Echinocandins in PCP
A forty-five-year-old man status post heart transplant three years ago was hospitalized with worsening dyspnea for two days. Lung imaging revealed widespread ground glass opacities in the upper lobes bilaterally. Pneumocystis jiroveci pneumonia (PCP) was suspected, and trimethoprim-sulfamethoxazole (TMP/SMX) was initiated at 20mg/kg/day intravenously. PCP diagnosis was confirmed on Day 2 of hospitalization by metagenomic sequencing. The patient continued to worsen and was transferred to the ICU on day 3. Caspofungin combination therapy was added at 100mg loading dose, followed by 70mg daily.
Although PCP is more common in the HIV population, rates have risen in the non-HIV immunocompromised population due to ongoing immunosuppression from transplant or oncology therapy. HIV patients respond better to treatment, with mortality rates between 5-10%. Mortality rates among the non-HIV (specifically solid organ transplant) population range from 30-50% with the current standard of care regimens, primarily TMP/SMX based1-2. Additional issues related to adverse reactions as high as 26% from TMP/SMX treatment3, also support the pursuit of better treatment options.
Echinocandins have presented an attractive potential option for treating these infections since the cyst wall of PCP contains (1-3)-beta-D-glucan.
Murine model studies have shown increased clearance of PCP when using a combination of caspofungin with TMP/SMX versus TMP/SMX alone4. Authors were cautious to note that caspofungin is anticipated to only be active against the cystic form of Pneumocystis, thus requiring an active medication like TMP/SMX to be administered concurrently for trophic forms of the disease.
Reports in humans have been limited to case series and retrospective chart reviews. Results regarding efficacy in this population have been equivocal.
Kamboj et al. reported on two patients who received echinocandin therapy. One patient began echinocandin nine days after starting TMP/SMX. The other patient received echinocandin therapy early due to initial suspicion of aspergillus. Intravenous pentamidine was added on day nine after confirmation of PCP—both patients died5.
In another study, four patients received caspofungin as salvage therapy6. Caspofungin was added to a patient’s regimens from 6-23 days post initiation of TMP/SMX therapy. Three of the four patients expired. Authors note this was a lower success rate than for other salvage regimens.
Huang et al. described two patients receiving salvage therapy initiated on day eight and day sixteen, respectively, after poor response to standard of care. Both patients improved and survived7.
Twenty-two patients were retrospectively reviewed by Wu et al8. Patients were initiated on TMP/SMX and caspofungin at the time of diagnosis. All patients in the review improved.
Eleven patients with severe PCP were analyzed, and five received combination therapy with an echinocandin. 2/6 in the SOC (five received TMP-SMX alone, and one patient received primaquine and clindamycin) group expired vs. 1/5 in the combination group9.
Hui et al. reported on 104 non-infected patients with confirmed PCP. These patients were divided into three groups: TMP/SMX monotherapy, TMP/SMX/echinocandin initial therapy, and TMP/SMX followed by echinocandin salvage therapy. While there were many confounding factors, the cohorts were matched at baseline. Initial treatment with an echinocandin matched with TMP/SMX showed the best overall response rate compared to the other two groups10.
Lastly, a group explored whether using beta-d-glucan (BDG) concentrations could better predict which patients would respond to combination therapy with an echinocandin. Patients were stratified based on BDG level. Patients with BDG over 800 pg/ml and on combination therapy with caspofungin and TMP/SMX had significantly lower mortality rates than monotherapy with TMP/SMX. This effect was not seen in patients with lower BDG levels11.
The high mortality rates of PCP and poor tolerance of standard therapy with TMP/SMX highlight a need for better therapeutic options. Although not a panacea, echinocandins can safely be considered as an additional therapy. More robust studies for this condition are needed.
Timing of echinocandin therapy and consideration of patient BDG levels may provide better predictors of which patients may benefit.
- Mansharamani, N. G., Garland, R., Delaney, D., & Koziel, H. (2000). Management and outcome patterns for adult Pneumocystis carinii pneumonia, 1985 to 1995: Comparison of HIV-associated cases to other immunocompromised states. In Chest (Vol. 118, Issue 3, pp. 704–711). Elsevier Inc. https://doi.org/10.1378/chest.118.3.704
- Boonsarngsuk, V., Sirilak, S., & Kiatboonsri, S. (2009). Acute respiratory failure due to Pneumocystis pneumonia: outcome and prognostic factors. In International journal of infectious diseases (Vol. 13, Issue 1, pp. 59–66). Elsevier Ltd. https://doi.org/10.1016/j.ijid.2008.03.027
- Helweg-Larsen, J., Benfield, T., Atzori, C., & Miller, R. F. (2009). Clinical efficacy of first- and second-line treatments for HIV-associated Pneumocystis jirovecii pneumonia: a tri-centre cohort study. The Journal of Antimicrobial Chemotherapy, 64(6), 1282–1290. https://doi.org/10.1093/jac/dkp372
- Lobo, M. L., Esteves, F., de Sousa, B., Cardoso, F., Cushion, M. T., Antunes, F., & Matos, O. (2013). Therapeutic potential of caspofungin combined with trimethoprim-sulfamethoxazole for pneumocystis pneumonia: a pilot study in mice. PloS One, 8(8), e70619. https://doi.org/10.1371/journal.pone.0070619
- Kamboj, M., Weinstock, D., & Sepkowitz, K. A. (2006). Progression of Pneumocystis jiroveci pneumonia in patients receiving echinocandin therapy. Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America, 43(9), e92-4. https://doi.org/10.1086/508282
- Kim, T., Hong, H.-L., Lee, Y.-M., Sung, H., Kim, S.-H., Choi, S.-H., Kim, Y. S., Woo, J. H., & Lee, S.-O. (2013). 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. Scandinavian Journal of Infectious Diseases, 45(6), 484–488. https://doi.org/10.3109/00365548.2012.760842
- Huang, H.-B., Peng, J.-M., & Du, B. (2018). Echinocandins for Pneumocystis jirovecii pneumonia in non-HIV patients: A case report. Experimental and Therapeutic Medicine, 16(4), 3227–3232. https://doi.org/10.3892/etm.2018.6587
- Wu, H.-H., Fang, S.-Y., Chen, Y.-X., & Feng, L.-F. (2022). Treatment of Pneumocystis jirovecii pneumonia in non-human immunodeficiency virus-infected patients using a combination of trimethoprim-sulfamethoxazole and caspofungin. World Journal of Clinical Cases, 10(9), 2743–2750. https://doi.org/10.12998/wjcc.v10.i9.2743
- Lu, Y.-M., Lee, Y.-T., Chang, H.-C., Yang, H.-S., Chang, C.-Y., Huang, C.-M., & Wei, J. (2017). Combination of Echinocandins and Trimethoprim/Sulfamethoxazole for the Treatment of Pneumocystis jiroveci Pneumonia After Heart Transplantation. Transplantation Proceedings, 49(8), 1893–1898. https://doi.org/10.1016/j.transproceed.2017.04.020
- Qi, H., Dong, D., Liu, N., Xu, Y., Qi, M., & Gu, Q. (2023). Efficacy of initial caspofungin plus trimethoprim/sulfamethoxazole for severe PCP in patients without human immunodeficiency virus infection. BMC Infectious Diseases, 23(1), 409. https://doi.org/10.1186/s12879-023-08372-z
- Jin, F., Liu, X.-H., Chen, W.-C., Fan, Z.-L., & Wang, H.-L. (2019). High initial (1, 3) Beta-d-Glucan concentration may be a predictor of satisfactory response of caspofungin combined with TMP/SMZ for HIV-negative patients with moderate to severe Pneumocystis jirovecii pneumonia. International Journal of Infectious Diseases: IJID: Official Publication of the International Society for Infectious Diseases, 88, 141–148. https://doi.org/10.1016/j.ijid.2019.08.015