Caspofungin Combined With TMP/SMZ in Treatment of Intractable Acute Pneumocystis jirovecii Pneumonia in Renal Transplant Recipients: Case Report and Literature Review

ABSTRACT

Pneumocystis jirovecii pneumonia (PJP) is a potential life‐threatening opportunistic infection that predominantly affects immunocompromised individuals, such as those with human immunodeficiency virus or organ transplant recipients. The treatment of PJP, particularly severe cases, remains challenging, as standardized treatment therapies often require prolonged durations without achieving significant clinical improvement. The present study describes the case of a 48‐year‐old female patient who suffered from severe refractory PJP following renal transplantation. Despite 3 weeks of conventional treatment, computed tomography images revealed persistent lung infection, and the PJP nucleic acid test remained positive. However, after initiating combination therapy with caspofungin and trimethoprim/sulfamethoxazole (TMP/SMZ) for 48 days, the PJP nucleic acid test yielded negative results, and marked resolution was observed in lung imaging. On the whole, in the management of PJP, particularly that of severe refractory cases following organ transplantation, extending the treatment duration may lead to improved outcomes. The case described herein demonstrates the potential efficacy of prolonged treatment with a combination of caspofungin and TMP/SMZ in facilitating infection clearance and promoting clinical recovery in non‐HIV patients with PJP.

Summary.

• For severe refractory Pneumocystis jirovecii pneumonia (PJP), combination therapy with caspofungin and trimethoprim/sulfamethoxazole (TMP/SMX) is required; treatment duration may need to be extended to achieve clinical efficacy.

Abbreviations

ART

anti‐retroviral therapy

CRRT

continuous renal replacement therapy

CT

computed tomography

HFNCO

high‐flow nasal cannula oxygenation

HIV

human immunodeficiency virus

ICU

intensive care unit

PEEP

positive end expiratory pressure

PJP

Pneumocystis jirovecii pneumonia

SpO₂

peripheral oxygen saturation

TMP/SMZ

trimethoprim/sulfamethoxazole

1. Introduction

Pneumocystis jirovecii pneumonia (PJP), previously known as P. carinii pneumonia (PCP), is a potentially life‐threatening opportunistic infection that predominantly affects immunocompromised individuals, including those with human immunodeficiency virus (HIV) infection or organ transplant recipients [1]. With the widespread use of highly active antiretroviral therapy and effective prophylaxis strategies, the incidence of PJP has markedly decreased among patients with HIV, with mortality rates now < 10% [2]. However, the number of PJP cases in non‐HIV immunocompromised patients, particularly organ transplant recipients, has exhibited a steady increase [3]. Among non‐HIV patients, kidney transplant recipients are particularly vulnerable, with PJP typically occurring at ~6 months post‐transplantation. The management of this disease is challenging in this population, and the treatment duration for moderate and severe cases is often prolonged. The present study describes the clinical case and treatment of a patient with severe refractory PJP following renal transplantation. The case described herein may provide a potential therapeutic approach for the management of PJP in renal transplant recipients.

2. Case History/Examination

A 48‐year‐old female patient was admitted to the Zhongnan Hospital of Wuhan University with a 1‐week history of chest tightness and asthma. The patient had undergone renal transplantation 6 months prior and was on ongoing immunosuppressive therapy. Upon admission, the patient presented with shortness of breath and fever, with a recorded temperature of 39.5°C. Her heart rate was 92 beats per minute, and her blood pressure was stable at 120/70 mmHg. The respiratory rate of the patient at rest was elevated at 23 breaths per minute, and her peripheral oxygen saturation was notably low, at 89% in room air. Auscultation revealed vesicular breath sounds over both lung fields. Arterial blood gas analysis revealed marked hypoxemia, with a partial pressure of oxygen of 55 mmHg, a reduced partial pressure of carbon dioxide of 30 mmHg, and a slightly alkalotic pH of 7.47. A chest computed tomography (CT) scan revealed diffuse bilateral ground‐glass opacities (Figure 1A).

FIGURE 1.

CT scan of the chest. (A) Upon admission, an axial CT scan of the chest revealed diffuse bilateral ground‐glass opacities, indicative of alveolitis associated with Pneumocystis jirovecii pneumonia. (B) At 1 day following transfer to the ICU, the ground‐glass opacities in the lung were notably aggravated. (C) At 8 days following transfer to the ICU, the further progression of the ground‐glass opacities was observed. (D) At 15 days following transfer to the ICU, persistent and extensive ground‐glass opacities were evident. (E) At 20 days following transfer to the ICU, the ground‐glass opacities exhibited additional worsening. (F) At 28 days following transfer to the ICU, the diffuse ground‐glass opacities remained prominent, reflecting the refractory nature of the infection. CT, computed tomography; ICU, intensive care unit.

3. Differential Diagnosis, Investigations and Treatment

Clinical evaluation strongly suggested PJP, prompting immediate antimicrobial therapy with intravenous caspofungin (70 mg loading dose followed by 50 mg maintenance dosing) combined with high‐dose sulfamethoxazole/trimethoprim (TMP 16 mg/kg/day and SMX 80 mg/kg/day in divided doses every 6 h). However, the patient's respiratory status deteriorated rapidly within 48 h, requiring ICU admission for non‐invasive ventilatory support and renal replacement therapy. Following transfer to the ICU, routine blood tests revealed severe leucopenia and agranulocytosis, with the leukocyte count decreasing to a critically low level of 0.01 × 10⁹/L. Immunological profiling revealed a marked reduction in the numbers of circulating CD4⁺ T‐lymphocytes (32/μL, 39%) and CD8⁺ T‐lymphocytes (28/μL, 34%), resulting in a CD4:CD8 ratio of 1.16 (normal range, 1.2–2.7). Additionally, a positive PJP DNA screening test confirmed the diagnosis. A repeat chest CT scan 1 day following admission to the ICU revealed worsening bilateral ground‐glass opacities (Figure 1B). Consequently, the treatment regimen comprised of caspofungin combined with TMP/SMZ was continued. Adjunctive glucocorticosteroid therapy with methylprednisolone was initiated at a dose of 40 mg administered intravenously twice daily, which was later tapered to a total daily dose of 60 mg after 1 week. To maintain adequate oxygenation, high‐flow nasal cannula oxygenation and non‐invasive mechanical ventilation were implemented. As the patient could not tolerate non‐invasive mechanical ventilation, invasive mechanical ventilation via tracheal intubation was initiated, with an inhaled oxygen fraction > 60% and persistent high respiratory drive despite sedation and analgesia. Despite these aggressive interventions, the respiratory condition of the patient did not exhibit any improvement. Subsequent chest CT scans revealed the further deterioration of bilateral ground‐glass opacities (Figure 1C,D), underscoring the refractory nature of the condition. At 1 week following tracheal intubation, a tracheotomy was performed to reduce the application of sedation and analgesia, thereby minimizing the associated side effects. A fiberoptic bronchoscopy revealed hyperemia with minimal airway secretions. Alveolar lavage specimens were collected for second‐generation gene sequencing to investigate potential pathogens; however, no notable findings were detected. Given the severe agranulocytosis of the patient, prophylactic antibiotics were administered. Despite these measures, the fifth chest CT scan revealed the further progression of lung involvement (Figure 1E), and diffuse changes persisted on a chest X‐ray (Figure 1F). Encouragingly, at 27 days following admission to the ICU, the respiratory condition of the patient began to improve. After 1 week, she was successfully weaned from the ventilator intermittently, and a follow‐up chest CT scan demonstrated the marked resolution of the previously noted abnormalities (Figure 2).

FIGURE 2.

Chest computed tomography scan performed at 37 days following transfer to the intensive care unit. (A) Pneumothorax and indwelling thoracic closed drainage tube and (B) marked improvement in the ground‐glass opacities was observed in both lungs.

4. Outcome and Follow‐Up

Following a total treatment duration of 48 days, the PJP nucleic acid test yielded negative results for the first time, marking a critical milestone in her recovery. Then the patient was transferred to a general ward after 1 week and discharged for continued recovery at home. Due to persistent CD4⁺ T‐cell counts below 200 cells/μL, we subsequently reduced TMP/SMX to standard prophylactic dosing (TMP 160 mg/day plus SMX 800 mg once daily) for secondary prophylaxis in immunocompromised patients, which will be maintained until CD4⁺ T‐cells recover above 200 cells/μL for at least 3 months. A comprehensive timeline flowchart is created to summarize the patient's clinical course and therapeutic interventions as Figure 3.

FIGURE 3.

A comprehensive timeline flowchart summarizing the patient's clinical course and therapeutic interventions.

5. Discussion

5.1. Epidemiology, Clinical Significance and Pathogenesis of PJP

Over the past decades, the incidence of PJP has exhibited a significant increase. Especially, PJP occurs in ~75% of individuals with AIDS, with mortality rates reaching up to 40% [4]. Following the widespread adoption of anti‐retroviral therapy, there has been a notable increase in the diagnosis of PJP among non‐HIV‐infected immunocompromised patients, indicating new challenges in the diagnosis, treatment, and prophylaxis for this expanding susceptible population [5, 6, 7]. Pneumocystis is an extracellular organism with a strong tropism for the lung and primarily inhabits alveolar spaces [8]. P. jirovecii is the leading cause of lethal pneumonia in immunocompromised patients, particularly in patients with impaired CD4⁺ T‐cell function, where the organism proliferates in alveolar spaces, leading to fatal infection. The inflammatory response in PJP is driven by key immune cells, inducing CD4⁺ T‐cells, alveolar macrophages, and neutrophils. Advanced stages of infection are characterized by the degeneration of type 1 pneumocytes, the hyperplasia of type 2 pneumocytes, and the disruption of the alveolar–capillary barrier, ultimately resulting in impaired gas exchange and respiratory failure [9]. These sequential changes result in abnormal serological profiles, offering potential diagnostic clues for the disease (Table 1).

TABLE 1.

Laboratory markers of PJP.

Laboratory markers	Clinical significance
(1–3)‐β‐d‐glucan (BDG)	A major component of the Pneumocystis cyst wall One of the effective diagnostic methods for PJP, characterized by a high negative predictive value
Surface glycoprotein (e.g., Msg, gpA)	A key component of the Pneumocystis cell wall Healthy individuals may carry Pneumocystis asymptomatically, leading to false‐positive antibody results Establishing baseline antibody levels in high‐risk populations and monitoring dynamic changes is more meaningful for diagnosis
Lactate dehydrogenase (LDH)	Elevated LDH supports PJP diagnosis, especially in HIV‐infected patients LDH rises significantly during rapid disease progression and declines with effective treatment, reflecting the severity of pulmonary inflammation and lung injury Correlates with impaired oxygenation (e.g., decreased PaO2) Limitation: Non‐specific; limited predictive value alone
S‐adenosylmethionine (SAM)	A potential biomarker for PJP HIV patients with PJP often exhibit low SAM levels, possibly due to Pneumocystis lacking SAM synthase
Krebs von den Lungen‐6 (KL‐6)	A mucin‐like glycoprotein expressed by type II alveolar epithelial cells Elevated in PJP‐induced lung injury, serving as an auxiliary diagnostic marker

5.2. Current Progress in Treatment Strategies for PJP

For the treatment of acute PJP, the first‐line therapy is TMP/SMX, administered at a dose of TMP (15–20 mg/kg/day) and SMX (75–100 mg/kg/day), divided into doses administered every 6–8 h for 21 days. Alternative therapeutic regimens for mild to moderate or moderate to severe diseases include combinations, such as dapsone + TMP, clindamycin + primaquine, atovaquone, pentamidine, and caspofungin (either alone or in combination with TMP/SMX). Notably, all patients with documented or suspected moderate to severe PJP should receive adjunctive corticosteroids as early as possible, and specific PJP therapy should be initiated within 72 h of diagnosis [3]. The management strategies for PJP according to disease severity are summarized in Table 2 [10, 11].

TABLE 2.

Treatment progression for PJP.

Classification of PJP		Treatment of PJP
Classification	Clinical manifestation	Treatment regiments	Dosage	Duration (days)
Mild PJP	Dysnoea on exertion PaO2 of > 80 mmHg SaO2 > 96% Normal/minimal changes on CXR	Frontline	TMP/SMX: TMP 15–20 mg and SMX 75–100 mg/kg/day (divided every 6 or 8 h) p.o.	21
		Additional treatment
		Second line	Dapsone + TMP: Dapsone 100 mg daily + TMP 15 mg/kg/day (three divided doses) Clindamycin + primaquine: Clindamycin (i.v. 600 mg every 6 h or 800 mg every 8 h; p.o. 450 mg every 6 h or 600 mg every 8 h) + primaquine 30 mg (base) once daily	21
Moderate PJP	Dysnoea on minimal exertion/possibly PaO2 60–80 mmHg SaO2 of 91%–96% Diffuse interstitial changes on CXR	Frontline	TMP/SMX: TMP 15–20 mg and SMX 75–100 mg/kg/day (divided every 6 or 8 h) p.o.	21
		Additional treatment	Prednisone: Days 1–5: 40 mg b.i.d.; Days 6–10: 40 mg daily; Days 11–21: 20 mg daily	21
		Second line	Dapsone + TMP: Dapsone 100 mg daily + TMP 15 mg/kg/day (three divided doses) Clindamycin + primaquine: Clindamycin (i.v. 600 mg every 6 h or 800 mg every 8 h; p.o. 450 mg every 6 h or 600 mg every 8 h) + primaquine 30 mg (base) once daily Pentamidine: 4 mg/kg once daily (infused over ≥ 60 min); may reduce to 3 mg/kg if toxicity occurs	21
Severe PJP	Dysnoea at rest PaO2 < 60 mmHg SaO2 < 91% Extensive interstitial changes with potential diffuse alveolar shadowing on CXR	Frontline	TMP/SMX: TMP 15–20 mg and SMX 75–100 mg/kg/day (divided every 6 or 8 h), start i.v. and switch to p.o. after clinical improvement	21
		Additional treatment	Prednisone: Days 1–5: 40 mg b.i.d.; Days 6–10: 40 mg daily; Days 11–21: 20 mg daily	21
		Second line	Pentamidine: 4 mg/kg once daily (infused over ≥ 60 min); may reduce to 3 mg/kg if toxicity occurs Caspofungin (±TMP/SMX): 70 mg on Day 1, then 50 mg daily starting day 2	21

Abbreviations: b.i.d., twice daily; CXR, chest radiograph; i.v., intravenous; p.o., per os (oral); PaO₂, partial pressure of oxygen in blood; SaO₂, oxygen saturation; t.i.d., three times daily.

In HIV‐infected patients, PJP is characterized by a more acute onset of symptoms, rapid disease progression, poorer clinical outcome, higher mortality rates, and an increased risk of developing co‐infections [12]. Therefore, extending the treatment duration is often necessary; in severe cases, combination therapy with caspofungin and TMP/SMZ has been employed. For patients with HIV who fail to respond to initial treatment, several traditional salvage regimens, such as the combined use of clindamycin and primaquine (42–44/48 [88%–92%]) or atovaquone (4/5 [80%]) have demonstrated significant therapeutic efficacy [13]. However, the efficacy of these traditional salvage regimens in non‐HIV patients with PJP remains limited.

5.3. Combination Therapy With Caspofungin and TMP/SMX in Non‐HIV Patients With PJP

Recent research has underscored the therapeutic potential of caspofungin in non‐HIV patients with PJP, demonstrating that echinocandins, administered as a 70 mg loading dose followed by 50 mg daily, represent an effective salvage therapy. This regimen has exhibited favorable and comparable mortality rates in non‐HIV patients relative to conventional salvage therapies, positioning echinocandin‐based treatment as a promising option for managing PJP in this population [14]. Furthermore, a previous retrospective study evaluating the efficacy of combination therapy with caspofungin and TMP/SMZ in non‐HIV patients with moderate to severe PJP revealed that satisfactory clinical responses were achieved, particularly in those with an initial (1,3)‐β‐d‐glucan concentration ≥ 800 pg/mL [15]. These findings reinforce the utility of caspofungin combined with TMP/SMZ as a robust therapeutic strategy for this challenging patient cohort.

5.4. Mechanisms of Caspofungin in Enhancing the Efficacy of TMP/SMZ in Non‐HIV Patients With Refractory PJP

Does initial combination therapy with caspofungin and TMP/SMZ demonstrate superior efficacy and comparable safety versus TMP/SMZ monotherapy or salvage regimens in non‐HIV patients with severe PJP? A recent study involving 93 non‐HIV‐infected patients with severe PJP demonstrated that the initial combination therapy of caspofungin plus TMP/SMX achieved significantly higher response rates (76.74%) compared to monotherapy and salvage therapy groups (p = 0.001), with notably lower 90‐day all‐cause mortality (39.53%) than the salvage therapy group (65.51%, p = 0.024) [16]. Another study of 38 non‐HIV PJP patients demonstrated that triple therapy (SMX‐TMP plus caspofungin and glucocorticoids) achieved significantly higher clinical response rates (100% vs. 66.7%, p = 0.005), lower adverse events (15% vs. 50%, p = 0.022), and shorter fever duration (7 days vs. 11.5 days, p = 0.029) compared to monotherapy [17]. These findings suggest this synergistic regimen offers superior efficacy and safety for severe non‐HIV‐associated PJP. Caspofungin enhances the efficacy of TMP/SMZ in non‐HIV patients with refractory PJP through multiple mechanisms, including cell wall disruption, synergistic action, modulation of inflammation, and targeting of trophic forms. These combined effects render caspofungin a valuable adjunct therapy in the management of refractory PJP, particularly in immunocompromised populations, such as renal transplant recipients. Caspofungin disrupts the pneumocystis cell wall by inhibiting β‐(1,3)‐d‐glucan synthesis, thereby weakening the organism and enhancing the penetration of TMP/SMZ [15]. This cell wall disruption synergizes with the inhibition of folate synthesis by TMP/SMZ, creating a dual mechanism that significantly promotes the eradication of the infection [8]. Additionally, caspofungin modulates the immune response by reducing the release of pro‐inflammatory cytokines, such as IL‐6 and TNF‐α, which helps limit tissue damage and improve clinical outcomes. Caspofungin also specifically targets the metabolically active trophic forms of pneumocystis, reducing the overall infection burden and further enhancing the efficacy of TMP/SMZ. Its unique mechanism of action may help overcome resistance to TMP/SMZ, which is often caused by mutations in the pneumocystis dihydropteroate synthase gene. By reducing both the fungal burden and inflammation, caspofungin creates a more favorable environment for immune recovery, facilitating infection clearance. Furthermore, its long half‐life and sustained activity support prolonged treatment, a critical factor in managing refractory PJP in immunocompromised patients.

5.5. Case Study: Caspofungin in a Non‐HIV Renal Transplant Recipient

The present study describes the use of caspofungin combined with TMP/SMZ in a non‐HIV patient with intractable acute Pneumocystis jirovecii pneumonia following renal transplantation. The guidelines recommend a standard treatment course of 3 weeks for PJP. Nevertheless, should the infection persist with no clinical improvement following this therapeutic course, the evidence‐based pathway for subsequent intervention remains to be established. This raises critical questions about whether to extend the treatment duration, switch to alternative therapies, or intensify supportive care measures. Such clinical scenarios demand meticulous risk–benefit analysis when considering extended therapies. This evaluation proves particularly crucial for immunocompromised hosts, including renal transplant recipients. Drug toxicity profiles, secondary infection risks, and the overall immune status of the patient play a critical role in therapeutic decision. There are limited reports available for reference, and cases documenting the long‐term treatment of PJP are limited, likely due to the tendency to discontinue treatment if no improvement is observed after the standard 3‐week course. Given that extending the treatment duration constitutes a deviation from clinical guidelines and may raise ethical concerns, the authors formally documented this case with both the Hospital Medical Administration Department and the Ethics Committee. Following comprehensive discussions with the patient and family members, written informed consent was obtained for the modified treatment protocol. Therefore, the authors opted to extend the treatment duration to 4–5 weeks, which ultimately led to symptom relief and the marked improvement in imaging findings. By the seventh week, the PJP nucleic acid test yielded negative results, marking a significant milestone in the recovery of the patient. In conclusion, when standard treatment with the conventional course fails to achieve satisfactory efficacy in patients with PJP, extending the treatment duration may lead to therapeutic success. The extremely low absolute lymphocyte count of the patient following various treatments may have contributed to the prolonged clearance time of PJP.

This case provides valuable insights into the management of refractory PJP in non‐HIV immunocompromised patients, particularly renal transplant recipients, and offers several key implications for future treatment strategies: (1) Standard 21‐day therapy may be insufficient, as this patient only responded after 48 days of caspofungin/TMP‐SMX combination therapy; (2) caspofungin demonstrates salvage value through its complementary cell wall‐targeting mechanism; (3) early corticosteroid intervention improves oxygenation; (4) serial β‐d‐glucan monitoring and CT imaging are essential for treatment guidance; (5) CD4⁺ count‐directed individualized regimens are crucial; and (6) advanced respiratory support forms the therapeutic foundation. These findings underscore the necessity for prolonged combination therapy in refractory PJP while highlighting the need for further validation studies. It should be noted that the ethical considerations for prolonged caspofungin/TMP‐SMX combination therapy in refractory Pneumocystis pneumonia (PJP) involve careful balancing of multiple factors. Guided by the principle of beneficence, this experimental regimen may be life‐saving when standard treatments fail, particularly for immunocompromised patients at high mortality risk. Concurrently, the principle of non‐maleficence requires rigorous monitoring for adverse effects like hepatorenal toxicity. Implementation prerequisites include obtaining fully informed consent, conducting individualized risk–benefit assessments, and establishing multidisciplinary monitoring protocols. While potential risks include cumulative toxicity and drug resistance, this approach maintains ethical justification for select refractory cases when strictly regulated, though further research is needed to optimize treatment protocols.

5.6. Limitations and Future Directions

While the findings of the present study highlight the potential efficacy of caspofungin combined with TMP/SMZ in treating refractory PJP in non‐HIV renal transplant recipients, several limitations should be acknowledged. Firstly, the analysis was based on a single case report, which limits the generalizability of the results. The unique clinical characteristics and immune status of the patient may not be representative of the broader population of non‐HIV immunocompromised patients with PJP. Additionally, the absence of a control group or comparative data from standard treatment protocols restricts the ability to draw definitive conclusions about the superiority of this combination therapy.

To address these limitations, future research is required to focus on well‐designed randomized controlled trials with larger sample sizes to validate the efficacy and safety of caspofungin combined with TMP/SMZ in refractory PJP. Such studies should include diverse patient populations, particularly non‐HIV immunocompromised individuals, to assess the broader applicability of this treatment strategy. Furthermore, investigations into the optimal duration of therapy, dosing regimens, and the role of biomarkers, such as (1,3)‐β‐d‐glucan in guiding treatment decisions, are warranted.

In addition to clinical trials, mechanistic studies exploring the synergistic effects of caspofungin and TMP/SMZ at the molecular level could provide deeper insight into their combined effects against P. jirovecii. Long‐term follow‐up studies are also required to evaluate the potential for relapse, drug resistance, and late complications associated with prolonged treatment.

By addressing these limitations and pursuing these research avenues, the medical community can develop more robust evidence‐based guidelines for the management of refractory PJP in non‐HIV patients; ultimately improving outcomes for this vulnerable population.

Author Contributions

Hongtao Hu: writing – original draft. Shen Xu: writing – review and editing. Wen Jiang: data curation. Baoping Xu: formal analysis. Jing Wang: resources, supervision. Gang Xu: supervision.

Disclosure

The authors have nothing to report.

Consent

Written informed consent was obtained from the patient for the publication of this case report and the accompanying images.

Conflicts of Interest

The authors declare no conflicts of interest.

Hu H., Xu S., Jiang W., Xu B., Wang J., and Xu G., “Caspofungin Combined With TMP/SMZ in Treatment of Intractable Acute Pneumocystis jirovecii Pneumonia in Renal Transplant Recipients: Case Report and Literature Review,” Clinical Case Reports 13, no. 8 (2025): e70819, 10.1002/ccr3.70819.

Data Availability Statement

The data generated in the present study may be requested from the corresponding author.