Successful treatment with echinocandin in an HIV-infected individual failing first-line therapy for Pneumocystis jirovecii pneumonia (2011)

In August 2010, a 39-year-old man was admitted to our hospital with acute respiratory failure that required prompt mechanical ventilation. A computed tomography scan showed extensive bilateral ground glass opacities and signs of destruction of subpleural parenchyma at the apex (Fig. 1a). The patient had a positive HIV ELISA test, a CD4 count of 4 cell/μl, and an HIV viral load of 1 140 000 copies/ml. Ceftriaxone, levofloxacin and trimethoprim-sulfamethoxazole were initiated. Broncheoalveolar lavage was diagnostic for Pneumocystis jirovecii, both immunofluorescence and PCR. On day 6 after admission, clindamycin was added to trimethoprim-sulfamethoxazole. The patient evolved in worsening conditions, requiring change to high frequency oscillatory mechanical ventilation. On day 12, imipenem and vancomycin were added but no concurrent infection was detected despite frequent blood and bacterial tracheal aspirate cultures. His condition worsened by a bilateral spontaneous pneumothorax (Fig. 1b). After 28 days, the patient continued with fever and severe respiratory failure. A new bronchoscopy showed persistent positive P. jirovecii immunofluorescence and PCR. Intravenous pentamidin was not available at the time at our center; therefore, caspofungin was added to trimethoprim-sulfamethoxazole, and clindamycin was stopped. After 3 days of caspofungin initiation, the patient became afebrile, respiratory parameters improved and inflammatory markers started to decrease. Immunofluorescence and PCR for P. jirovecii were again performed on a tracheal aspirate resulting now negatives. The patient was successfully extubated after 60 days of mechanical ventilation and discharged from hospital in good condition.Fig. 1: Computed tomography chest scan.(a) On admission; (b) On day 25.DNA was extracted from bronqueoloalveolar lavage fluid performed on admission. In order to search for dihydropteroate synthase (DHPS) mutations, the DHPS gene was amplified as described [1]. Both strands were sequenced using BigDye Terminator v3.1 Cycle Sequencing Kit in an ABI Prism 310 DNA Sequencer (Applied Biosystems, Foster City, California, USA). The DHPS gene sequence of the patient's isolate resulted identical to wild-type DHPS gene. The overall prognosis of patients developing P. jirovecii pneumonia (PCP), whose degree of hypoxemia requires intensive care, remains poor, with mortality up to 50% in patients requiring ventilatory support [2]. Several studies have reported the association between exposure to sulfa drugs and substitutions of two amino acids within the putative sulfa-binding site of DHPS, at positions 55 (threonine to alanine) and 57 (proline to serine) [3,4]. However, whether Pneumocystis DHPS gene mutations confer clinical resistance to trimethoprim-sulfamethoxazole, remains unclear [3]. Second-line recommended drugs are intravenous pentamidine or clindamycin and primaquine. Pentamidine has shown efficacy comparable to trimethoprim-sulfamethoxazole, although it has several toxicities and is not usually available outside developed countries [5]. Echinocandins are active against a wide variety of fungi in vitro and in vivo, and although they are well tolerated and have minimal drug–drug interactions, they are not currently approved for treating PCP. The cysts of P. jirovecii have a wall rich in β-1,3-D glucan, and, although rapid cyst clearence is achieved under echinocandins in animal models, trophozoite forms persist. However, recently enhanced survival was shown in echinocandin-treated mice, together with significant reductions of cyst numbers in lungs and remodeling of Pneumocystis morphology [6]. Whether this finding will translate into a reduction of progression and morbidity in humans is not known [7]. Clinical experience with echinocandins in the treatment of human PCP is scarce. Successful caspofungin administration for PCP (alone or in combination with trimethoprim-sulfamethoxazole) has been described in six case reports, all non-HIV individuals: two cases of leukemia [8,9], one case of bone marrow transplant [10], four cases of solid organ transplant [11], one case of Wegener's disease [12], and one case in an elderly patient [13]. There is only one report of unfavorable outcome in two oncohematological patients in whom deaths were presumed as being secondary to progressive PCP despite echinocandin addition [14]. In HIV-infected patients, there are no published reports with the exception of a poster abstract presentation [15]. In this abstract report, five patients with advanced HIV infection and severe PCP, were initially treated with intravenous trimethoprim-sulfamethoxazole. Four of them received caspofungin as a second or third-line therapy in combination with other agents, and one as a single-agent fourth-line therapy. All recovered successfully. Not infrequently, we have to deal with patients developing PCP that fail conventional therapy. Administration of an echinocandin with trimethoprim-sulfamethoxazole could provide benefits by decreasing the inflammatory responses associated with β-1,3-glucan and facilitating the clearance of the infection [6]. We report the first case of clinical and microbiological cure with caspofungin as a rescue therapy in an HIV patient with severe PCP, unresponsive to trimethoprim-sulfamethoxazole and clindamycin, with no proved sulfa resistance. Echinocandins should be considered as an alternative for cases of severe PCP unresponsive to first-line therapy. Acknowledgements We thank Professor Julio Ramirez, MD, from University of Louisville, for his valuable comments on the manuscript. Conflicts of interest All authors declare that there are no conflicts of interest. No funding was received.