Rongrong Wang,1 Xiuhua Wu,1 Xishao Xie,2 Chunchun Wei,2 Jianyong Wu,2,* Kuifen Ma1,*

1Department of Clinical Pharmacy, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People’s Republic of China; 2Kidney Disease Center, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, People’s Republic of China

Correspondence: Kuifen Ma Department of Clinical Pharmacy, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, People’s Republic of China, Email [email protected] Jianyong Wu Kidney Disease Center, Zhejiang University School of Medicine First Affiliated Hospital, Hangzhou, 310003, People’s Republic of China, Email [email protected]

Objective: Emerging evidence suggests that low doses of sulfamethoxazole-trimethoprim (TMP-SMX) may offer protection against Pneumocystis jiroveci pneumonia (PJP) in kidney transplant recipients. However, cases of PJP following the withdrawal of prophylaxis have been documented. This study aimed to investigate the relationship between the occurrence of PJP and different regimes of low-dose TMP-SMX prophylaxis.
Methods: This retrospective observational study was conducted in the First Affiliated Hospital of Zhejiang University in China. Recipients diagnosed with PJP were included, and four controls were matched for each case based on transplantation time, age, and sex. Multivariate conditional logistic regression was employed to compare the odds of PJP occurrence among different TMP-SMX regimens.
Results: From January 1, 2017, to December 31, 2020, 1763 patients underwent kidney transplantation at our center. Thirty-one patients developed PJP post-transplantation, and 124 patients without PJP were included as controls. One patient developed PJP during the prophylaxis period, and the others occurred after TMP-SMX discontinuation, resulting in a PJP incidence rate of 1.36% over the follow-up period. Compared to controls, the PJP group received a significantly lower cumulative TMP-SMX dose (median: 57 single-strength dose [SSD] tablets vs 100 tablets; p = 0.001) and had a shorter prophylaxis duration (median: 6.00 months vs 10.00 months; p = 0.004). They also exhibited higher CMV infection rates (29.0% vs 4.8%, p p = 0.018), and reduced CD 4+ cell counts (354.12/L vs 542.58/L, p = 0.05). Multivariate analysis revealed that a higher cumulative TMP-SMX dose was significantly associated with a lower risk of PJP (p = 0.005). Subgroup analysis indicated that at least 6 months of TMP-SMX prophylaxis is necessary for PJP prevention in recipients on quarter-strength daily (SMX/TMP 100/20 mg, p = 0.022) or half-single strength daily (SMX/TMP 200/40 to 400/80 mg, p = 0.005) regimens.
Conclusion: An adequate prophylactic duration of either quarter-strength daily TMP-SMX or half-single strength daily TMP-SMX may protect kidney transplant recipients from PJP.

Keywords: Pneumocystis jiroveci pneumonia, low dose, sulfamethoxazole-trimethoprim, kidney transplant, anti-Pneumocystis prophylaxis

Introduction

Pneumocystis jiroveci pneumonia (PJP) continues to pose a significant threat to kidney transplant recipients.1–3 The incidence of PJP can reach up to 5%–15% in solid organ transplant recipients in the absence of universal prophylaxis, carrying a high mortality rate of 10% to 50%.4 As a first-line anti-Pneumocystis prophylaxis, trimethoprim-sulfamethoxazole (TMP-SMX)5,6 is also recommended for kidney transplantation recipients.4,7,8 Advances in prophylactic strategies and immunosuppressive regimens have reduced the incidence of PJP in transplant recipients to 0.3%–2.5%.7

The standard dosage of prophylactic TMP-SMX for adult transplant recipients is 80 mg of TMP/400 mg of SMX daily (single-strength dose, SSD) or 160 mg of TMP/800 mg of SMX (double-strength dose, DSD) three times per week.8 A comprehensive meta-analysis9 compared different anti-Pneumocystis prophylactic regimens and concluded that TMP-SMX was the most efficacious, despite its severe side effects that lead to a high discontinuation rate. The DSD of TMP-SMX three times per week presents lower risks than daily administration but still carries a 14.5% likelihood of discontinuation within year.9

TMP-SMX is associated with concerning adverse reactions, including bone marrow suppression, hepatitis, and hyperkalemia.4 Furthermore, it may impair renal function by inhibiting creatinine secretion, inducing crystalline nephropathies, and causing interstitial nephritis.10,11 Differentiating between drug-related renal injury and renal rejection once these effects occur is challenging. Consequently, clinical centers often resort to lower doses of TMP-SMZ than those recommended by guidelines to reduce these risk factors.12,13

Current guidelines recommend standard-dose TMP-SMX prophylaxis over 6 months for PJP prevention in immunocompromised patients.4 However, some recent published clinical observations challenge this recommendation. In kidney transplant recipients, a retrospective study demonstrated that dose reduction of TMP-SMX due to frequent adverse reactions did not result in any PJP cases, supporting the efficacy of lower-dose regimens for PJP prophylaxis.14 Among heart transplant recipients, a 5-year observational study further established that thrice-weekly SSD TMP-SMX administered for one year effectively prevented PJP, with zero breakthrough infections observed during a median follow-up.15 These findings suggest that reduced-dose TMP-SMX exhibits comparable efficacy to standard dosing in clinical practice. Nevertheless, controversies still persist: a pediatric solid organ transplant cohort study utilizing a low-dose TMP-SMX regimen (TMP 2.5 mg/kg/dose, thrice weekly) reported no confirmed breakthrough PJP infections among 234 patients; however, 2.6% (n = 6) required empirical transitioned to therapeutic dosing due to clinical suspicion of PJP. While reduced-dose TMP-SMX regimens demonstrate substantial advantages in safety and tolerability, critical questions regarding potential suboptimal protection from insufficient dosing and optimal treatment duration remain unresolved.

In our prior study, we discovered that a quarter- to half-strength daily dose of TMP-SMX offered protection to kidney transplant recipients against PJP during the prophylaxis period, aligning with a recently published study.13 However, some recipients still developed PJP after the prophylactic drug withdrawal. The relationship between the occurrence of PJP and the duration or dosage of TMP-SMX prophylaxis remains unexplored. Consequently, a case–control study was conducted at our center to compare the odds of PJP across different TMP-SMX regimens.16–18

MethodStudy Design and Participants

This retrospective observational study was conducted at the First Affiliated Hospital of Zhejiang University (FAHZJ) in China. The inclusion criteria were: (1) patients who underwent kidney transplantation between January 1, 2017, and December 31, 2020; (2) patients diagnosed with PJP after kidney transplantation were included as infected cases. Four controls were selected for each infected case by matching for transplantation time, age, and sex; (3) complete follow-up data were available.

The study adhered to the principles outlined in the Helsinki Declaration of 1975 and the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement.19 The FAHZJ-authorized ethics committee granted ethical approval for this study. The ethics committee exempted informed consent due to the anonymity of the data and the absence of patient identification information. All organs were voluntarily donated with written informed consent and followed the Declaration of Istanbul.

Definitions and Diagnosis

A matched index date was allocated to each control according to the time of PJP in the matched patients.

The single-strength dose (SSD) of TMP-SMX is 80 mg TMP/400 mg SMX; the half-strength dose (HSD) of TMP-SMX is 40mg TMP/200 mg SMX; the quarter-strength dose (QSD) of TMP-SMX is 20mg TMP/100 mg SMX.

The diagnosis methods were consistent with those reported in previous study.12 PJP was definitively established either through the detection of pneumocystis cysts or trophozoites in bronchoalveolar lavage fluid, or by utilizing a combination of methods including next-generation sequencing analysis (NGS) of bronchoalveolar lavage fluid or blood samples, along with radiographic confirmation via computed tomography (CT) scans. Additionally, measurements of blood beta-D-glucan levels were incorporated into the comprehensive diagnostic workflow to ensure accurate diagnosis. CMV infection was defined as detecting CMV DNA in blood or other tissue, regardless of symptoms.20

Data Collection

Electronic medical records and follow-up data were reviewed to collect necessary information, including age, body mass index (BMI), sex, donor source, primary renal disease, preoperative dialysis duration, immunosuppression regimens, CMV infection history, creatinine at discharge, CD4+ and CD8+ T lymphocyte count a week post-surgery, acute rejection history, TMP-SMX dose, and TMP-SMX duration.

TMP-SMX Dose

TMP-SMX is routinely used to prevent PJP in recipients with creatinine clearance below 150 μmol/L after kidney transplantation. The main initial dose was HSD of TMP-SMX daily, and the maintenance dose would be adjusted to a QSD of TMP-SMX daily if the serum creatinine increased by 10% or other adverse reactions related to TMP-SMX occurred. If further reduction is deemed necessary, stop entirely.

Statistical Analysis

The count data is expressed as n (%), and the measurement data is presented as means (standard deviation [SD]) or medians (interquartile range [IQR]), as appropriate. Student’s t-tests or the Mann–Whitney U-test were performed as appropriate to compare quantitative data between different groups; Pearson χ2 or Fisher exact test was used to compare categorized parameters. Multivariate conditional logistic regression was used to compare the risk factors for PJP. Demographic data, laboratory test indicators, graft types, immunosuppressive therapy, CMV infections, rejections pre-PJP, serum creatinine levels, dialysis course pre-transplant, total number of lymphocytes, absolute CD4+ and CD8+ T lymphocyte counts, TMP-SMX dose, and TMP-SMX duration were investigated. Factors with a univariate p-value of ≤0.05 were entered into the multivariate logistic regression analysis.21,22 A two-tailed p-value <0.05 was considered statistically significant. The R software (R Core Team, www.r-project.org) was used for analysis.

Sample Size Calculation

According the reported exposure rates23 of TMP-SMX prophylaxis <6 months and the data from our previous PJP cohort12 (40% in cases vs 15% in controls, OR of 3.8), we used standard formulas24 with α=0.05 (two-tailed), 80% power, 0.2 correlation coefficient for exposure and 1:4 case–control matching, the calculated minimum required sample size was 28 cases and 112 controls to detect an OR of 3.8.

ResultsCharacteristics of Included Patients

From January 1, 2017, to December 31, 2020, 1763 recipients underwent renal transplantation in our center, with 24 cases (1.4%) developing PJP during the follow-up. Seven recipients who underwent renal transplantation in other centers but received treatments in our center were also enrolled in the PJP group (Figure 1). In total, 155 recipients were included, with 31 cases in the PJP group and 124 cases without PJP in the control group (Figure 1). The median follow-up duration of the study cohort was 28.0 (IQR:21.5–40.4) months. All patients enrolled in this study were successfully followed up until the completion of the study. Ninety-six patients were male, with a mean age of 37.94 (SD 11.70). The median time from PJP or matched index date after transplantation was 16.40 (IQR: 6.60–21.65) months at inclusion, and the primary renal disease included primary glomerulonephritis in 88 patients, polycystic kidney disease in five patients, hypertensive nephropathy in three patients, diabetes nephropathy in two patients, and other diseases in 57 patients. Ninety-six patients received grafts from donors after death and 59 from living donors. Among the 31 PJP patients, 19 were definitively diagnosed through NGS or Gomori’s methenamine silver staining (GMS) staining, while 12 received clinical diagnoses based on characteristic pulmonary CT findings combined with elevated blood β-D-glucan levels. Compared to the control group, patients with PJP had a higher incidence of CMV infections (29.0% vs 4.8%, p < 0.001), higher levels of serum creatinine at discharge (174.80 μmol/L vs 134.58 μmol/L, p < 0.018), and lower CD 4+ T lymphocyte counts (354.12/L vs 542.58/L, p = 0.05). The duration of PJP from transplantation or the matched index date after transplantation, age, and gender ratio were similar between the two groups. Characteristics of included patients are shown in Table 1 and Supplement Table 1 (excluding recipients in other centers).

Table 1 Characteristics of the Patients at Baseline

Figure 1 Study flow diagram.

Characteristics of PJP in RT Recipients

The median time to develop PJP after renal transplantation was 16.40 (IQR 7.30–20.80) months in 31 patients with PJP, 6.23 (IQR 4.70–15.30) months in recipients did not use TMP-SMX, 18.05 (IQR 9.03–20.78) months in recipients used QSD daily TMP-SMX, and 15.90 (IQR 10.88–19.78) months in recipients used HSD&SSD daily TMP-SMX. Of these, one patient developed a breakthrough infection during prophylaxis with QSD daily TMP-SMX, and others occurred after the discontinuation of TMP-SMX. The median time between infections and the discontinuation of TMP-SMX was 6.83 months in recipients who used QSD daily TMP-SMX (IQR 5.00–11.80 months), and 6.88 months in recipients who used HSD&SSD daily TMP-SMX (IQR6.19–9.43 months).

Prophylaxis Against PJP

As prophylaxis against PJP, two (1.3%) patients used SSD daily TMP-SMX, 50 (32.3%) used HSD daily TMP-SMX, 91 (58.7%) used QSD daily TMP-SMX, and 12 (7.7%) did not use TMP-SMX. There is a significant difference in the prophylaxis therapy between the two groups (p < 0.001, Table 1). In the PJP group, 22.6% of recipients did not use prophylaxis, which was higher compared with 4.0% in the control group. Recipients in the PJP group took fewer cumulative TMP-SMX doses than those in the PJP group (Table 2, p = 0.001). The prophylactic regimens for PJP in subgroup cohort (excluding recipients from other centers and their corresponding matches) are presented in Supplemental Table 2.

Table 2 Prophylaxis Against PJP in Enrolled Patients

The median TMP-SMX duration was 6.00 (IQR: 0.30–12.00) months in the PJP group, which was significantly shorter than 10.00 (IQR: 6.00–12.00) months in the control group (p = 0.004, Table 2). In the control group, 94.4% (QSD daily TMP-SMX) and 83.3% (HSD&SSD daily TMP-SMX) of recipients used TMP-SMX more than six months, which was 75.0% in the PJP group with different TMP-SMX regimens. In the control group, 60.6% of recipients used TMP-SMX QSD daily for more than 12 months, while the rate was 37.5% in recipients who used TMP-SMX HSD&SSD daily.

Risk for PJP Among Recipients Used Different TMP-SMX Regimes

Factors with a univariable p-value of ≤0.05 were entered into the multivariate conditional logistic regression, including CMV infections, CD4+ T lymphocyte counts, serum creatinine outpatient and cumulative dose of TMP-SMX (Table 1 and Table 2). The results of TMP-SMX with a higher cumulative dose were related to lower PJP occurrence (OR 0.077, 95% CI: 0.013–0.459, p = 0.005, Table 3). As the cumulative dose of TMP-SMX was related to both TMP-SMX dosage and duration, a subgroup analysis further investigated the effects of different TMP-SMX regimens (Table 4). Factors with a univariable p-value of ≤0.05 were entered into the multivariate conditional logistic regression for adjusting (CMV infection, Scr outpatient, and CD4+ T lymphocyte counts). The results showed that the minimum duration of 6 months effectively prevented PJP in recipients on quarter-strength daily (SMX/TMP 100/20 mg, p = 0.022, Table 4) or half-single strength daily (SMX/TMP 200/40 to 400/80 mg, p = 0.005, Table 4) regimens. However, shorter than six months was insufficient. The multivariate conditional logistic regression was conducted in recipients excluded from other centers, and the result was consistent with the primary analysis (Supplement Tables 3 and Supplement Table 4).

Table 3 Risk Factors for PJP After Kidney Transplantation

Table 4 Subgroup Analysis of Different TMP-SMX Regimes Against PJP

Outcomes of PJP

Regular follow-up was carried out for those infected recipients. After PJP, one patient died due to treatment failure (TMP-SMX combined caspofungin). This patient developed PJP 8.5 months after discontinuing QSD daily TMP-SMX. Other infected patients recovered after treatments. The treatment details were described in our previous study.12

Discussion

For the present, TMP-SMX remains the first-line choice for PJP prophylaxis.7,8,20 All the other PJP prophylaxis are recommended as second-line treatment, as the disadvantages in efficacy, cost and tolerability.4,7 However, the current recommended dose of TMP-SMX in guidelines is still associated with a relatively high incidence of adverse events and commonly leads to dose reduction or even discontinuation of TMP-SMX.14,25–27 So, it is necessary to balance the side-effect profiles and the efficacy of TMP-SMX by optimizing its dosage. Our study investigated the odds of PJP occurrence among different TMP-SMX regimens and firstly found that both low-dose TMP-SMX strategies (HSD&SSD or QSD daily) with sufficient duration can protect against PJP in recipients who underwent renal transplantation. Our finding demonstrates that QSD or HSD&SSD daily TMP-SMX can provide PJP prophylaxis in kidney transplant recipients with adequate prophylactic duration. The results may challenge current guideline recommendations advocating for higher-dose regimens and reveal a strategic opportunity to optimize prophylaxis protocols. However, robust prospective studies are required to validate the low-dose prophylaxis protocols of TMP-SMX.

Several RCTs studied the prophylaxis for PJP in transplantation patients,27–30 but the low limit of TMP-SMX’s dose in these studies was SSD TMP-SMX daily. Two retrospective cohort studies about kidney transplantation patients investigated the lower prophylactic dose.14,31 Among these, the efficacy and adverse effects of SSD TMP-SMX thrice weekly were described. The cumulative dose of this regimen per week is near the HSD of TMP-SMX daily in our study. In the two studies, Prasad et al reported a high rate (50%) of reducing the initiating daily SSD TMP-SMX, mainly due to hyperkalemia and leukopenia.14 The TMP-SMX dose was reduced to SSD thrice or twice weekly, and no PJP occurred in any transplant patients over a follow-up period of 12 months. Zmarlicka et al examined the tolerability of SSD TMP-SMX thrice weekly in 78 kidney transplant patients.31 Ten patients discontinued TMP-SMX (a median therapy period of 194 days) due to hyperkalemia, leukopenia, and diarrhea. No episodes of PJP occurred in this cohort. The discontinuation rate of this regimen was lower than SSD TMP-SMX daily in other studies (ranging from 25% to 40%).32,33 Based on these data, the intensity of TMP-SMX lower than SSD daily may be effective and has an advantage in safety and drug retention. However, the efficacy and risks of even low-intensity TMP-SMX have been rarely reported.

In our center, the initial dose of TMP-SMX was mainly HSD daily. The maintenance dose would be adjusted to QSD daily if the serum creatinine increased or other adverse reactions related to TMP-SMX occurred. Therefore, both SSD and HSD TMP-SMX daily were commonly used. Only one patient developed a breakthrough infection during the prophylaxis period, and other PJPs occurred after the discontinuation of TMP-SMX. With the current anti-Pneumocystis prophylaxis, the breakthrough infection rate is low (0.06%), and the overall morbidity of PJP was 1.36% in our center, which was similar to the result in previous studies with higher doses of TMP-SMX.4,34 The results indicate that low-dose TMP-SMX regimens used in our center can protect against PJP.

In a recent study, Chen et al demonstrated that low-dose TMP-SMX prophylaxis significantly reduces the incidence of PJP within 6 months following kidney transplantation and has a favourable safety profile.13 However, cases of PJP occurring 6 months post-kidney transplantation have been reported in kidney transplant.35,36 In our previous study, we also discovered that a daily regimen of TMP-SMX, switching from a QSD to HSD, provided robust protection against PJP in kidney transplant recipients during the prophylactic period.12 Nevertheless, a number of recipients went on to develop PJP following the cessation of the prophylactic medication, with the majority of cases occurring after 6 months post-transplantation. It is essential to determine whether the incidence of PJPs was associated with the duration or the dosage of TMP-SMX. Accordingly, we investigated the combination effect of TMP-SMX dose and duration and found that a minimum duration of 6 months effectively prevented PJP in recipients on a quarter-strength daily or half-single strength daily TMP-SMX regimen. The recommended duration for a standard dose of TMP-SMX is three to six months, or at least four months for transplant recipients, as outlined in Guidelines published prior to 2017.7,37,38 In the updated guideline from the American Society of Transplantation Infectious Diseases Community, a minimum of 6 months of prophylaxis has been recommended.4 The necessity of recommending extended prophylaxis periods for low-dose TMP-SMX regimes presents a significant challenge that was not further investigated in our study due to the limitations in the number of participants. Further research is required to determine the optimal specific duration threshold for low-dose prophylaxis. It should be noted that the duration significantly differed in recipients who used different TMP-SMX doses. In the control group, 60.6% of recipients used TMP-SMX QSD daily for more than 12 months, while the rate was 37.5% in recipients who used TMP-SMX HSD&SSD daily. The TMP-SMX dose would be decreased or discontinued with the occurrence of TMP-SMX-related adverse reactions. Longer duration indicated a better tolerance of TMP-SMX QSD daily in kidney transplant recipients. Since the majority of PCP cases occurred after discontinuation of anti-Pneumocystis prophylaxis, improved tolerability may contribute to improved outcomes.

Our study highlights that CMV was significantly related to PJP, with prior evidence showing 46.2% of PJP patients had concurrent CMV viremia39 and a significantly higher prevalence of CMV infection within one year before PJP onset (23% vs 4%, p < 0.001),40 suggesting CMV as a key predisposing factor. Mechanistic studies demonstrate that CMV not only causes lymphopenia but also reshapes the T-cell compartment, disrupts monocyte function (impairing phagocytosis and antigen presentation), and produces immunomodulatory viral IL-10, all of which may contribute to impaired Pneumocystis jiroveci clearance.40–42 Furthermore, univariate analysis confirmed an association between low CD4+ T cell counts and increased PJP susceptibility, aligning with established evidence that lymphopenia—particularly CD4+ counts below 200 cells/μL—constitutes a major risk factor.43 This association reflects compromised adaptive immunity, heightening vulnerability to PJP. Elevated LDH (>300 IU/mL) and β-D-glucan testing show high sensitivity for PJP, though limited specificity. These biomarkers are routinely employed in clinical practice to assist in diagnosis and risk stratification, particularly for immunocompromised patients presenting with atypical clinical symptoms or inconclusive radiological findings. Current clinical guidelines4 advocating for combined biomarker assessment, which can facilitate the development of more effective prevention strategy.

There are some limitations of this study. Firstly, this was a retrospective, case–control study with a small sample size. Although the matching method and the multivariate conditional logistic regression were used, the confounding and selection bias cannot be avoided. In the context of universal prophylaxis, the incidence of PJP is low, so the sample size in the PJP group was limited. Seven recipients who underwent renal transplantation in other centers were enrolled in the PJP group, which may introduce heterogeneity. We conducted sensitivity analysis through excluding these recipients, the results consistent with the primary analysis, suggesting that center-related factors had minimal impact on the observed associations. In the future, well-designed, prospective, and multicenter studies are needed to provide more robust evidence. Another limitation was the lack of a direct comparison of the efficacy and risk between HSD daily TMP-SMX and the guideline-recommended regimen. Only three patients used the SSD TMP-SMX as prophylaxis against PJP, so the comparison cannot be performed. Besides, unmeasured infections (such as bacterial/fungal) were not adjusted for due to incomplete retrospective data. Despite these limitations, our study represents a real-world scenario that provides data about promising TMP-SMX prophylaxis with a relatively low dosage, which may contribute to laying the groundwork for the development of strategies with both good tolerance and powerful prevention effects.

Conclusion

TMP-SMX with a dose lower than the guideline-recommended is used in practice to confine its risks. We conducted a case–control study to analyze the odds of PJP from different SMZ prevention programs. After ruling out the effects of other known risk factors, we found that doses of TMP-SMX lower than the guideline-recommended with sufficient duration can protect recipients who underwent kidney transplantation against PJP.

Abbreviation

TMP-SMX, sulfamethoxazole-trimethoprim; PJP, Pneumocystis jiroveci pneumonia; SSD, single-strength dose; double-strength dose, DSD; FAHZJ, the First Affiliated Hospital of Zhejiang University; STROBE, Strengthening the Reporting of Observational Studies in Epidemiology; SD, standard deviation; IQR, interquartile range; BMI, body mass index; GMS, Gomori’s methenamine silver staining.

Data Sharing Statement

Data is provided within the manuscript.

Ethics Declarations and Consent to Participate

Ethical approval was obtained from the authorized ethics committee of the First Affiliated Hospital of Zhejiang University (approved ID: 2018-1083). The ethics committee exempted informed consent due to the anonymity of the data and the absence of patient identification information. All organs were voluntarily donated with written informed consent and followed the Declaration of Istanbul.

Acknowledgments

We thank all the authors for their contribution. It was not appropriate or possible to involve patients or the public in the design, or conduct, or reporting, or dissemination plans of our research.

Author Contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Funding

This study was supported by the Zhejiang Provincial Medical and Health Science and Technology Plan (2020ZH004).

Disclosure

The authors declare no competing interests in this work.

References

1. Utsunomiya M, Dobashi H, Odani T, et al. Optimal regimens of sulfamethoxazole-trimethoprim for chemoprophylaxis of Pneumocystis pneumonia in patients with systemic rheumatic diseases: results from a non-blinded, randomized controlled trial. Arthritis Res Ther. 2017;19(1):7. doi:10.1186/s13075-016-1206-8

2. Utsunomiya M, Dobashi H, Odani T, et al. An open-label, randomized controlled trial of sulfamethoxazole-trimethoprim for Pneumocystis prophylaxis: results of 52-week follow-up. Rheumatol Adv Pract. 2020;4(2):rkaa029. doi:10.1093/rap/rkaa029

3. Singh R, Bemelman FJ, Hodiamont CJ, Idu MM, Ten Berge IJ, Geerlings SE. The impact of trimethoprim-sulfamethoxazole as Pneumocystis jiroveci pneumonia prophylaxis on the occurrence of asymptomatic bacteriuria and urinary tract infections among renal allograft recipients: a retrospective before-after study. BMC Infect Dis. 2016;16(1):90. doi:10.1186/s12879-016-1432-3

4. Fishman JA, Gans H. Pneumocystis jiroveci in solid organ transplantation: guidelines from the American Society of Transplantation Infectious Diseases Community of Practice. Clin Transplant. 2019;33(9):e13587. doi:10.1111/ctr.13587

5. Li H, Lu Y, Tian G, et al. A regimen based on the combination of trimethoprim/sulfamethoxazole with caspofungin and corticosteroids as a first-line therapy for patients with severe non-HIV-related pneumocystis jirovecii pneumonia: a retrospective study in a tertiary hospital. BMC Infect Dis. 2024;24(1):152. doi:10.1186/s12879-024-09031-7

6. Song S, Zhang Y, Yu J, Xie C, Chen Y, Zhang X. Time to trimethoprim/sulfamethoxazole initiation among patients with rheumatic disease complicated by Pneumocystis jirovecii pneumonia: impact on 90-day mortality. BMC Infect Dis. 2022;22(1):961. doi:10.1186/s12879-022-07940-z

7. BL Kasiske, MG Zeier, JR Chapman, et al. KDIGO clinical practice guideline for the care of kidney transplant recipients. Am J Transplant. 2009;9(Suppl 3):S1–155.

8. Yu Y, Yang H, Yu X, et al. Critical appraisal of the quality and content of clinical practice guidelines for pneumocystis jiroveci pneumonia (PJP) prophylaxis using the AGREE II instrument. J Clin Pharm Ther. 2020;45(6):1325–1333. doi:10.1111/jcpt.13213

9. Ioannidis JP, Cappelleri JC, Skolnik PR, Lau J, Sacks HS. A meta-analysis of the relative efficacy and toxicity of Pneumocystis carinii prophylactic regimens. Arch Intern Med. 1996;156(2):177–188. doi:10.1001/archinte.1996.00440020081010

10. Stern A, Green H, Paul M, Vidal L, Leibovici L. Prophylaxis for Pneumocystis pneumonia (PCP) in non-HIV immunocompromised patients. Cochrane Database Syst Rev. 2014;2014(10):Cd005590. doi:10.1002/14651858.CD005590.pub3

11. Perazella MA, Herlitz LC. The Crystalline Nephropathies. Kidney Int Rep. 2021;6(12):2942–2957. doi:10.1016/j.ekir.2021.09.003

12. Shan W, Wang L, Qin J, Peng W, Ma K. Clinical Characteristics and Epidemiological Analysis of Pneumocystis Jirovecii Pneumonia Infection in Kidney Transplant Patients with Trimethoprim-Sulfamethoxazole Dose Reduction Prophylaxis Strategy. Infect Drug Resist. 2024;17:2299–2306. doi:10.2147/IDR.S461206

13. Chen RY, Li DW, Wang JY, et al. Prophylactic effect of low-dose trimethoprim-sulfamethoxazole for Pneumocystis jirovecii pneumonia in adult recipients of kidney transplantation: a real-world data study. Int J Infect Dis. 2022;125:209–215. doi:10.1016/j.ijid.2022.10.004

14. Prasad GVR, Beckley J, Mathur M, et al. Safety and efficacy of prophylaxis for Pneumocystis jirovecii pneumonia involving trimethoprim-sulfamethoxazole dose reduction in kidney transplantation. BMC Infect Dis. 2019;19(1):311. doi:10.1186/s12879-019-3944-0

15. 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. doi:10.3390/transplantology6010003

16. Arend SM, Westendorp RG, Kroon FP, et al. Rejection treatment and cytomegalovirus infection as risk factors for Pneumocystis carinii pneumonia in renal transplant recipients. Clin Infect Dis. 1996;22(6):920–925. doi:10.1093/clinids/22.6.920

17. Lufft V, Kliem V, Behrend M, Pichlmayr R, Koch KM, Brunkhorst R. Incidence of Pneumocystis carinii pneumonia after renal transplantation. Impact of immunosuppression. Transplantation. 1996;62(3):421–423. doi:10.1097/00007890-199608150-00022

18. Fishman JA. Infection in solid-organ transplant recipients. N Engl J Med. 2007;357(25):2601–2614. doi:10.1056/NEJMra064928

19. von Elm E, Altman DG, Egger M, Pocock SJ, Gøtzsche PC, Vandenbroucke JP. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) Statement: guidelines for reporting observational studies. Int J Surg. 2014;12(12):1495–1499. doi:10.1016/j.ijsu.2014.07.013

20. Razonable RR, Humar A. Cytomegalovirus in solid organ transplant recipients-Guidelines of the American Society of Transplantation Infectious Diseases Community of Practice. Clin Transplant. 2019;33(9):e13512. doi:10.1111/ctr.13512

21. Chowdhury MZI, Turin TC. Variable selection strategies and its importance in clinical prediction modelling. Fam Med Comm Health. 2020;8(1):e000262. doi:10.1136/fmch-2019-000262

22. Zhang W, Wang R, Jin P, et al. Clinical characteristics and outcomes of liver transplant recipients infected by Omicron during the opening up of the dynamic zero-coronavirus disease policy in China: a prospective, observational study. Am J Transplant. 2024;24(4):631–640. doi:10.1016/j.ajt.2023.09.022

23. Ji J, Wang Q, Huang T, et al. Efficacy of Low-Dose Trimethoprim/Sulfamethoxazole for the Treatment of Pneumocystis jirovecii Pneumonia in Deceased Donor Kidney Recipients. Infect Drug Resist. 2021;14:4913–4920. doi:10.2147/IDR.S339622

24. Dupont WD. Power calculations for matched case-control studies. Biometrics. 1988;44(4):1157–1168. doi:10.2307/2531743

25. Gaut P, Daar ES. Editorial response: prophylaxis for Pneumocystis carinii pneumonia--an evolving tale of two populations. Clin Infect Dis. 1999;29(4):784–786. doi:10.1086/520434

26. El-Sadr WM, Luskin-Hawk R, Yurik TM, et al. A randomized trial of daily and thrice-weekly trimethoprim-sulfamethoxazole for the prevention of Pneumocystis carinii pneumonia in human immunodeficiency virus-infected persons. Terry Beirn Community Programs for Clinical Research on AIDS (CPCRA). Clin Infect Dis. 1999;29(4):775–783. doi:10.1086/520433

27. Torre-Cisneros J, De la Mata M, Pozo JC, et al. Randomized trial of weekly sulfadoxine/pyrimethamine vs. daily low-dose trimethoprim-sulfamethoxazole for the prophylaxis of Pneumocystis carinii pneumonia after liver transplantation. Clin Infect Dis. 1999;29(4):771–774. doi:10.1086/520432

28. Fox BC, Sollinger HW, Belzer FO, Maki DG. A prospective, randomized, double-blind study of trimethoprim-sulfamethoxazole for prophylaxis of infection in renal transplantation: clinical efficacy, absorption of trimethoprim-sulfamethoxazole, effects on the microflora, and the cost-benefit of prophylaxis. Am J Med. 1990;89(3):255–274. doi:10.1016/0002-9343(90)90337-d

29. Hibberd PL, Tolkoff-Rubin NE, Doran M, et al. Trimethoprim-sulfamethoxazole compared with ciprofloxacin for the prevention of urinary tract infection in renal transplant recipients. A double-blind, randomized controlled trial. Online J Curr Clin Trials. 1992;15:1.

30. Olsen SL, Renlund DG, Jb O, et al. Prevention of Pneumocystis carinii pneumonia in cardiac transplant recipients by trimethoprim sulfamethoxazole. Transplantation. 1993;56(2):359–362. doi:10.1097/00007890-199308000-00021

31. Zmarlicka M, Martin ST, Cardwell SM, Nailor MD. Tolerability of low-dose sulfamethoxazole/trimethoprim for Pneumocystis jirovecii pneumonia prophylaxis in kidney transplant recipients. Prog Transplant. 2015;25(3):210–216. doi:10.7182/pit2015153

32. Gabardi S, Millen P, Hurwitz S, Martin S, Roberts K, Chandraker A. Atovaquone versus trimethoprim–sulfamethoxazole as P neumocystis jirovecii pneumonia prophylaxis following renal transplantation. Clin Transplant. 2012;26(3):E184–90. doi:10.1111/j.1399-0012.2012.01624.x

33. Giullian JA, Cavanaugh K, Schaefer H. Lower risk of urinary tract infection with low-dose trimethoprim/sulfamethoxazole compared to dapsone prophylaxis in older renal transplant patients on a rapid steroid-withdrawal immunosuppression regimen. Clin Transplant. 2010;24(5):636–642. doi:10.1111/j.1399-0012.2009.01129.x

34. Neofytos D, Hirzel C, Boely E, et al. Pneumocystis jirovecii pneumonia in solid organ transplant recipients: a descriptive analysis for the Swiss Transplant Cohort. Transpl Infect Dis. 2018;20(6):e12984. doi:10.1111/tid.12984

35. Lee G, Koo TY, Kim HW, et al. Comparison of early and late Pneumocystis jirovecii Pneumonia in kidney transplant patients: the Korean Organ Transplantation Registry (KOTRY) Study. Sci Rep. 2022;12(1):10682. doi:10.1038/s41598-022-14580-5

36. Mulpuru S, Knoll G, Weir C, et al. Pneumocystis pneumonia outbreak among renal transplant recipients at a North American transplant center: risk factors and implications for infection control. Am J Infect Control. 2016;44(4):425–431. doi:10.1016/j.ajic.2015.11.012

37. Baker RJ, Mark PB, Patel RK, Stevens KK, Palmer N. Renal association clinical practice guideline in post-operative care in the kidney transplant recipient. BMC Nephrol. 2017;18(1):174. doi:10.1186/s12882-017-0553-2

38. EBPG Expert Group on Renal Transplantation. European best practice guidelines for renal transplantation. Section IV: long-term management of the transplant recipient. IV.7.1 Late infections. Pneumocystis carinii pneumonia. Nephrol Dial Transplant. 2002;17(4):36–39.

39. Zou J, Qiu T, Zhou J, et al. Clinical Manifestations and Outcomes of Renal Transplantation Patients With Pneumocystis jirovecii Pneumonia and Cytomegalovirus Co-infection. Front Med Lausanne. 2022;9:860644. doi:10.3389/fmed.2022.860644

40. Eberl I, Binquet C, Guilloteau A, et al. CMV Infection and Lymphopenia: warning Markers of Pneumocystis Pneumonia in Kidney Transplant Recipients. Transpl Int. 2024;37:12192. doi:10.3389/ti.2024.12192

41. Freeman ML, Mudd JC, Shive CL, et al. CD8 T-Cell Expansion and Inflammation Linked to CMV Coinfection in ART-treated HIV Infection. Clin Infect Dis. 2016;62(3):392–396. doi:10.1093/cid/civ840

42. Planchon MS, Fishman JA, El Khoury J. Modulation of Monocyte Effector Functions and Gene Expression by Human Cytomegalovirus Infection. Viruses. 2024;16(12):1809. doi:10.3390/v16121809

43. Apostolopoulou A, Fishman JA. The Pathogenesis and Diagnosis of Pneumocystis jiroveci Pneumonia. J Fungi. 2022;8(11). doi:10.3390/jof8111167