Echinocandins in PCP

Case Vignette

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.

Discussion

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 based^1-2. 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.

References

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