Discussion
Mediastinitis is a rare but potentially lethal complication of heart transplantation, occurring in 1-10% of cases with Staphylococcusspp. and Enterobacter spp. as the most common pathogens. [4] Our patient presented with two rare pathogens of mediastinitis, A. fumigatus and A. baumannii .
Aspergillus has been recognized as a major opportunistic pathogen and accounts for the most common mycoses in cardiac transplant recipients. [1] Diagnosis can be challenged by discriminating colonization from invasive infection and because strains morphologically identified as putative A. fumigatus are recognized as different species by molecular methods with decreased antifungal susceptibility. [5] This may lead to a delay of targeted treatment resulting in an excessive mortality. Despite negative blood cultures, invasive infection could be documented by numerous intraoperative specimens from the sternum, native and transplanted aorta including anastomosis, all intrathoracic organs and the thoracic wall. Microbiology uniformly showed characteristic culture and genomic sequencing documented hyphae consistent with Aspergillus on microscopic examination, positive serum galactomannan test and the presence of A. fumigatus . Hence, a diagnosis of invasive aspergillosis could be made in accordance with the definition of the US Centres for Disease Control. [6]
A. fumigatus mediastinitis in our patient developed within the usual time of onset of invasive aspergillosis reported to be between 36 and 52 days post transplantation. [1] Besides recent cardiac transplantation, the current patient presented with previously reported risk factors for fungal infections such as postoperative wound discharge, renal failure, administration of multiple antibiotics, ventricular assist device before surgery, as well as severe malnutrition and diabetes mellitus. [1, 3]
Given the unique extent of the disease, the basic principle of therapy [6], i.e. intravenous antifungal treatment, tapering of immunosuppression and surgical re-exploration alone was thought not to be sufficient. With regards to the pathology of invasive aspergillosis resulting in infarction and necrosis of affected organs and poor drug delivery to tissue, our treatment regime was based on the conviction of the necessity to clean large surfaces without blood supply from thick layers of fungal material not only mechanically but also with local antiseptics.
A combination of repeated debridements with an open chest treatment, cavity baths with aqueous voriconazole and chlorhexidine, intravenous administration of voriconazole and caspofungin and lastly a chest wall reconstruction by a muscle flap plasty were necessary leading to successful recovery.
A combined systemic antifungal therapy was started with caspofungin and voriconazole, the latter guided by testing susceptibility and serum concentration. Voriconazole, a triazole with activity against yeasts and molds including Aspergillus spp. [7] performed superior when compared with amphotericin B, and is now recommended as primary treatment of invasive aspergillosis including its uncommon manifestations such as mediastinitis and osteomyelitis. [6, 8] Voriconazole was administered systemically in the only two reported surviving cases of Aspergillus mediastinitis after OHT. [2, 4] Monitoring of its serum levels is recommended in transplanted patients because of impaired renal function and significant interactions with cyclosporine, tacrolimus and sirolimus [1, 6]. In the current case, oral voriconazole was continued for 12 months to prevent relapse of infection, which has been reported to occur several months after seemingly successful treatment. The role of combined primary or salvage antifungal therapy is uncertain and warrants a prospective, controlled clinical trial. [6]
The use of topical voriconazole in addition to its intravenous administration has recently been found to be effective in cases ofAspergillus keratitis and endophtalmitis when administered intravitreally [9-11]. Biocidal activity of chlorhexidine againstA. fumigatus was reported when applied topically at a concentration of 0.06% for 30 to 60 minutes and its stable and lasting adherence on human tissue without being absorbed. [12] In addition, effectiveness of topical chlorhexidine was confirmed in the treatment of fungal keratitis without any adverse effects. [13] Based on this data, we decided to use chlorhexidine in the same way as the voriconazole solution as local antifungal treatment.
After the fourth surgical session, examinations revealed a sterile condition with respect to A. fumigatus . However, a superinfection with a multi-drug resistant A. baumannii was reported. Mediastinits due to A. baumannii is rare, with \soutonly two reported cases in immunocompetent subjects, successfully treated with ampicillin-sulbactam and a pan-resistant type with tigecycline. [14, 15] Notably, only one case of multi-drug resistant A. baumanniiin sternal wound after OHT has been reported. Favourable outcome was achieved with extensive debridement, systemic colistin and minocycline as well as wound irrigation with 5% chlorhexidine and NPWT dressing. [16] Safe and effective topical use of colistin 0.19% has been reported in the treatment of corneal infection by multi-drug resistantPseudomonas aeruginosa . [17] Hence, we used diluted colistin as described above in combination with intravenous colistin. Lastly, after the completion of topical antimicrobial therapy, a rotationallatissimus dorsi muscle flap into the thoracic cavity and complete closure of the sternum resulted in a restitutio ad integrum .