Combination of voriconazole and caspofungin as primary therapy for invasive aspergillosis in solid organ transplant recipients: a prospective, multicenter, observational study

BACKGROUND.: The efficacy of the combination of voriconazole and caspofungin when used as primary therapy for invasive aspergillosis in organ transplant recipients has not been defined. METHODS.: Transplant recipients who received voriconazole and caspofungin (n=40) as primary therapy for invasive aspergillosis (proven or probable) in a prospective multicenter study between 2003 and 2005 were compared to a control group comprising a cohort of consecutive transplant recipients between 1999 and 2002 who had received a lipid formulation of AmB as primary therapy (n=47). In vitro antifungal testing of Aspergillus isolates to combination therapy was correlated with clinical outcome. RESULTS.: Survival at 90 days was 67.5% (27/40) in the cases, and 51% (24/47) in the control group (HR 0.58, 95% CI, 0.30-1.14, P=0.117). However, in transplant recipients with renal failure (adjusted HR 0.32, 95% CI: 0.12-0.85, P=0.022), and in those with A. fumigatus infection (adjusted HR 0.37, 95% CI: 0.16-0.84, P=0.019), combination therapy was independently associated with an improved 90-day survival in multivariate analysis. No correlation was found between in vitro antifungal interactions of the Aspergillus isolates to the combination of voriconazole and caspofungin and clinical outcome. CONCLUSIONS.: Combination of voriconazole and caspofungin might be considered preferable therapy for subsets of organ transplant recipients with invasive aspergillosis, such as those with renal failure or A. fumigatus infection.     

Paraplegia due to aspergillosis. Successful conservative treatment of two cases

Aspergillus infection of the spine is rare; for it to lead to paraplegia is still more rare. When this does occur it is usually treated by decompression and antifungal agents, but the results have usually been poor. We report two cases of successful conservative treatment of Aspergillus paraplegia in patients with chronic granulomatous disease.     

Aspergillus osteomyelitis of the thumb in a 5-year-old child

Aspergillus osteomyelitis is a rare condition and is a recognized infection of the immunosuppressed. The pediatric cases that were documented suggest that in children, chronic granulomatous disease is the major underlying disease [Tack et al.1982 73(2):295–300, Baez-Escudero et al. 2000 Case report—primary sternal Aspergillus osteomyelitis. Infect Med 17(7):505–516]. We report an interesting case of Aspergillus osteomyelitis of the thumb in a 5-year-old boy with aplastic anemia. The infection progressed despite a combination of antifungal therapy with Voriconazole and surgical debridement. The thumb was amputated and the child recovered. This case highlights the difficulty in diagnosing Aspergillus osteomyelitis and also the failure of conventional management in this child, which resulted in the amputation of the thumb as a life-saving measure. We believe this to be the first case report of Aspergillus osteomyelitis in the thumb.     

Drainage of Aspergillus "primitive" brain abscess with long-term survival. Case report

Aspergillus species are second only to Candidosis as the most common cause of fungal infections of the central nervous system in immunocompromised patients. Very rare is the sole abscessual cerebral localization in nonimmunocompromised patients. Successful treatment of Aspergillus brain abscess has been reported only few times. A case of Aspergillus "primitive" brain abscess treated by surgical therapy associated with local and general mirated antifungal therapy is described. The long-term survival with complete clinical and radiological recovery is reported.     

Aspergillar prosthetic hip infection with false aneurysm of the common femoral artery and cup migration into the pelvis

We report a case of Aspergillus fumigatus infection of a total hip arthroplasty. This rare infection was demonstrated at surgical revision of a loosened prosthesis with migration of the cup into the pelvis associated with a false aneurysm of the femoral artery. A vascular time was required before the orthopedic revision. This case illustrates the importance of the preoperative work-up in the event of cup migration. The double approach was required in our patient to control and repair the vascular structures. The difficult treatment of Aspergillus fumigatus is also discussed.     

Fungemia Associated with Left Ventricular Assist Device Support

Abstract  Objective: Infections remain an important complication of left ventricular assist device (LVAD) support. While relatively uncommon, fungal infections present a serious concern given a high association with adverse events including death. We sought to further characterize the epidemiology of fungemias during LVAD support. Methods: Retrospective review of 292 patients receiving LVAD support from October 1996 to April 2009 at the University of Michigan Health System was done. Results: Seven cases of LVAD-associated fungemia were observed during the study period (0.1 infections/1000 days of device support). Five patients had infection with Candida species and two with Aspergillus species. The two patients with Aspergillus infection presented with disseminated disease, quickly dying of multiorgan failure, and sepsis. All five patients with Candida infections were successfully treated with systemic antifungal therapy along with transplantation in four of five patients. The fifth patient is receiving mechanical support as destination therapy. He remains on long-term suppression with high-dose fluconazole. Conclusions: Fungal infections appear to be a rare but serious complication of LVAD support. Future studies should aim to improve our understanding of risk factors for fungal infection during mechanical support, especially disseminated Aspergillus . Short-term perioperative antifungal prophylaxis with fluconazole appears to be an effective and reasonable approach to prevention.     

Survival after disseminated invasive aspergillosis in a multivisceral transplant recipient

Disseminated invasive aspergillosis is a serious and potentially lethal infectious complication of immunosuppressed individuals, including transplant recipients. We report here a successfully treated case of disseminated Aspergillus fumigatus infection involving the lungs, brain, and endocardium in a multivisceral transplant recipient. In addition to supportive measures, the patient was aggressively treated with a combination of three antifungal agents, and all immunosuppression was significantly lowered with close observation for rejection. After 3 months of therapy, the patient cleared the fungal infection, made a full recovery of his cerebral function, and was discharged to a rehabilitation facility.     

A longitudinal study of lung transplant recipients infected with Aspergillus: genetic polymorphism of A fumigatus.

BACKGROUND: Aspergillus infection is a well-known complication of lung transplantation and remains associated with high mortality rates. Molecular typing methods are required to elucidate the complex epidemiology of Aspergillus disease in lung transplant recipients. METHODS: Eight lung transplant recipients from one hospital were followed for A fumigatus colonization or infection. Forty-four sequential isolates from these patients were selected and typed by three molecular methods (random amplified polymorphic DNA, sequence-specific DNA primer and multi-locus enzyme electrophoresis). RESULTS: Sixteen different types were identified of which 14 were specific to 1 patient. A factorial correspondence analysis showed that variability between sequential isolates from a single patient was as high as between isolates from the other patients. Lung transplant recipients presented many different genotypes, reflecting the environmental diversity of A fumigatus. Nevertheless, throughout their follow-up, 2 of the 8 lung transplant recipients harbored a common genotype that was not replaced by others. CONCLUSIONS: These results confirm the important genetic polymorphism of the A fumigatus population. The observed genotypes were not related to the type of Aspergillus disease or anti-fungal treatment used nor to the outcome of the patient. These data confirm that all A fumigatus molecular types present the same pathogenic risk.     

Culture of a prosthetic valve excised for streptococcal endocarditis positive for Aspergillus fumigatus 20 years after previous A fumigatus endocarditis

Culture of a mitral valve prosthesis excised for streptococcal endocarditis yielded Aspergillus fumigatus. The patient had undergone valve replacement 20 years earlier for A fumigatus endocarditis. Data suggest that quiescent A fumigatus may have survived in a biofilm on the surface of the prosthesis. An antifungal therapy was initiated for 6 months.     

Aspergillus peritonitis in peritoneal dialysis: case report and a review of the literature

Aspergillus peritonitis is a rare complication of continuousambulatory peritoneal dialysis. The case is described of a 68-year-oldman in whom Aspergillus fumigatus was isolated from the peritonealdialysate after recurrent peritonitis with Gram-negative rodsin association with diverticulosis. Treatment consisting ofremoval of the catheter and intravenous administration of amphotericinB followed by oral itraconazole was successful. A review of the sparse literature (12 cases) displays uncertaintiesregarding diagnostic awareness, culture diagnosis, and therapeuticmanagement. Next to institution of appropriate antifungal therapy,early removal the peritoneal dialysis catheter is recommended,as delayed removal of the catheter appears to be associatedwith increased mortality and morbidity.     

Extent of surgical intervention in primary soft-tissue aspergillosis.

Primary invasive Aspergillus Infection of the soft tissue is rare and typically affects immunocompromised patients in several distinct patterns of clinical presentation. In general, the role of surgery in the treatment of this disease is the removal of infected or necrotic tissue to prevent dissemination and mortality. However, the specific surgical recommendations have varied widely among reports due to the varied clinical circumstances in each series. The authors present the case of a patient with a primary invasive Aspergillus infection. They review the reported surgical experience with this disease, and discuss outcomes and surgical approaches in the context of several variations in clinical presentation. In all situations, antifungal therapy and prompt surgical intervention are critical in treating these initially localized but potentially lethal infections. The extent of intervention can range from minor debridement to amputation, and is based on the presence of persistent immunocompromise, the presence and extent of tissue necrosis, and the rate of progression during antifungal therapy.     

Risk factors for Mycobacterium abscessus infection in cystic fibrosis patients; a case-control study

Mycobacterium abscessus is a nontuberculous mycobacterium that is increasingly recognized as an opportunistic pathogen in cystic fibrosis (CF) patients. Factors that predispose CF patients to infection by this environmental bacterium remain unknown. In a case-control study of 22 CF patients with M. abscessus infection and 22 CF controls, we investigated risk factors for MAB infection as well as the positioning of MAB infection in relation to the other pathogens infecting CF patients. No clear risk factors were found; steroid treatment and CF related diabetes were equally common among cases and controls. M. abscessus disease affects CF patients of varying age, lung function and co-morbidities. Antimicrobial maintenance therapy did not prevent M. abscessus infection. A history of Stenotrophomonas maltophilia infection was significantly more frequent among cases than among controls and there may be a relation with Aspergillus fumigatus infection, or both may be signs of advanced lung damage that predisposes to MAB disease. The absence of clear risk factors and the omnipresence of MAB in the environment suggest that MAB infection in CF patients is a random event. Its symptoms and impact on lung function seem to warrant treatment.     

Continual intracavitary administration of amphotericin B as an adjunct in the treatment of aspergillus brain abscess: case report and review of the literature.

Aspergillus brain abscess is often a fatal disease, regardless of the mode of therapy. Most often seen in the compromised host, it is notoriously refractory to systemic antifungal agents and intrathecal antimycotics. Even with radical surgical debridement, only 13 patients, including the present case, have survived longer than 3 months after being treated for aspergillus brain abscess or granuloma. Studies have shown poor penetration of amphotericin B into the brain and cerebrospinal fluid. One way to achieve therapeutic levels of the agent near the abscess is through the direct introduction of the agent into the abscess site via an indwelling catheter. In the present case, a woman with an aspergillus abscess of the left temporal lobe was treated by a combination of systemic agents, radical debridement, and local therapy, resulting in a cure with a follow-up of 6 years. This is the first reported instance of the use of long-term, local antifungal therapy delivered to the area of the abscess cavity, using a closed reservoir system, and this patient is only the second renal transplant patient reported to have survived aspergillus brain abscess. This form of treatment produced no untoward long-term side effects or neurological sequelae. Local irrigation with antifungal agents should be considered in conjunction with systemic antifungal drugs and drainage and/or debridement in cases of fungal intracerebral aspergilloma. This technique may also prove useful with other fungal brain lesions.     

Aspergillosis of the nose and paranasal sinuses in neutropenic patients at an oncology center

Invasive aspergillosis of the nose and paranasal sinuses is one of the presentations of aspergillosis in granulocytopenic patients with neoplastic disorders. It is most prevalent among patients with leukemia and granulocytopenia and is associated with a high mortality rate. We report five cases of invasive aspergillosis of the nose and paranasal sinuses in profoundly neutropenic patients treated with broad spectrum antibiotics. Both Aspergillus fumigatus and Aspergillus flavus were cultured and identified in this entity. Awareness of this disease and early diagnosis made by culture and histologic examinations of biopsy material are essential. Treatment consisting of amphotericin B therapy and surgical debridement can be effective in eradicating this form of aspergillosis.     

Necrotizing pulmonary aspergillosis

Necrotizing or invasive aspergillary infection of the lungs has previously been considered a rare condition affecting only the debilitated or seriously ill. Four patients with necrotizing pulmonary aspergillosis are described, and the mycological and histopathological findings are discussed. The diagnosis in the first patient was not made until necropsy, following death from fulminating pulmonary infection. Of three patients treated with natamycin, two made a satisfactory recovery; the other died later from bronchial carcinoma. Previous multiple antibiotic therapy in each case may have been a contributory factor to infection with Aspergillus fumigatus. We suggest that fungal infection of the lungs should be actively sought in patients with pulmonary disease, especially in those receiving multiple antibiotic or corticosteroid therapy.     

Intracranial mycotic infections in neurosurgical practice

Summary Intracranial mycotic infections requiring neurosurgical intervention are being diagnosed more frequently. This study is a review of 17 cases of intracranial mycotic infections that were treated in a neurosurgical unit in Saudi Arabia over an 8-year period. A primary focus of infection was identified in 41% of patients while 18% of patients had a predisposing factor. Forty-seven per cent of patients presented with a brain abscess (solitary 29%, multiple 18%) while 35% had a granuloma, 18% meningitis and ventriculitis and 12% hydrocephalus. The Aspergillus species and Ramichloridium machenziei were the commonest pathogens. Following the appropriate surgical and antimicrobial treatment, the mortality rate was 41% and there was evidence of residual disease at follow-up in 18%. The reason for a fatal outcome was failure to consider a fungal aetiology and to obtain a tissue diagnosis early-because of late referral (2 cases), as well as failure to respond to antimycotic therapy (4 cases) and rupture of the internal carotid artery due to Aspergillus arteritis (one case). It is concluded that an early tissue diagnosis is crucial in the management of intracranial mycotic infection so that the appropriate surgical and antimycotic treatment can be started early.     

Aspergillus Mastoiditis in a Patient with Systemic Lupus Erythematosus: A Case Report

Fungal mastoiditis caused by Aspergillus fumigatus predominantly occurs in immunocompromised patients. Invasive temporal bone mycoses are rare. They are usually associated with host immunodeficiency, are difficult to diagnose, and many cases are fatal. Treatment consists of antifungal chemotherapy, surgical debridement, and attempts to control the underlying immunological condition. Published reports describe patients with previous ear pathology and associated facial nerve dysfunction. We report a case in a patient with systemic lupus erythematosus. A good outcome followed surgical debridement and the use of a new triazole antifungal agent, voriconazole. Our patient's facial nerve function was unaffected. The presence of normal facial nerve function, however, does not exclude the possibility of invasive fungal mastoiditis.     

Aspergillus osteomyelitis of the spine

Aspergillosis involving either the vertebral body or the intervertebral disc is a rare cause of osteomyelitis of the spine. The following is a report of five cases of Aspergillus fumigatus infection of the spine treated successfully with amphotericin B and 5-flucytosine. In three patients, the diagnosis was established at closed-needle biopsy; two patients with paraplegia had an anterior decompression and fusion. The follow-up period ranged from 19 to 48 months.     

Free latissimus dorsi flap used in treatment of cerebral aspergillosis: a case report and review of the literature

Cerebral aspergillosis infection is a rare disease in children that carries extremely high morbidity and mortality. Although occurring most commonly in the immunosuppressed patient, cerebral aspergillosis infection has been reported after trauma or neurosurgical procedures. Amphotericin B is the main medical therapy for cerebral aspergillosis. However, surgical treatment is often required for cases of abscess or granuloma formation. Despite aggressive antifungal treatment and surgical intervention, aspergillosis of the central nervous system is often fatal. We present a case report in which a free latissimus dorsi muscle flap was used in conjunction with antifungal medication and surgical debridement to treat intracranial and epidural aspergillosis in a young male following complex craniofacial trauma.     

Candida albicans osteomyelitis of the spine: progressive clinical and radiological features and surgical management in three cases

Candida albicans vertebral osteomyelitis is rare. Three cases are presented. Without antifungal treatment, they developed spinal collapse and neurological deterioration within 3–6 months from the onset of symptoms. There was a delay of 4.5 and 7.5 months between the onset of symptoms and surgery. All patients were managed with surgical debridement and reconstruction and 12-week fluconazole treatment. The neurological deficits resolved completely. The infection has not recurred clinically or radiologically at 5–6 years follow-up. Although rare, Candida should be suspected as a causative pathogen in cases of spinal osteomyelitis. Without treatment the disease is progressive. As soon as osteomyelitis is suspected, investigations with MRI and percutaneous biopsy should be performed followed by medical therapy. This may prevent the need for surgery. However, if vertebral collapse and spinal cord compression occurs, surgical debridement, fusion and stabilisation combined with antifungal medications can successfully eradicate the infection and resolve the neurological deficits.