Doses Of Trimethoprim-sulfamethoxazole Research Articles

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.

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.

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

Outcomes of Children with Osteoarticular Infections Treated with Trimethoprim-Sulfamethoxazole versus Clindamycin

Abstract Background Early transition to oral antibiotic therapy for the treatment of children with osteoarticular infections (OAI; osteomyelitis [OM], septic arthritis [SA]) has become increasingly common, yet the choice of optimal regimen remains a challenge. With increasing resistance, poor palatability and reported allergies to commonly used oral antibiotics, the treatment options for children with OAI are limited. Trimethoprim-sulfamethoxazole (TMP-SMX) is a commonly used antibiotic, with activity against frequently encountered pathogens causing OAI, yet data regarding outcomes of children with OAI treated with TMP-SMX is limited. We sought to describe the characteristics and outcomes of children with OAI treated with TMP-SMX compared to clindamycin. Methods Records of children <18 years old, admitted to Riley Hospital for Children (Indianapolis, IN) between January 2010 to June 2021 for acute OAI were reviewed. Patients were identified by ICD-9/10 codes and an order for TMP-SMX or clindamycin. Patients were excluded if they did not receive TMP-SMX or clindamycin as their primary oral treatment of OAI, had symptoms >30 days, had a hardware associated infection, were immunocompromised or had an alternative diagnosis. Demographic, clinical, and outpatient/follow up data were recorded. Treatment was considered successful if the patient completed treatment with the discharge oral antibiotic (either TMP-SMX or clindamycin), and there was no evidence of infection at the end therapy. Treatment failure was defined as inability to tolerate the medication, development of an infection related complication, recurrent or chronic osteomyelitis. Additionally, significant adverse drug events (ADEs) were recorded. Results A total of 148 children met eligibility criteria (30 TMP-SMX and 118 clindamycin). Demographic and clinical characteristics are highlighted in Table 1. Children receiving TMP/SMX were younger (1.75 years) compared to those receiving clindamycin (7 years). Osteomyelitis was the most common infection type in both groups (47% in the TMP/SMX group vs. 48% in the clindamycin group). Staphylococcus aureus was the causative pathogen in 37% and 49%, while no organism was recovered in 57% and 43% in the TMP/SMX and clindamycin groups, respectively. Complications during hospitalization occurred in 13% in the TMP/SMX group, compared to 16% in the clindamycin group. The median dose of TMP-SMX was 13.4 mg/kg/day (IQR 11.3-14.9) and 38.7 mg/kg/day (IQR 33.4-40.2) for clindamycin. There was no difference in adverse drug events between the two groups with 2 patients (7%) in the TMP/SMX group developing an ADE compared to 13 patients (11%) in the clindamycin group (p=0.74, OR 0.58 [95% CI: 0.12-2.51]). Five (17%) of patients in the TMP/SMX group and 12 (10%) in the clindamycin group were lost to follow up. Of the patients that completed follow-up, there was no difference in treatment success with 84% (21 of 25) in the TMP/SMX and 92% (97 of 106) in the clindamycin group (p=0.27, OR 0.49 [95% CI: 0.15-1.54]) being successfully treated. Conclusions TMP-SMX was well tolerated and not associated with higher odds of treatment failure compared to clindamycin. A larger, prospective, randomized, comparative effectiveness study to control for potential confounding variables, and detect smaller, yet potentially clinically relevant outcome differences is warranted.

Trimethoprim-Sulfamethoxazole for Pediatric Osteoarticular Infections.

Trimethoprim-sulfamethoxazole (TMP-SMX) is active against most Staphylococcus aureus isolates but is not widely used for treatment of pediatric osteoarticular infections. This was a comparative effectiveness study of hospitalized patients ≤18 years treated with TMP-SMX versus other antibiotic regimens for acute osteoarticular infections between 2016 and 2021 at three hospitals using inverse probability of treatment weighted propensity score analysis. The primary outcome was treatment failure, a composite of unanticipated emergency department (ED) or outpatient visits, hospital readmissions, extension or change of antibiotic therapy due to inadequate clinical response, or death, all within 6 months after completing antibiotics. The secondary outcome was antibiotic-associated adverse events (AEs) within 6 months. The exposed group for the treatment failure analysis included children who received ≥7 days of TMP-SMX and did not experience treatment failure while on another antibiotic. Children receiving at least one dose of TMP-SMX were the exposed group for the AE analysis. 116 patients met eligibility criteria; 26 (22.4%) patients were classified into the TMP-SMX cohort and 90 (77.6%) into the other antibiotics cohort (most commonly clindamycin, vancomycin, and cefazolin). There was no significant difference in treatment failure between TMP-SMX and other antibiotics (43% vs 19%; 95% CI 0.9-10.4). More patients in the TMP-SMX cohort experienced an unplanned ED or outpatient visit (OR 4.8, 95% CI 1.3-17.8). There was no difference in hospital readmission, antibiotic change, or duration extension. Exposure to TMP-SMX was associated with more AEs (41% vs 19%, p=0.012). Treatment with TMP-SMX was not associated with greater clinical failure but was associated with more AEs compared to alternative agents for the treatment of pediatric acute osteoarticular infections.

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.

Pharmacokinetics of Trimethoprim-Sulfamethoxazole in the Green Iguana (Iguana iguana)

Abstract A single 30 mg/kg dose of trimethoprim-sulfamethoxazole (TMS) was administered orally (n = 17) and intravenously (n = 13) in a crossover study design, with a 10 day washout period, to determine drug pharmacokinetics in healthy adult green iguanas (Iguana iguana). Blood samples were collected at 0 (pretreatment), 1, 2, 4, 8, 12, 24, 36, 48, 72, and 96 h after PO and IV drug administration, including a 6 h sample for the IV protocol. Plasma drug concentrations were determined by liquid chromatography–tandem mass spectrometry, and oral bioavailability of trimethoprim (&amp;gt;100%) and sulfamethoxazole (69.4%) were then established. Pharmacokinetic parameters were estimated using a two-stage, noncompartmental analysis of naïve-averaged data. Following the crossover study, a multidose drug trial was performed to determine steady-state nädir plasma drug concentrations. Green iguanas (n = 10) were given 30 mg/kg TMS PO once daily for 7 days, with blood collected from each animal on the eighth day, 24 h after the final dose of TMS. Based on once daily oral dosing for 7 days, steady-state nädir drug concentrations of trimethoprim and sulfamethoxazole were 396 ± 116 and 5,290 ± 5,130 μg/l, which are below the minimum inhibitory concentrations breakpoints of TMS (≤2 μg per ml/38 μg per ml for susceptible organisms and ≥4 μg per ml/76 μg per ml for resistant organisms) for human isolates, per the Clinical and Laboratory Standards Institute. However, the ratio of trimethoprim:sulfamethoxazole remained greater than 1:40 up to 12 h after single oral dose exposure and at the 24 h sampling after multiple dosing at steady-state.

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.

1233. Serious Toxicities During Antimicrobial Therapy for Disseminated Nocardia Infection in Solid Organ Transplant Recipients

BackgroundManagement of disseminated Nocardia (NC) infection in transplant recipients requires prolonged antimicrobial therapy. Treatment can be particularly challenging if NC is resistant to standard agents. Drug toxicities can further limit options. We present a series of transplant patients with multi-drug resistant, disseminated NC infection complicated by serious adverse reactions to sequential antimicrobials.MethodsThis is a prospective review monitoring response to treatment of disseminated NC as well as adverse events to therapies. ResultsThe first case is a 66-year old heart transplant patient who presented with fever and cough. Investigations revealed N. otitidiscaviarum lung lesion and multiple brain abscesses. Trimethoprim-sulfamethoxazole (TMP-SMX) and linezolid were started empirically. NC was fully susceptible to linezolid only, and intermediate to quinolones and tobramycin. Linezolid was switched to ciprofloxacin due to ongoing cytopenia, and dose of TMP-SMX was reduced due to renal insufficiency. Repeat brain MRI showed enlarging abscesses; regimen was changed to linezolid and moxifloxacin. Severe peripheral neuropathy led to linezolid discontinuation and initiation of high-dose doxycycline plus moxifloxacin. One year into therapy, he presented with a large aortic dissection. His long-term quinolone therapy was felt to be contributory. He underwent aortic stent placement and remains on doxycycline monotherapy. The second case is a 74-year old female renal transplant patient who presented with fevers. A perinephric abscess was found which grew N. farcinica resistant to floroquinolones and clarithromycin, and intermediate to doxycycline. Further imaging also revealed pulmonary and brain involvement. TMP-SMX was started but soon switched to linezolid due to acute kidney injury. One month later she presented with severe thrombocytopenia and subdural hematoma thought to be secondary to linezolid. She died despite surgery. ConclusionThis series illustrates challenges encountered in the treatment of disseminated NC infection in transplant recipients. Multidrug resistant NC coupled with serious toxicities of therapies often severely limits treatment options. Counseling patients and closely monitoring for adverse events is essential. Disclosures All Authors: No reported disclosures

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.

#73: Outcomes of Children with Osteoarticular Infections Treated with Trimethoprim–Sulfamethoxazole

Abstract Background Early transition to oral antibiotic therapy for the treatment of children with osteoarticular infections (OAI; osteomyelitis [OM], septic arthritis [SA]) has become increasingly common, yet the choice of optimal regimen remains a challenge. With increasing resistance, poor palatability, and reported allergies to commonly used oral antibiotics, including anti-Staphylococcal penicillins and clindamycin, the treatment options for children with OAI are limited. Trimethoprim–sulfamethoxazole (TMP-SMX) is a commonly used antibiotic, with activity against frequently encountered pathogens causing OAI, yet data regarding outcomes of children with OAI treated with TMP-SMX is limited. Thus, we sought to describe the characteristics and outcomes of children with OAI, at our institution, treated with TMP-SMX. Methods Records of children aged ≤18 years old, admitted to Riley Hospital for Children between 2010 and 2018, treated with TMP-SMX for acute OAI were reviewed. Patients were identified by ICD-9/-10 codes and order for TMP-SMX. Patients were excluded if they did not receive TMP-SMX for treatment of OAI, had symptoms &amp;gt;30 days, or had an alternative diagnosis. Demographic, clinical, and outpatient/follow-up data were recorded. Treatment was considered successful if the patient completed treatment with TMP-SMX, and there was no evidence of infection at the end of therapy. Treatment failure was defined as the inability to tolerate the medication, development of an infection-related complication, recurrent or chronic osteomyelitis. Additionally, significant adverse drug events were recorded. Results Eighty-three subjects were identified; however, after screening, 21 subjects were deemed eligible. The majority were non-Hispanic white, males, with a median age of 1.5 years (Interquartile range [IQR], 1–3 years) (Table 1). Twelve patients (57%) had OM, seven (33%) SA, and two (10%) had both OM and SA. A pathogen was recovered in 12 patients (57%), with Staphylococcus aureus being most common. All S. aureus isolates were methicillin resistant, and three were clindamycin resistant. The median duration of intravenous antibiotics prior to discharge was 3 days (IQR 2–4 days). All patients were transitioned to a TMP-SMX containing regimen prior to discharge. The median dose of TMP-SMX was 12.7 mg/kg/day (IQR 11.3–14.9). Reasons for choosing TMP-SMX varied, with the majority (62%) being physician preference. Treatment regimens varied with the majority (62%) receiving TMP-SMX monotherapy. Two patients developed adverse drug reactions attributed to TMP-SMX. Of the 18 patients that completed follow-up, 14 (78%) successfully completed treatment with TMP-SMX. Three patients developed recurrent infections and one patient was unable to finish therapy with TMP-SMX due to developing acute kidney injury. Conclusions In our study, TMP-SMX was well tolerated; however, only 78% of patients were successfully treated. The majority of treatment failures had prolonged bacteremia due to MRSA perhaps suggesting a higher bacterial burden. The poor outcome in these patients is likely multifactorial, and antibiotic contribution is unknown. TMP-SMX may be a reasonable treatment option for children with OAI when the disease is mild; however, caution should be exercised with severe disease, especially when associated with bacteremia. Prospective, randomized control trials are needed to aid in guideline development and understand the role of TMP-SMX in the treatment of children with OAI.

1491. Standard- vs. High-dose Trimethoprim-Sulfamethoxazole for Stenotrophomonas maltophilia pneumonia

Background Stenotrophomonas maltophilia is a multidrug-resistant pathogen known to cause pneumonia with associated mortality rates up to 44%.1,2 Trimethoprim-sulfamethoxazole (TMP-SMX) is the drug of choice based on available clinical evidence and excellent in-vitro susceptibility rates.3 High-dose TMP-SMX strategies recommend between 15-20mg/kg/day of the TMP component, however this has been associated with increased adverse drug events (ADE).4,5 The optimal dosing strategy remains unclear and it is unknown whether lower doses of TMP-SMX would achieve similar outcomes.MethodsPatients with positive respiratory cultures for S. maltophilia who received at least 72 hours of TMP-SMX therapy for hospital-acquired or ventilator-associated pneumonia from January 2010 to March 2020 were included. Doses were categorized as standard-dose (SD) TMP-SMX (< 15 mg/kg/day TMP) or high-dose (HD) TMP-SMX (≥ 15 mg/kg/day TMP) after adjusting for renal function. The primary outcome was clinical success, defined as the composite of resolution of signs/symptoms of pneumonia, in-hospital survival, and no escalation of care. Secondary outcomes included hospital length of stay (LOS), 30-day mortality, 30-day readmission, and ADE.ResultsOf the 44 patients meeting inclusion criteria for the study, 27 received SD and 17 received HD TMP-SMX therapy. Patients received 12 mg/kg/day (IQR 11-14) and 16 mg/kg/day (IQR 16-19) in the SD and HD groups, respectively. There was no difference in clinical success between the SD and HD group (41% vs 59%, p=0.24). Secondary outcomes were similar between both groups except for 30-day hospital readmission; the SD group had significantly lower readmission rates (6% vs 69%, p < 0.01). Rates of adverse events were not statistically different between the two groups.ConclusionThis study provides evidence that SD TMP-SMX may achieve similar clinical efficacy to HD TMP-SMX. We found no significant difference in clinical success, LOS, 30-day mortality, or adverse events between groups. Although HD TMP-SMX is the current recommendation for S. maltophilia infections, concerns about tolerability and adverse effects suggest that further clinical and pharmacodynamic research is needed.Disclosures All Authors: No reported disclosures

145. the Efficacy and Safety of Low Dose Trimethoprim-sulfamethoxazole for the Treatment of Pneumocystis Pneumonia: A Systematic Review and Meta-analysis

Background Pneumocystis jirovecii pneumonia (PJP) is an opportunistic fungal infection causing significant morbidity and mortality in immunocompromised patients. The conventional treatment of PJP is sulfamethoxazole-trimethoprim (SMX-TMP) dosed at 15–20 mg/kg/day of the trimethoprim component. This high-dose regimen is associated with severe adverse reactions that result in patient harm or treatment discontinuation. Studies have suggested similar mortality and an improved adverse effect profile using lower dose (< 15 mg/kg/day) SMX-TMP. Our objective of this meta-analysis was to evaluate the safety and efficacy of lower dose SMX-TMP for PJP pneumonia.MethodsWe conducted a systematic review and meta-analysis according to PRISMA guidelines. Pubmed and Embase databases were searched from inception to January 15, 2020, for studies in English evaluating low-dose SMX-TMP (< 15 mg/kg/day) compared with conventional dosing for the treatment of PJP. Additionally, conference proceedings were reviewed to address potential publication bias. Outcomes evaluated in our meta-analysis include survival and adverse reactions. We performed a sensitivity analysis using E-values to determine the robustness of our results.ResultsAfter excluding studies that did not meet our inclusion criteria, four studies were analyzed for adverse reaction rates and three for mortality rates. Overall, there was no significant difference in mortality between low-dose and conventional-dose SMX-TMP groups (relative risk [RR]: 0.55, 95% confidence interval [CI], 0.18 -1.70). There was a significant decrease in the rate of adverse reactions for the low-dose group compared with the conventional-dose group (RR: 0.70, 95% CI, 0.53 - 0.91). Sensitivity analyses using E-Values reflect a confounder with RR 2.2 or greater could explain away the estimate on adverse events leading to no difference while mortality would require RR 5.6 to reflect worse outcomes with low dose.Mortality Forest Plot Adverse Effects Forest Plot ConclusionThis meta-analysis shows a significant decrease in adverse reactions and similar mortality rates with lower-dose SMX-TMP compared with conventional dosing. A low-dose SMX-TMP regimen in the treatment of PJP should be considered a viable option with the potential to decrease treatment discontinuation and reduce harm.Disclosures All Authors: No reported disclosures

SUN-185 Severe Hyponatremia and Type 4 Renal Tubular Acidosis (Functional Hypoaldosteronism) Secondary to Trimethoprim

Introduction:Trimethoprim-sulfamethoxazole (TMP-SMX) is a commonly used antibiotic. We present a case of severe hyponatremia and Type 4 renal tubular acidosis (functional hypoaldosteronism) in a patient treated with TMP-SMX.Clinical Case:A 62 year old gentleman with hypertension, dyslipidemia and a surgically repaired abdominal aortic aneurysm developed an aortic graft infection. He was admitted to hospital for acute right lower limb ischemia with embolic phenomena, and underwent surgical graft explantation. He required multiple courses of antibiotics post operatively.He was initially referred to Endocrinology for severe hyponatremia, deemed likely to be from a salt losing nephropathy secondary to polymyxin. Thyroid function and morning cortisol levels were normal. He was managed with intravenous hypertonic saline and oral salt tablets. The hyponatraemia resolved a week after polymyxin was stopped.Intravenous TMP-SMX was commenced the next day at 240 mg BD. A week later, the hyponatremia recurred, with concomitant hyperkalemia and a normal anion gap metabolic acidosis.The serum sodium was 126 mmol/L (reference interval (RI) 135-145) and the serum osmolality 275 mmol/kg (RI 275- 305). Urine studies showed a high urinary sodium (154 mmol/L) and osmolality (481 mmol/kg), consistent with renal salt wasting. The serum potassium rose to a peak of 6.1 mmol/L (RI 3.5 - 5.0), with a normal anion gap metabolic acidosis (bicarbonate 17 mmol/L (RI 21 – 31)). A paired urine pH of 8 pointed to an inability to acidify the urine.Given the clinical course and laboratory investigations, the diagnosis of TMP-associated hyponatremia and Type 4 RTA was made. Oral resonium was started to correct hyperkalemia, with a combination of oral sodium chloride and sodium bicarbonate used to treat the hyponatremia and metabolic acidosis. Fludrocortisone was not used given the concerns of causing hypertension in a patient with a diseased aortic graft.The dose of TMP-SMX was gradually reduced with improvement of the acid-base and electrolyte abnormalities, lending weight to our diagnosis. After the dose of the TMP-SMX was reduced to 80 mg BD, the hyperkalemia and metabolic acidosis resolved. The oral sodium chloride and sodium bicarbonate were gradually tailed off and stopped after cessation of the TMP-SMX.Clinical Lesson:Trimethoprim blocks the epithelial sodium channel (ENaC) of the principal cells in the terminal portion of the nephron, similar to potassium sparing diuretics like amiloride and triampterene. The resulting hyponatremia, hyperkalemia and metabolic acidosis can be life threatening. Therefore, monitoring of electrolytes and acid base status is important, particularly in susceptible patients or in those where a high dose of trimethoprim is required.

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.

Long-term Results of Trimethoprim-Sulfamethoxazole Versus Placebo to Reduce the Risk of Recurrent Toxoplasma gondii Retinochoroiditis

To compare the effects of 1 year of treatment with trimethoprim-sulfamethoxazole (TMP-SMZ) vs placebo in reducing the risk of recurrence of toxoplasmic retinochoroiditis during a 6-year follow-up period. Randomized, double-masked clinical trial. This cohort included 141 subjects recruited in Campinas, Brazil. The inclusion criterion was unilateral active recurrent toxoplasmic retinochoroiditis. All subjects were treated with 1 dose of TMP-SMZ (160mg/800mg) twice daily for 45days, and all lesions healed after this treatment. After this initial treatment, subjects were randomly assigned to group 1 (1 TMP-SMZ dose every other day for 311days) or group 2 (1 identical placebo tablet containing starch with no active ingredients every other day for 311days). Between the second and sixth years of follow-up appointments, none of the subjects received treatment unless a new recurrence episode had occurred. The primary outcomes were recurrent toxoplasmic retinochoroiditis within the first year of follow-up and recurrent toxoplasmic retinochoroiditis in the 6 years of follow-up. The cumulative probability of recurrence 1, 2, 3, 4, 5, and 6 years after the initial infection was, respectively, 13.0% (9/69), 17.4% (12/69), 20.3% (14/69), 23.2% (16/69), 26.1% (18/69), and 27.5% (19/69) in the placebo group and 0%, 0%, 0%, 0%, 0%, and 1.4% (1/72) in the TMP-SMZ group (P < .001; log-rank test). There were 3 cases (3/69; 4.3%) of multiple recurrences in the same individual in the placebo group. No treatment-limiting toxicity or side effects were observed in either group. New recurrences were more frequent among female subjects. TMP-SMZ may be used safely for prophylaxis of recurrent toxoplasmic retinochoroiditis and may provide long-term benefits.

Oral eradication therapy for melioidosis: Important but not without risks

ObjectivesThe purpose of this study was to quantify the adverse effects from oral eradication therapy for melioidosis, which is usually with high dose trimethoprim-sulfamethoxazole for 3–6 months. MethodsThis retrospective cohort study reviewed side effects from oral eradication therapy in patients presenting with first episode culture-confirmed melioidosis in the tropical north of Australia’s Northern Territory between 1st October 2012 and 1st January 2017. Results234 patients presented for the first time with culture-confirmed melioidosis. Of these, 16 (6.8%) died during the intensive phase treatment and 6 (2.6%) did not have complete treatment at Royal Darwin Hospital. Of the remaining 212 patients, 203 (95.8%) were initially prescribed trimethoprim-sulfamethoxazole as oral eradication therapy, 6 (2.8%) were prescribed doxycycline and 3 (1.4%) had no eradication therapy. Of the 203 prescribed trimethoprim-sulfamethoxazole, 61 (30.0%) experienced adverse effects, which necessitated a cessation, a change in antibiotic or reduction in dose. ConclusionsIn patients treated for melioidosis in northern Australia there are high rates of adverse effects from oral trimethoprim-sulfamethoxazole, frequently necessitating a change in therapy or a reduction in dose. Given the side effects and low rates of oral therapy completion in our region we emphasise the importance of the prior often prolonged intensive phase intravenous therapy and using weight based trimethoprim-sulfamethoxazole dosing for eradication therapy.

Trimethoprim-sulfamethoxazole induced circulatory shock in a human immunodeficiency virus uninfected patient: a case report and review

BackgroundSevere systemic reactions resembling septic shock have been described following trimethoprim-sulfamethoxazole (TMP-SMX) administration. Nearly all cases described in the literature occurred in HIV-infected patients.Case presentationWe present a 42-year-old woman with a history of systemic lupus erythematosus (SLE) who was admitted to the Intensive Care Unit (ICU) twice with fever and circulatory shock after taking a dose of TMP-SMX 800–160 mg. She had no respiratory distress, urticarial rash or eosinophilia on presentation. Infectious workup during both admissions was negative and treatment with antibiotics, steroids and vasopressors was de-escalated with clinical improvement. She was found to be HIV negative, however, labs revealed a low CD4+ count.ConclusionsTMP-SMX can rarely result in a severe, non-anaphylactic circulatory shock; if initially unrecognized, patients may undergo repeat drug exposure with an associated high morbidity risk. While more commonly reported in HIV individuals, this case demonstrates that TMP-SMX related circulatory shock can occur in a HIV negative patient.

Safety of the concomitant use of methotrexate and a prophylactic dose of trimethoprim-sulfamethoxazole.

The objective of this study was to investigate risk factors for cytopenia when a prophylactic dose of trimethoprim-sulfamethoxazole (TMP-SMX) was co-administered with methotrexate (MTX). Patients who received MTX with or without a prophylactic dose of TMP-SMX were included. Patients who received a therapeutic dose of TMP-SMX were excluded. The MTX-alone and MTX with TMP-SMX groups (MTX group and MTX + TMP-SMX group, respectively) were matched in a 4:1 ratio according to age, creatinine level, mean corpuscular volume and MTX dose. Cytopenia was defined as a haemoglobin level decrease by > 2g/dl, platelet count of < 150,000/mm3 or white blood cell count of < 3500/mm3. The Cox proportional hazards model was used to evaluate risk factors for cytopenia in patients administered with MTX. The incidence of cytopenia did not significantly differ between the MTX group and MTX + TMP-SMX group (5.0 vs 5.7%, p > 0.999). According to the Cox proportional hazards model, chronic liver disease (hazard ratio [HR] 5.829, 95% confidence interval [CI] 1.211-28.063, p = 0.028) was associated with an increased risk of cytopenia. However, the concomitant use of a prophylactic dose of TMP-SMX (HR 1.717, 95% CI 0.352-8.371, p = 0.504) was not significantly associated with an increased risk of cytopenia. Compared with the use of MTX alone, the concomitant use of MTX with a prophylactic dose of TMP-SMX was not significantly associated with an increased risk of cytopenia. Thus, a prophylactic dose of TMP-SMX can be safely used with MTX.

Possible Trimethoprim–Sulfamethoxazole-Induced Hemolytic Anemia: A Case Report

Objective: To report a case of hemolytic anemia in a patient who received trimethoprim/sulfamethoxazole (TMP-SMX) for a urinary tract infection (UTI). Summary: A 47-year-old woman recently diagnosed with uncomplicated UTI received 3 doses of TMP-SMX. She developed yellowing of the skin and eyes, lethargy, mild abdominal pain, and dry mucous membranes. Laboratory testing demonstrated significant anemia with red blood cells (RBCs) of 1.99, hemoglobin (Hgb) of 6.3 g/dL, and hematocrit (Hct) of 18.1%. TMP-SMX was immediately discontinued. The patient was given methylprednisolone 60 mg intravenously (IV) followed by oral steroids and infused with 3 units of packed RBCs over the course of a 10-day inpatient admission. On discharge, the patient continued oral steroids. Outpatient follow-up indicated Hgb of 11.0 g/dL and Hct of 32.7%, 41 days after hospital discharge. Utilizing the Naranjo adverse drug reaction probability scale, there is a probable association between the patient’s hemolytic anemia and TMP-SMX. Conclusion: We report a case of hemolytic anemia resulting from the use of TMP-SMX. Although this is a rare adverse effect, clinicians should be aware of the signs and symptoms of hemolytic anemia, and so appropriate treatment can be administered should it occur.