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trichosporon species is now emerging as an important life - threatening opportunistic systemic pathogen , especially in leukemia patients
although the optimal antifungal therapy for treatment has yet to be established , voriconazole seems to be preferred as first - line antifungal agent in past decade , according to the promising effect both in clinic and in pre - clinical studies .
however , recently we observed a case of breakthrough t. asahii infection while receiving voriconazole , which calls for an alternative treatment strategy .
an adult with acute erythroleukemia ( aml - m6 ) was admitted for induction chemotherapy including decitabine , idarubicin and cytarabine . during the treatment
, a suspected catheter - associated infection and mucositis occurred consecutively which resulted in the administration of teicoplanin , tinidazole and fluconazole ( 400  mg / d ) sequentially for about 2 weeks . at the first day after chemotherapy ( day+1 ) , the fever developed up to 38.2  c when teicoplanin and fluconazole were still administered .
neither ct scan nor blood culture has positive finding . concerning the risk of serious infection during the immunosuppression period , the antibiotic strategy was empirically modified to piperacillin - tazobactam , vancomycin combined with voriconazole ( 6  mg / kg/12  h for the first day , followed by 4  mg / kg/12  h ) , and the temperature gradually returned to normal within 3 days .
the granulocyte counts fell to lower than 0.510/l at day + 4 . at day + 12
, the temperature rose again up to 39.2  c , while the chest ct scan revealed diffused nodular infiltrates in both of the lungs .
blood culture was performed in both peripheral and central venous catheter samples , and as a pre - emptive treatment , anti - infection regimen was switched to imipenem - cilastatin , linezolid , and liposomal amphotericin b ( liposomal amb ) at a target dose of 3  mg / kg everyday .
blood culture yielded t. asahii in both samples 3 days later ( identification was taken by vitek 2 compact , 94% reliability index ) . during the first 3 days of liposomal amb administration , daily peak temperature remained around 39.0  c , whereas serum creatinine rose from 60.4  mol / l to 199.8  mol / l . due to the progressive renal dysfunction ,
the dose of liposomal amb was reduced to 2  mg / kg at day + 15 . instead ,
caspofungin 50  mg every day ( 70  mg for the first dose ) was combined . meanwhile ,
g - csf was administered at a dose of 300  g / d to accelerate the hematopoietic recovery .
hyperpyrexia was controlled at day + 17 , and finally returned to normal at day + 19 when the neutropenia period ended .
complete remission was achieved as confirmed by bone marrow examination , and renal dysfunction was also gradually recovered later .
the combination anti - fungal therapy continued for 3 weeks , until the previous nodules in chest ct completely disappeared .
blood culture was repeated for several times before the discontinuation of anti - fungal therapy , and all the results were negative .
with voriconazole as secondary prophylaxis , the patient then received subsequent consolidation chemotherapy and an identical - sibling bone marrow transplant in 3 months without any manifestation of invasive fungal infection , which hinted the clearance of t. asahii .
reported risk factors of disseminated t. asahii infection include malignancies , neutropenia , chronic active hepatitis , cystic fibrosis , administration of immunosuppressive agents , use of broad - spectrum antibiotics , and disruption of the skin  mucosa barrier .
the route of invasion includes respiratory tract , gastrointestinal tract , central venous catheter or percutaneous interventional treatment [ 79 ] . in this case , previous infections , neutropenia after chemotherapy , and combined antibiotics might jointly result in subsequent t. asahii invasion , even if antifungal agent had been used .
several studies have demonstrated low sensitivity in vitro of t. asahii to common antifungal agents , and breakthrough trichosporonosis has been reported during the administration of various antifungal agents [ 1013 ] .
the susceptibility to amb is varied , and echinocandins display low activity against trichosporon species .
voriconazole is probably the most sensitive drug against t. asahii in vitro , which has also succeeded in a number of cases , including breakthrough infections [ 4,1417 ] .
however , it has been reported that the correlation between clinical and mycological resistance is poor , and cases of successful treatment with amb or echinocandins alone can be found in literatures when used alone or in combination .
a joint clinical guideline for the diagnosis and management of rare invasive yeast infections was recently published by escmid / ecmm , in which the optimal option to treat trichosporon species has yet been established .
voriconazole , which is the preferred antifungal agent , is recommended in grade b strength , with level iii evidence .
however , this case developed trichosponosis during the treatment of voriconazole , which led physicians into a dilemma .
amb is supposed to be an alternative option but toxicities frequently limit their dose as well as efficacy . with more acquaintance of t. asahii and the development of antifungal agents , combined administration of antifungal agents
attracts more attention for obtaining better clinical results and for reducing the antifungal doses . in vivo and in vitro studies have demonstrated a better synergic effect between amb and echinocandin ( either caspofungin or micafungin ) not only in trichosporon species , but also in candida species , aspergillus species , fusarium species and cryptococcus neoformans 
 .
the probable mechanism of synergy is that echinocandins could enhance the penetration of amb into the cell membrane , causing an increase in the antifungal activity of amb .
firstly used liposomal amb and caspofungin to successfully treat an acute leukemia patient with t. asahii fungaemia .
de vasconcelos and his colleagues cured an invasive t. asahii infection in an acute myeloid patient by amb with caspofungin .
our observation suggested that even with a lower dose , the combination therapy of liposomal amb and caspofungin may synergistically improve the antifungal activity with better tolerance . in patients with voriconazole - breakthrough trichosporonosis who can not tolerate standard - dose amb
renal dysfunction is a frequently observed feature of amb , which may limit the dose of the drug .
however , our observation suggested that even if the dose of liposomal amb is reduced , the combination therapy of liposomal amb and caspofungin may synergistically improve the antifungal activity with minimum toxicity . despite a successful treatment against disseminated t. asahii infection , subsequent chemotherapy or hematopoietic stem cell transplantation is still challenging .
however , recrudescence of trichosporonosis did not occur in this case , which hinted the clearance of t. asahii .
unfortunately , the lack of susceptibility test and other post - mortem examinations did not allow us to identify this isolate further .
although the combined regimen is effective , the clinical outcome seems to also depend on the patients hematologic recovery of the underlying disease .
thus , to improve the immunosuppressive status is obligatory in the treatment strategy , and an appropriate antifungal therapy allows the patient to live through this period post - chemotherapy , which usually lasts for 2 weeks or longer . because of the excellent activity against a broad spectrum of fungi as well as the convenience of maintenance treatment with oral products , voriconazole is widely used as empirical or pre - emptive treatment for fungal infection . to our knowledge , breakthrough disseminated infection of t. asahii during voriconazole administration has not been reported previously .
our observations in this case provide an encouraging treatment option in this special clinical setting .
we concluded that liposomal amb combined with caspofungin may potentially eradicate t. asahii , and clinical experience of this combination regimen is worth to be more accumulated .
this work was funded by jiangsu provincial special program of medical science ( grant no .
zx201102 ) , the priority academic program development of jiangsu higher education institutions ( papd ) , national public health grand research foundation ( no . 201202017 ) , and the program of national clinical key subject construction .
trichosporon species is an important life - threatening opportunistic systemic pathogen , especially in leukemia patients . 
 voriconazole is proved to be a promising agent in past decade . however , recently we observed a case of breakthrough trichosporon asahii infection while receiving voriconazole , which calls for an alternative treatment strategy . 
 a combination therapy of liposomal amphotericin b ( amb ) plus caspofungin  in which liposomal amb dose was reduced due to renal toxicity  was administered to successfully treat this patient .