Salvage treatment of Pneumocystis jirovecii pneumonia with micafungin and clindamycin: a case report

Introduction

Pneumocystis jirovecii (PJ) is an opportunistic fungal pathogen with a biphasic life cycle that can cause severe pneumonia in immunocompromised hosts including patients with human immunodeficiency virus (HIV) and non-HIV (malignancies, solid organ transplant, and chronic inflammatory diseases) (1). Pneumocystis jirovecii pneumonia (PJP) can be fatal and is associated with complications including acute respiratory distress syndrome and chronic decrease in pulmonary function (2). Patients with non-HIV PJP often have more severe disease leading to mortality rates of up to 75.6% for those admitted to the intensive care unit (1).

The first-line treatment of PJP is trimethoprim/sulfamethoxazole (TMP/SMX) 15 to 20 mg/kg/day intravenous (IV) or oral (PO) based on the TMP component (3,4). This dose is associated with high rates of adverse effects such as hyperkalemia, cytopenias, rash, and renal dysfunction. Tritle et al. reported a frequency of 30.8% of adverse effects with conventional dosing (>15 mg/kg/day). While dose reduction (<15 mg/kg/day) may reduce the risk for adverse effects (risk ratio =0.7 compared to >15 mg/kg/day), they still can occur with a reported frequency of 7%. These challenges highlight the need for safe and effective alternative treatment options (5).

Second-line treatment options for moderate PJP in order of preference include primaquine and clindamycin followed by dapsone and TMP. For severe disease, alternatives include primaquine and clindamycin followed by intravenous pentamidine. However, these therapies may result in lower efficacy and their use is similarly limited by toxicities (2,3). Echinocandins are well-tolerated antifungals that work by inhibiting synthesis of beta-d-glucan (BDG), a structural polysaccharide within the cell wall of PJ’s cystic form and have been suggested as possible therapeutic alternatives for PJP (6-8). We report a patient who successfully completed PJP treatment with micafungin and clindamycin after developing intolerances to traditional therapies. We present this article in accordance with the CARE reporting checklist (available at https://amj.amegroups.com/article/view/10.21037/amj-23-131/rc).

Case presentation (Table 1)

A 76-year-old Caucasian male weighing 81 kilograms with granulomatosis with polyangiitis was initiated on prednisone 30 mg PO daily and rituximab six weeks prior to admission. Atovaquone 1,500 mg PO daily was initiated two weeks prior to admission for PJP prophylaxis. He presented on the day of admission (D1) with dyspnea on exertion and an oxygen saturation of 96% on room air. He was afebrile with a blood pressure of 124/56 mmHg, heart rate of 70 beats/minute, and respiratory rate of eighteen breaths/minute. Notable laboratory findings included a serum creatinine (SCr) of 2.9 mg/dL (baseline 2.4 mg/dL) and a white blood cell count (WBC) of 13.9×10⁹/L. His chest X-ray and computed tomography (CT) chest scan on D1 demonstrated diffuse bilateral ground glass opacities with consolidated areas in the bilateral lung base (Figure 1). A point-of-care SARS-CoV2 nasal swab was negative, and a serum BDG assay was collected.

Figure 1 The computed tomography chest scan on the day of admission shows diffuse bilateral ground glass opacities with consolidated areas in the bilateral lung base.

On D2, his dyspnea worsened at rest, and he was placed on 1 L/min by nasal cannula (NC). The primary team consulted infectious diseases. On D4, he underwent bronchoscopy with bronchoalveolar lavage (BAL). On D5, the patient’s serum BDG returned as >500 pg/mL, and his oxygen requirements increased to 3 L/min NC. He was started on TMP/SMX 5 mg/kg/dose every twelve hours (two double-strength tablets PO twice daily), which was a renally-adjusted dose. His Pneumocystis polymerase chain reaction (PCR) from the BAL was positive.

On D8, the patient’s oxygen requirement increased to 6 L/min NC. His potassium increased to 5.4 mg/dL, SCr increased to 4.2 mg/dL, blood urea nitrogen (BUN) increased to 89 mg/dL, and urine output decreased to 0.2 mL/kg/h. Due to acute kidney injury (AKI), therapy was transitioned from TMP/SMX to primaquine 30 mg PO daily and clindamycin 900 mg IV every eight hours. He tested negative for glucose-6-phosphate deficiency (G6PD).

Although renal function improved with discontinuation of TMP/SMX, the patient’s oxygen requirement increased over the next several days, resulting in transfer to the intensive care unit and intubation. On D12, venous blood gas revealed a methemoglobin level of 17.4% attributed to primaquine. He was transitioned back to TMP/SMX 5 mg/kg via tube (VT) every twelve hours, and his methemoglobinemia was treated with a single dose of IV methylene blue 1.5 mg/kg. While he initially responded to methylene blue, he subsequently received IV vitamin C 1,500 mg every six hours for six doses for persistently elevated methemoglobin levels.

After re-initiation of TMP/SMX, the patient’s AKI again worsened and continuous renal replacement therapy (CRRT) was started on D15. To avoid further renal injury, he was switched to dapsone 100 mg VT daily and TMP 300 mg VT daily. From D13 to D20, the patient’s methemoglobin levels fluctuated between 8.4% and 11.5% while the patient remained intubated with a stable fraction of inspired oxygen (FiO₂) of 40% and positive end-expiratory pressure (PEEP) of 8 cm H₂O.

Due to persistently elevated methemoglobin levels limiting liberation from mechanical ventilation, dapsone and TMP were discontinued, and combination therapy with micafungin 100 mg IV daily and clindamycin 900 mg IV every eight hours was initiated on D20 (9-11). Over the next several days, methemoglobin levels decreased from 6.5% to 1.3% and he was extubated on D23.

On D26, after six days of micafungin and clindamycin, the patient completed his treatment for PJP. He transitioned to the medical ward on D27 and was discharged home on D36 with atovaquone 1,500 mg PO daily for secondary PJP prophylaxis. He required intermittent hemodialysis and oxygen from hospital discharge through two months post-discharge. Currently, he no longer requires dialysis or oxygen, and he had no recurrence of PJP.

All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration (as revised in 2013). Publication of this case report and accompanying images was waived from patient consent according to the Duke University Hospital ethics committee/institutional review board.

Discussion

Echinocandins, in combination with clindamycin, represent a novel PJP treatment option based on their mechanism of action. PJ is structurally distinct from other fungi in that it lacks ergosterol within its cell membrane. For this reason, PJ cannot be treated with polyenes or azole antifungals (6). With a unique biphasic life cycle, PJ exists in either a trophic or cystic form. The trophic form is the primary form in the alveolar space during an active infection, and the cystic form is primarily responsible for human transmission. Only the cystic form of PJ contains BDG within its cell wall, which is the target for echinocandins. Since echinocandins do not have activity against the trophic form, addition of a traditional treatment option such as TMP/SMX or clindamycin should be considered; however, successful treatment of PJP with echinocandin monotherapy has been reported (9-11).

Treatment guidelines suggest caspofungin monotherapy or in combination with TMP/SMX as an alternative or salvage treatment option for PJP based on retrospective case series and case reports (3,4). Most data on echinocandin therapy for PJP is with caspofungin or anidulafungin. Cushion et al. reported that these two agents reduced cyst burden in mice to a greater extent compared to micafungin, which required higher doses (one mg/kg/day) to show similar reduction in burden compared to the other echinocandins (6). Yang et al. described a successful case of PJP treated with caspofungin 50 mg IV daily and clindamycin 600 mg IV twice daily. They also reviewed 22 other cases of immunocompromised patients with PJP treated with caspofungin monotherapy, or in combination with other agents as either first, second, or third-line therapy. Four patients (18%) failed therapy while the others (82%) fully recovered (9). There were no apparent differences in baseline characteristics between those who failed and those who recovered.

Huang et al. performed a retrospective cohort study of 34 patients with PJP receiving echinocandins either as monotherapy or in combination with TMP/SMX (10). There was no difference in all-cause and PJP-related in-hospital mortality between echinocandin and TMP/SMX combination therapy versus echinocandin monotherapy (16.7% vs. 17.4%, P>0.999). Factors such as severity of illness (70.6% moderate-severe), duration of echinocandin therapy (median twelve days), and specific echinocandin (anidulafungin: 68%, caspofungin 21%, micafungin 11%) did not statistically differ between those who survived and those who did not. Data using micafungin as the echinocandin of choice is limited, and this study only included four patients who received micafungin (10). There have been sixteen case reports describing echinocandin use for treatment in non-HIV patients with PJP (Table 2) (9,11-18). None of these cases utilized micafungin, and most cases either used TMP/SMX (N=12) in combination with echinocandins versus an alternate agent (N=2). Therefore, our case adds to the literature by demonstrating safety and efficacy in a non-HIV patient treated with micafungin and clindamycin.

Specific levels of serum BDG may predict the efficacy of echinocandin therapy. Higher levels of BDG during PJP infection indicate a higher burden of organisms in the cystic phase which is why echinocandins may be effective (6). Jin et al. reviewed 126 patients with PJP who received caspofungin and TMP/SMX or TMP/SMX monotherapy. In patients with a BDG of >800 pg/mL (N=54), three-month mortality was significantly lower in the echinocandin combination therapy group compared to the monotherapy group (20% vs. 56%; P=0.010). Echinocandin combination therapy also had higher rates of positive response in this group (80% vs. 38%, P<0.001) (19). In the case reported by Yang et al., the patient presented with an initial BDG of 984.6 pg/mL (9). Our patient’s BDG was >500 pg/mL (upper limit of detection), which may have been a positive predictor for his response to echinocandin therapy.

The strength of this case report is that it provides a reasonable treatment alternative for completing a course for PJP if intolerances or side effects occur. While this patient did experience a favorable outcome, the main limitation to this report is the risk for confounding factors. Echinocandin therapy may be an effective salvage regimen if patients experience intolerance to first-line agents; however, the optimal duration of therapy has not been studied. The duration of therapy in other reports ranges from four to 24 days, which is based on the timing of intolerance and remaining duration of therapy needed to complete the total course. The patient presented in this case report finished the last six days of his 21-day course for PJP with echinocandin combination therapy due to timing of adverse effects. Given that the patient received fifteen days of therapy with first-line agents, the other agents likely contributed to his positive outcome. However, the patient would not have been able to successfully complete the 21-day course with first-line therapy due to intolerance and side effects from several first-line treatment options.

Conclusions

Echinocandins have a favorable safety profile and may be considered as salvage therapy for PJP after failing or experiencing intolerance to other agents. They should be used in combination with an agent active against the trophic form of PJ in the alveoli. Based on the mechanism of action, echinocandins may be particularly useful in patients with a serum BDG of >500 pg/mL.

Acknowledgments

Funding: None.

Footnote

Reporting Checklist: The authors have completed the CARE reporting checklist. Available at https://amj.amegroups.com/article/view/10.21037/amj-23-131/rc

Peer Review File: Available at https://amj.amegroups.com/article/view/10.21037/amj-23-131/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://amj.amegroups.com/article/view/10.21037/amj-23-131/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration (as revised in 2013). Publication of this case report and accompanying images was waived from patient consent according to the Duke University Hospital ethics committee/institutional review board.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Kanj A, Samhouri B, Abdallah N, et al. Host Factors and Outcomes in Hospitalizations for Pneumocystis Jirovecii Pneumonia in the United States. Mayo Clin Proc 2021;96:400-7. [Crossref] [PubMed]
2. Morris AM, Huang L, Bacchetti P, et al. Permanent declines in pulmonary function following pneumonia in human immunodeficiency virus-infected persons. The Pulmonary Complications of HIV Infection Study Group. Am J Respir Crit Care Med 2000;162:612-6. [Crossref] [PubMed]
3. Cooley L, Dendle C, Wolf J, et al. Consensus guidelines for diagnosis, prophylaxis and management of Pneumocystis jirovecii pneumonia in patients with haematological and solid malignancies, 2014. Intern Med J 2014;44:1350-63. [Crossref] [PubMed]
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:e13587. [Crossref] [PubMed]
5. Tritle BJ, Hejazi AA, Timbrook TT. The effectiveness and safety of low dose trimethoprim-sulfamethoxazole for the treatment of pneumocystis pneumonia: A systematic review and meta-analysis. Transpl Infect Dis 2021;23:e13737. [Crossref] [PubMed]
6. Cushion MT, Linke MJ, Ashbaugh A, et al. Echinocandin treatment of pneumocystis pneumonia in rodent models depletes cysts leaving trophic burdens that cannot transmit the infection. PLoS One 2010;5:e8524. [Crossref] [PubMed]
7. Desoubeaux G, Lemaignen A, Ehrmann S. Scientific rationale for inhaled caspofungin to treat Pneumocystis pneumonia: A therapeutic innovation likely relevant to investigate in a near future…. Int J Infect Dis 2020;95:464-7. [Crossref] [PubMed]
8. Desoubeaux G, Lemaignen A, Alanio A, et al. Re: 'Which trial do we need? Combination treatment of Pneumocystis jirovecii pneumonia in non-HIV infected patients' by Cornely et al. Clin Microbiol Infect 2023;S1198-743X(23)00279-3.
9. Yang DH, Xu Y, Hong L, et al. Efficacy of caspofungin combined with clindamycin for Pneumocystis jirovecii pneumonia in a systemic lupus erythematosus patient: A case report and literature review. Respir Med Case Rep 2019;26:108-11. [Crossref] [PubMed]
10. Huang YS, Liu CE, Lin SP, et al. Echinocandins as alternative treatment for HIV-infected patients with Pneumocystis pneumonia. AIDS 2019;33:1345-51. [Crossref] [PubMed]
11. Huang HB, Peng JM, Du B. Echinocandins for Pneumocystis jirovecii pneumonia in non-HIV patients: A case report. Exp Ther Med 2018;16:3227-32. [Crossref] [PubMed]
12. Li H, Huang H, He H. Successful treatment of severe Pneumocystis pneumonia in an immunosuppressed patient using caspofungin combined with clindamycin: a case report and literature review. BMC Pulm Med 2016;16:144. [Crossref] [PubMed]
13. Kim T, Hong HL, Lee YM, et al. Is caspofungin really an effective treatment for Pneumocystis jirovecii pneumonia in immunocompromised patients without human immunodeficiency virus infection? Experiences at a single center and a literature review. Scand J Infect Dis 2013;45:484-8. [Crossref] [PubMed]
14. Tu GW, Ju MJ, Xu M, et al. Combination of caspofungin and low-dose trimethoprim/sulfamethoxazole for the treatment of severe Pneumocystis jirovecii pneumonia in renal transplant recipients. Nephrology (Carlton) 2013;18:736-42. [Crossref] [PubMed]
15. Jiang XQ, Fang L, Mei XD, et al. Pneumocystis jiroveci pneumonia in patients with non-Hodgkin's lymphoma after Rituximab-containing regimen: two cases of report and literature review. J Thorac Dis 2013;5:E162-6. [PubMed]
16. Mu XD, Que CL, He B, et al. Caspofungin in salvage treatment of severe pneumocystis pneumonia: case report and literature review. Chin Med J (Engl) 2009;122:996-9. [PubMed]
17. Hof H, Schnülle P. Pneumocystis jiroveci pneumonia in a patient with Wegener's granulomatosis treated efficiently with caspofungin. Mycoses 2008;51:65-7. [Crossref] [PubMed]
18. Utili R, Durante-Mangoni E, Basilico C, et al. Efficacy of caspofungin addition to trimethoprim-sulfamethoxazole treatment for severe pneumocystis pneumonia in solid organ transplant recipients. Transplantation 2007;84:685-8. [Crossref] [PubMed]
19. Jin F, Liu XH, Chen WC, et al. High initial (1, 3) Beta-d-Glucan concentration may be a predictor of satisfactory response of c aspofungin combined with TMP/SMZ for HIV-negative patients with moderate to severe Pneumocystis jirovecii pneumonia. Int J Infect Dis 2019;88:141-8. [Crossref] [PubMed]