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Article

Single-Center 5-Year Observational Study of Thrice-Weekly Single-Strength Sulfamethoxazole–Trimethoprim as Adequate Prophylaxis for Pneumocystis jirovecii Pneumonia in Patients with Heart Transplants

by
Kevin Lor
1,*,
Catherine Le
2,
Evan Kransdorf
1 and
Michelle Kittleson
1
1
Department of Cardiology, Smidt Heart Institute, Cedars Sinai Medical Center, 127 S. San Vicente Blvd., Los Angeles, CA 90048, USA
2
Department of Infectious Disease, Cedars Sinai Medical Center, 8635 W 3rd St Suite 465W, Los Angeles, CA 90048, USA
*
Author to whom correspondence should be addressed.
Transplantology 2025, 6(1), 3; https://doi.org/10.3390/transplantology6010003
Submission received: 12 December 2024 / Revised: 15 January 2025 / Accepted: 26 January 2025 / Published: 5 February 2025
(This article belongs to the Section Solid Organ Transplantation)
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Abstract

Background/Objectives: Pneumocystis jirovecii pneumonia is a significant contributor to morbidity and mortality in patients with solid organ transplants. Sulfamethoxazole–trimethoprim prophylaxis has greatly reduced the incidence of this deadly fungal infection. Traditional prophylactic dosing includes single strength (400–80 mg) daily or double strength (800–160 mg) thrice weekly, but is limited by side effects. This study evaluates the efficacy and tolerability of a sulfamethoxazole–trimethoprim single-strength thrice-weekly prophylactic dosing strategy. Methods: This was a single-center, retrospective chart review of 421 patients with 423 total heart transplants at Cedars Sinai Medical Center between July 2016 and June 2020.A total of 361 patients (363 heart transplants) were started on single-strength sulfamethoxazole–trimethoprim thrice weekly for 1 year, based on institutional guidelines. Results: Patients were followed for a median of 3.86 years (range 0.17 to 6.57). Sulfamethoxazole–trimethoprim was started at a median of 7 days (range 0 to 132) for median duration of 11.5 months (range 0.25 to 22). There were no documented Pneumocystis jirovecii pneumonia cases during the study period. At 1 year, 36% of patients had discontinued sulfamethoxazole–trimethoprim. The most common causes for discontinuation were leucopenia (30.8%) and hyperkalemia (2.2%). Conclusions: In our experience, single-strength sulfamethoxazole–trimethoprim thrice weekly for 1 year effectively prevents Pneumocystis jirovecii pneumonia after heart transplant. Further multicenter studies with other patient populations will need to be performed to explore this well-tolerated strategy.

1. Introduction

Pneumocystis jirovecii pneumonia (PCP) has contributed to significant morbidity and mortality in patients with immunodeficiency over the last four decades, but its role as an opportunistic fungal infection had gone unnoticed for a significant period of time prior to the 1980s. Infection rates surged from about 100 cases per year in the 1960s and 1970s to over 20,000 cases per year by 1990 [1,2]. Without chemical prophylaxis, infection rates in patients with heart transplants reportedly ranged between 2% and 41%. Prophylaxis decreases that rate significantly, estimated at 0.3–2.6% in kidney transplants and 2–5.1% in heart transplants, while a meta-analysis by Green et al. suggested a 90% reduction in PCP rates [3,4,5,6].
The 2019 American Society of Transplantation guidelines for PCP prophylaxis recommend double-strength (DS) SMX-TMP 800–160 mg thrice weekly (TIW) or single strength (SS) 400–80 mg daily for at least 6–12 months during the highest-risk period of infection [3,7]. However, side effects are common and result in temporary discontinuation, dose reduction, or frequency reduction [8,9,10,11]. Our study describes the tolerability and overall incidence of PCP using a reduced SS dosage of SMX-TMP thrice weekly for one year after heart transplant.

2. Materials and Methods

This is a retrospective, descriptive analysis of 421 patients who received a total of 423 hearts transplanted at Cedar Sinai Medical Center over a 5-year period between July 2016 and June 2020. The study was approved by our Institutional Review Board. Patients’ medical charts were reviewed through Epic® and Care Everywhere® for a follow-up period of at least two years following heart transplant until February 2023, in order to assess PCP for at least one additional year after stopping the one-year prophylaxis. Care Everywhere® was used for chart review for patients who had transferred transplant care to a different hospital. All data were tabulated using Microsoft Excel® version 2408. No statistical analysis was used, as this is a descriptive study.
Demographic data were collected for age at the time of transplant, gender, date of transplant, initial or redo transplant, and additional organs simultaneously transplanted. Birthplace was also documented, as Pneumocystis can be environmental in origin with a latency period. Presence of Pneumocystis jirovecii on bronchoalveolar lavage or sputum was used to determine infection.
Clinical data included serum creatinine, permanent intermittent hemodialysis, and white blood cell count. Date of initiation and date of discontinuation of SMX-TMP was also documented with a calculation of overall duration if there was any intermittent stoppage of SMX-TMP. Chart review was used to ascertain reasons for premature SMX-TMP discontinuation prior to one year with documentation of alternative therapies to SMX-TMP (dapsone or atovaquone).
Induction with anti-thymocyte globulin (ATG) as per our protocol was indicated if patients had any preformed donor specific antibodies (DSAs), calculated panel reactive antibody (cPRA) sensitization of greater than 10%, concurrent heart-kidney or heart-liver transplant, elevation in serum creatinine to greater than 2 mg/dL immediately after transplant, or primary graft dysfunction. Anti-CD20 monoclonal antibody or bortezomib was used as desensitization therapy prior to transplant in highly sensitized patients with a high likelihood of having preformed DSAs. After transplant, they were used in patients who developed strong binding de novo DSAs.
A combination of tacrolimus, mycophenolate, and either intravenous methylprednisolone or oral prednisone is our standard maintenance immunosuppression. Patients were switched from tacrolimus to cyclosporine if they had an intolerance to tacrolimus. Patients were switched from tacrolimus to a proliferation signal inhibitor (PSI) if they had renal dysfunction. Patients were switched from mycophenolate to a PSI if they had any DSA or rejection. Patients remained on prednisone indefinitely if they had any DSA, rejection, other inflammatory or rheumatologic diseases, or a concurrent dual-organ transplant. They were weaned off prednisone at one year if they did not meet any of these criteria.
Sixty transplants (14.2%) were excluded from further evaluation due to preexisting sulfa allergy, premature death within 3 months of heart transplant (none of which was due to PCP), inability to initiate SMX-TMP due to worsening renal function or hyperkalemia, or heart–lung dual-organ recipients, as these patients were on SMX-TMP DS TIW as per our lung transplant protocol (Figure 1), leaving 361 patients (363 heart transplants) for inclusion in this study.

3. Results

3.1. Baseline Characteristics

The average patient age at transplant was 54.4 ± 13.3 years, and 74% of patients were male. There were 63 concurrent dual-organ transplants (59 kidneys and 4 livers) and 28 redo heart transplants, with 2 patients receiving their first and second heart transplant during the study period. A total of 116 (32.1%) patients were born in Southern California, 129 (35.7%) were born in the United States outside of Southern California, and 116 (32.1%) were born internationally. In sum, 118 patients repatriated to their home center or moved before 2 years (with 103 of these patients within 1 year). Partial follow-up records for these patients were obtained from medical records through Care Everywhere®. Follow-up records for at least 2 years or more from the date of transplant were available for most patients (88.6%).

3.2. PCP Incidence

During a median follow up of 3.86 years (range 0.17–6.57 years), we did not find any documented cases of PCP. Overall, 51 patients died during the follow up period: 11 (21.6%) were due to SARS-CoV-2 infection-related complications, 9 (17.6%) due to cardiovascular death, including rejection, 9 (17.6%) due to malignancy complications, 4 (7.8%) due to other pneumonia not due to Pneumocystis, and 3 deaths where cause was not documented, but were sudden and unexpected and thought unlikely due to PCP. There were two documented cases of Nocardia infection and there was no documented Toxoplasma gondii infection.

3.3. PCP Prophylaxis Timing

SMX-TMP was initiated after transplant at a median of 7 days (range 0–132 days), with only 11 patients (3%) initiated after 1 month, for an overall median duration of 11.5 months (range 0.25 to 22 months), excluding 30 patients (8.3%) whose total duration was undocumented. SMX-TMP was stopped at 12 months in 136 patients (37.3%), while 159 patients (43.8%) stopped SMX-TMP before 12 months (Figure 2).
In 130 patients, SMX-TMP was documented as discontinued for adverse effects, and in 40 of those patients, it was restarted without recurrence. SMX-TMP was not rechallenged in the remaining 90 patients, with 63 switched to either dapsone or atovaquone, while 27 did not restart any PCP prophylaxis. The median duration of PCP prophylaxis for patients who stopped SMX-TMP without an alternative was 4.75 months (range 0.25 to 11 months).

3.4. SMX-TMP Adverse Effects

In the first year following transplant, 53.2% of patients had experienced leucopenia, defined as white blood cell count (WBC) less than 4000/mm3, on two or more consecutive measurements, but physician-documented discontinuation of SMX-TMP due to leucopenia was noted for only 30.8% of patients. Although 9.6% of patients developed a twofold increase in serum creatinine and 2.5% of patients required intermittent hemodialysis, the physician-documented discontinuation of SMX-TMP due to renal insufficiency occurred in only 1.4% of all patients. Hyperkalemia resulted in physician-documented SMX-TMP discontinuation in 2.2% of patients. Additional reasons for physician-documented SMX-TMP discontinuation are shown in Figure 3.
Dose adjustments of SMX-TMP were made at the treating physician’s discretion and were due to renal insufficiency (3.3% adjusted to twice weekly and 1.4% to weekly dosing) or concurrent Nocardia infection (0.3% of patients adjusted to high-dose 1.5 DS TID). SMX-TMP SS daily was used in 0.8% for unclear reasons. The majority of patients (94.2%) were documented as continuing on SMX-TMP SS thrice weekly.

3.5. Immunosuppression

Most of our heart transplants (66.6%) underwent induction therapy with ATG. Forty-one patients received either anti-CD20 therapy (n = 26) or bortezomib (n = 15) at some point pre- or post-transplant. Overall, 61 patients developed documented rejection during the follow-up period and 52 patients were treated with solumedrol 500 mg intravenous for 3 days and/or prednisone 100 mg/day oral bolus × 3 days. Both regimens were usually followed by a rapid 5–10 day taper to 20 mg/day for 2–4 weeks, then a gradual taper to 5 mg daily over 3–6 months.
At 12 months post-heart transplant, 260 patients (71.6%) were maintained on tacrolimus and mycophenolate, 67 patients (18.5%) were on tacrolimus and a PSI, 3 patients (0.8%) were on tacrolimus and azathioprine, and 12 patients (3.3%) were on tacrolimus alone. Cyclosporine-based therapies (either monotherapy, with mycophenolate or with PSI) were maintained in 18 patients (5%) and PSI with mycophenolate was maintained in 3 patients (1%). Daily mean mycophenolate mofetil (MMF) equivalent dose was 1415.2 mg +/− 732.8 mg at 1 year. If patients were on mycophenolate sodium (MPS), a conversion of 180 mg MPS equal to 250 mg MMF was used to calculate MMF equivalent dose. At our center, patients were rapidly weaned to prednisone 20 mg/day in 1–2 weeks from transplant and maintained on 20 mg/day until approximately 1 month after transplant. Patients were slowly tapered to 10 mg/day by the third month, and then slowly weaned to a maximum of prednisone 5 mg/day by the sixth month post-transplant. Patients were then maintained on prednisone 5 mg/day indefinitely if they had any DSA, rejection, other inflammatory or rheumatologic diseases, or a simultaneous dual-organ transplant. If there were no extenuating factors, then patients were slowly weaned off prednisone by the first year.

4. Discussion

Our study demonstrates the safety, tolerability, and efficacy of a reduced-dosage prophylaxis regimen for PCP in patients with heart transplants. SMX-TMP SS thrice weekly for one year after heart transplantation resulted in zero incidence of PCP infection over a median follow-up period of 3.86 years following heart transplant. This is the first and largest study showing that reduced-frequency SMX-TMP dosing for one year may be sufficient for the prevention of PCP in heart transplants.
In Prasad et al., SMX-TMP SS daily was reduced to twice or thrice weekly due to adverse effects in 47% of their kidney transplants (overall 23% for leucopenia and 19% for hyperkalemia) [10]. However, in our cohort, only 36% of all patients had discontinued SMX-TMP due to adverse effects (25% stopping permanently), with 30.8% for leucopenia and just 2.2% for hyperkalemia. This suggests that adopting a reduced-dose regimen may mitigate additional hyperkalemia risks, as trimethoprim only has weak potassium-sparing diuretic properties and a dose-dependent direct correlation with serum potassium levels. The risk of hyperkalemia in patients with solid organ transplants is also increased due to calcineurin inhibitors. In our study, we only evaluated discontinuation due to hyperkalemia that was documented as such, and we did not evaluate the overall number of patients with any hyperkalemia episode or the use of potassium-lowering medications, so it is possible that our study is underestimating the SMX-TMP effect of hyperkalemia in our patients.
While leucopenia had occurred at least once in over 50% of all patients by the first year and resulted in 30.8% of all patients discontinuing SMX-TMP due to leucopenia, patients were also on other myelosuppressive drugs, including ATG, mycophenolate, and valganciclovir, and thus myelosuppression is not solely due to SMX-TMP. Interestingly, while MPA inhibits inosine monophosphate dehydrogenase and guanine synthesis in humans, causing leucopenia, it also achieves the same inhibition in P. jirovecii, thereby arresting mitosis and potentially protecting against a Pneumocystis infection [12,13,14].
Acute renal injury after heart transplant is also multifactorial and likely not due to nephrotoxicity from prophylactic dosing of SMX-TMP. Other possible renal injury causes include preexisting renal injury, prolonged surgical time, volume resuscitation, and prior frailty. About 10% of our patient population experienced a twofold increase in creatinine, with 2.5% requiring hemodialysis, but SMX-TMP was rarely discontinued by the physician in our patient population due to renal dysfunction (1.4%). Although sulfamethoxazole can form crystals in the nephron leading to acute kidney injury, this adverse effect is more commonly observed with a related drug, sulfadiazine, and at significantly higher treatment doses [15]. In addition to being less nephrotoxic than sulfadiazine, sulfamethoxazole for prophylaxis is dosed at 10 to 20 times less than that of treatment, further reducing nephrotoxicity risk. Trimethoprim can increase serum creatinine levels in the blood by inhibiting creatinine secretion in the tubules, but its effect on serum creatinine levels is reversible and transient, without any impact on actual glomerular filtration rate [16].
Notably, 27 patients (7.5%) inadvertently discontinued all PCP prophylaxis at a median of about 5 months, but none of these patients developed PCP. Although this is a small subset of the cohort, it posits that a reduced duration of SMX-TMP for prophylaxis should be further studied, as immunosuppression from prednisone and ATG induction is significantly reduced by 6 months.
We did not observe that augmented immunosuppression, such as the use of ATG, rituximab, or corticosteroid use, contribute to PCP either. The risk of PCP associated with immunologics like rituximab or ATG remains debatable in the literature [4,12,17,18,19]. Furthermore, studies varied widely on the exact amount and duration of prednisone that increases PCP risk. For instance, the American Thoracic Society suggested that prednisone greater than 20 mg/day for at least 8 weeks significantly increases the risk for PCP in patients without HIV [20,21]. In patients with cancer, Sepkowitz [22] and Mecoli [23] concluded that only 4 weeks of prednisone increased PCP risk, whereas other studies varied widely on dose and duration anywhere from 15–40 mg/day and 4–12 weeks [3,6,24,25].
Our study has some limitations. Firstly, this was a single-center retrospective cohort chart review study relying on accuracy of the patients’ chart, resulting in information bias. SMX-TMP duration (or side effects) was determined by its presence on medication lists or its discontinuation being explicitly documented in the medical chart, which may not be accurate. Our protocol maintains one year of prophylaxis. If patients relocated, this information would have been relayed to the patient’s transplant center, but the documentation on SMX-TMP discontinuation could be delayed. Furthermore, adherence to the medication regimen was not verified, but since we did not have any PCP cases in our cohort, this supports that a reduced dosage of SMX-TMP SS thrice weekly may be equally efficacious as DS thrice weekly or SS daily.
Another limitation is our inability to fully account for confounding factors that would affect the risk of acquiring PCP. For example, maintenance prednisone dosing is often inaccurately documented, and commonly there are incongruencies between the medical notes, the patient’s medication list in the chart, and verbal instructions that were not documented in the patient’s chart (though it is unlikely that maintenance prednisone doses at six months after transplant would have been higher than 5 mg/day as per our institution’s protocol). Similarly, T-cell enumeration and T-cell function assays were not routinely collected, so it is unknown whether T-cell recovery also mitigated risk of PCP.
Being a single-center study in Los Angeles, California, our patient population was diverse and heterogeneous, resulting in no latent reactivation of Pneumocystis. As per the CDC, up to 20% of adults can be latent carriers, taking months to be cleared of the organism [26,27]. Some studies cite latency as the main source, as P. jirovecii antibodies can be detected at a young age [3,28,29,30,31,32]; however, we did not conduct baseline serologic testing.
Other studies suggest airborne and close contact transmission as the primary mode of infection [3,26,33,34,35,36,37]. We did not evaluate the incidence of PCP in all patients at our hospital during the study period or the proximity of our patients to those patients with PCP. However, we did not observe any PCP, as our patients were likely separated from any patients infected with Pneumocystis. Also, global efforts to prevent PCP in patient with immunodeficiencies such as HIV/AIDS contributed to an overall decline in PCP outbreaks in all patients, including patients with transplants, so the likelihood of encountering a patient with PCP will be lower. Pneumocystis pneumonia rates in patients with HIV/AIDS declined from 95 cases per 1000 patient-years in 1995 to 8.4 cases per 1000 patient-years by 2008 [38].
Our study population was uniquely urban and international, and these results may not apply to other populations at risk for PCP, including persons with HIV/AIDS, other primary immunodeficiencies, or those living in regions with different Pneumocystis prevalence. Regardless, our study demonstrates an effective protocol for adopting a reduced-frequency SMX-TMP SS regimen that could reduce post-transplant complications, side effects, and costs, as the use of alternative agents can be costly (atovaquone) or have severe adverse effects like hemolytic anemia (dapsone). Prospective, randomized, multicenter studies using a similar reduced-frequency regimen would be important to conduct, and our results could even provide a basis for studying an even shorter duration of prophylaxis.

5. Conclusions

SMX-TMP SS thrice weekly for one year following heart transplantation effectively prevented Pneumocystis pneumonia in patients with heart transplants across all degrees of immunosuppressive regimens and therapies. Patients on this regimen developed similar rates of leucopenia compared to traditional regimens, but markedly decreased rates of hyperkalemia, determined by documented physician discontinuation. Prospective, randomized, and multicenter trials are warranted to further evaluate this reduced-dose regimen.

Author Contributions

Conceptualization, K.L.; data curation, K.L.; formal analysis, K.L.; methodology, K.L.; writing—original draft, K.L.; writing—review and editing, K.L., C.L., E.K. and M.K. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

The study was conducted in accordance with the Declaration of Helsinki and approved by the Institutional Review Board of Cedars Sinai (protocol code 00022311, initial approval 5 May 2010 with annual renewals until 2018 when the IRB determined that annual renewals were no longer required for minimal risk studies such as this study.

Informed Consent Statement

Informed consent was obtained from all subjects involved in the study.

Data Availability Statement

The original contributions presented in this study are included in the article. Further inquiries can be directed to the corresponding author.

Conflicts of Interest

The authors declare no conflicts of interest.

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Figure 1. Inclusion and exclusion criteria for our cohort.
Figure 1. Inclusion and exclusion criteria for our cohort.
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Figure 2. Duration of SMX-TMP SS prophylaxis, with 43.8% on prophylaxis for less than 12 months, 47.9% on prophylaxis for 12 months or longer, and 8.3% on prophylaxis for an unknown duration.
Figure 2. Duration of SMX-TMP SS prophylaxis, with 43.8% on prophylaxis for less than 12 months, 47.9% on prophylaxis for 12 months or longer, and 8.3% on prophylaxis for an unknown duration.
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Figure 3. Of the 363 heart transplants, 64% continued therapy without any disruption, while 36% had either temporary or permanent discontinuation. The majority of cessations of SMX-TMP were due to leucopenia followed by hyperkalemia.
Figure 3. Of the 363 heart transplants, 64% continued therapy without any disruption, while 36% had either temporary or permanent discontinuation. The majority of cessations of SMX-TMP were due to leucopenia followed by hyperkalemia.
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MDPI and ACS Style

Lor, K.; Le, C.; Kransdorf, E.; Kittleson, M. Single-Center 5-Year Observational Study of Thrice-Weekly Single-Strength Sulfamethoxazole–Trimethoprim as Adequate Prophylaxis for Pneumocystis jirovecii Pneumonia in Patients with Heart Transplants. Transplantology 2025, 6, 3. https://doi.org/10.3390/transplantology6010003

AMA Style

Lor K, Le C, Kransdorf E, Kittleson M. Single-Center 5-Year Observational Study of Thrice-Weekly Single-Strength Sulfamethoxazole–Trimethoprim as Adequate Prophylaxis for Pneumocystis jirovecii Pneumonia in Patients with Heart Transplants. Transplantology. 2025; 6(1):3. https://doi.org/10.3390/transplantology6010003

Chicago/Turabian Style

Lor, Kevin, Catherine Le, Evan Kransdorf, and Michelle Kittleson. 2025. "Single-Center 5-Year Observational Study of Thrice-Weekly Single-Strength Sulfamethoxazole–Trimethoprim as Adequate Prophylaxis for Pneumocystis jirovecii Pneumonia in Patients with Heart Transplants" Transplantology 6, no. 1: 3. https://doi.org/10.3390/transplantology6010003

APA Style

Lor, K., Le, C., Kransdorf, E., & Kittleson, M. (2025). Single-Center 5-Year Observational Study of Thrice-Weekly Single-Strength Sulfamethoxazole–Trimethoprim as Adequate Prophylaxis for Pneumocystis jirovecii Pneumonia in Patients with Heart Transplants. Transplantology, 6(1), 3. https://doi.org/10.3390/transplantology6010003

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