To the Editors:
We report successful treatment of disseminated Candida albicans infection in a child with a combination of antifungal agents and Mycograb (Neu Tec Pharma Plc, Manchester, U.K.), a human recombinant antibody against Candida heat shock protein 90 (hsp90).
An 8-year-old girl with Down's syndrome and oral phobia underwent placement of a gastrostomy to assist with feeding. Her only significant past medical history was of a persistent ductus arteriosus which had been ligated in infancy.
One week after insertion of the gastrostomy she presented to her local hospital with signs of peritonitis. A laparotomy the next day revealed a leaking gastrostomy, and multiple intra-abdominal abscesses were found. She underwent drainage of the abscesses, gastropexy and tightening of the gastrostomy, and therapy was commenced with intravenous cefuroxime and metronidazole.
She was extubated postoperatively and sent to the ward where during the next 2 days she developed increasing respiratory distress, eventually requiring intubation and ventilation in the pediatric intensive care unit (PICU). She developed acute respiratory distress syndrome and had diffuse bilateral infiltrates and pleural effusions on chest radiograph. She developed septic shock requiring inotropic support. C. albicans and coagulase-negative staphylococci were subsequently isolated from peritoneal fluid taken at laparotomy, and the patient was treated with intravenous fluconazole and vancomycin on day 2 of admission to the PICU. She remained febrile and was difficult to ventilate and oxygenate with a persistent inotrope requirement. C. albicans was isolated in blood taken from an arterial catheter, central venous catheter and peripheral cultures, central venous catheter tip, arterial catheter tip, urine and 2 bronchoalveolar lavage specimens. She had 2 chest computerized tomography scans performed on days 11 and 24 of her PICU stay, both of which showed diffuse bilateral consolidation, atelectasis and effusions. A sonogram on days 13 and 19 of her PICU admission showed mitral valve papillary muscle vegetation; follow-up sonography on day 41 was normal. Inflammatory markers were abnormal intermittently.
Various combinations of antifungal drugs were given: fluconazole (day 2–9) liposomal amphotericin B (day 9–18), flucytosine (day 17–24) and caspofungin (day 19–41). On day 20, Mycograb treatment was started for 7 days (1 mg/kg twice daily intravenously) because the patient was still clinically unstable and difficult to ventilate; this was well-tolerated with no apparent side effects. She was also given corticosteroids for inotrope-refractory shock at this stage. A short synacthen test was performed at this stage to check adrenal steroid responsiveness, the results of which were normal. On day 21, there was clinical improvement, and ventilation was weaned from high frequency oscillation to conventional ventilation. Between days 21 and 25 she continued to improve, with falling inotrope requirement. She received the last dose of Mycograb on day 26. On day 27, a bronchoalveolar lavage specimen was clear of C. albicans. The last positive blood culture for C. albicans was on day 13. She continued to improve clinically and was extubated to face mask ventilation on day 34. On day 45, she was discharged to the ward; on day 58, she was discharged home, fully recovered.
This case is the first reported use of Mycograb in a child with Candida sepsis. In this case, C. albicans was isolated from several sites for several days. Her last positive culture for Candida was on day 13 of admission, but there was no clinical improvement in her systemic inflammatory response until day 21. She received several antifungal agents throughout her illness; therefore it is difficult to attribute her clinical improvement to any one antifungal agent, but progressive clinical improvement began 24 hours after adding Mycograb to caspofungin therapy. At the same time, corticosteroids were introduced for inotrope-refractory shock, however, she had a normal response to a short synacthen test, making the addition of steroids unlikely to have contributed significantly to her recovery. The last sonographic evidence of endocarditis was the day before Mycograb treatment was started.
We did not observe any adverse effects as a result of the Mycograb infusions.
In a double blind, placebo-controlled trial, Mycograb, an inhibitor of hsp90, given for 5 days in combination with liposomal amphotericin B resulted in an improved outcome compared with using liposomal amphotericin B alone in adults with invasive candidiasis.1
Hsp90 has recently been described as a “fungal Achilles' heel,” because the presence of an hsp90 inhibitor reduced fungal resistance to caspofungin or fluconazole in vitro.2 Although it is not possible to attribute the patient's recovery to any single agent, there was steady improvement clinically after the introduction of Mycograb. This is the first reported use of Mycograb in combination with caspofungin to treat a case of refractory candidiasis in a child.
Helen Elizabeth Rowlands, MB, BS, MRCPCH
Kevin Morris, MB, BS, MRCP, MD, FRCPCH
Clive Graham, MB, BS, MRCP, MRCPath
Birmingham Children's Hospital
Birmingham, United Kingdom
1. Pachl J, Svoboda P, Jacobs F, et al. A randomized, blinded, multicenter trial in of lipid-associated amphotericin B alone versus in combination with an antibody-based inhibitor of heat shock protein 90 in patients with invasive candidiasis. Clin Infect Dis
2. Heitman J. A fungal Achilles' heel. Science