In the other 291 patients, TMP-SMX was well tolerated and no related adverse event was observed. Four tablets of TMP-SMX a week may be sufficient to prevent PCP during R-CHOP. In addition, minimum toxicities are expected by this method. As demonstrated in our study, the elderly patients who need R-CHOP are increasing. In this context, our data provide a valuable insight into the total strategy of lymphoma treatment.

Renal Insufficiency in Concert with Renin-angiotensin-aldosterone Inhibition Is a Major Risk Factor for Hyperkalemia Associated with Low-dose Trimethoprim-sulfamethoxazole in Adults.

Low-dose trimethoprim-sulfamethoxazole (TMP-SMX) is commonly used to prevent pneumocystis pneumonia in daily practice. Previous reports have shown a relationship between high- or standard-dose of TMP-SMX and hyperkalemia, however it remains unclear whether this is true for low-dose TMP-SMX. In this study we sought to determine the risk factors for hyperkalemia associated with low-dose TMP-SMX. In this retrospective cohort study, 186 consecutive adult patients who received TMP-SMX as prophylaxis for pneumocystis pneumonia from January 2014 to January 2015 were evaluated. Data on the patients' age, gender, baseline estimated glomerular filtration rate (eGFR), baseline serum potassium, maximum serum potassium, duration reaching the maximal serum potassium level, dosage, and concomitant use of angiotensin-converting enzyme inhibitors (ACEi)/angiotensin receptor blockers (ARB), β-blockers, non-steroidal anti-inflammatory drugs and potassium-sparing diuretics were retrospectively collected. Hyperkalemia was defined as a serum potassium level ≥5 mEq/L. Univariate and multivariate analyses were performed. The median age of the patients was 66 years and 51.1% were men. Hyperkalemia associated with low-dose TMP-SMX was observed in 32 patients (17.2%). The median duration to reach the maximal serum potassium level was 12 days. The multivariate logistic regression analysis identified renal insufficiency to be a major risk factor for hyperkalemia associated with low-dose TMP-SMX (eGFR <60 mL/min/1.73 m(2), adjusted OR 4.62). Moreover, in the subpopulation of patients with renal insufficiency, ACEi/ARB use was considered to be a major risk factor for hyperkalemia (adjusted OR 3.96). Renal insufficiency in concert with ACEi/ARB use is a major risk factor for hyperkalemia induced by low-dose TMP-SMX.