A review of German Scedosporium prolificans cases from 1993 to 2007.

Scedosporium prolificans is one of the most life-threatening fungal opportunistic pathogens due to its high resistance to common systemic antifungal agents. While a close relative of Pseudallescheria boydii, S. prolificans has a more limited geographic range being primarily found in Australia, USA and Spain. Infections have also been reported from several other European countries and from Chile. Twenty patients with Scedosporium prolificans infection or colonization from August 1993 to May 2007 were retrospectively reviewed in Germany. They had all been identified at or reported to the Reference Laboratory for Pseudallescheria/Scedosporium spp. in Berlin. Twelve of 13 patients with haematological disorders and/or on immunosuppressive therapy developed a fatal invasive scedosporiosis. Colonization of the respiratory tract was reported for one patient after heart-lung-transplantation, all six patients with cystic fibrosis and one with chronic sinusitis. Molecular studies of the S. prolificans isolates confirmed that parts of the 18S, the Internal Transcribed Spacer (ITS) regions and the D1/D2 domain of the 28S region of rDNA are monomorphic. However, sequencing of parts of the translation elongation factor EF1-alpha (EF-1alpha) and the chitin synthase (CHS-1) genes revealed the presence of three and two distinct genotypes, respectively. Two informative mutations were found in EF-1alpha and a single nucleotide exchange in the CHS-1 gene.

European cluster of imported falciparum malaria from Gambia.

A cluster of 56 patients returning from Gambia with falciparum malaria has been noted in several countries of the European Union since September this year. TropNetEurop, the European Network on Imported Infectious Disease Surveillance, collected and reported the cases. Lack of awareness and, consequently, of prophylactic measures against malaria were apparent in the majority of patients.

PCR based identification and discrimination of agents of mucormycosis and aspergillosis in paraffin wax embedded tissue.

BACKGROUND: Invasive fungal infections are often diagnosed by histopathology without identification of the causative fungi, which show significantly different antifungal susceptibilities. AIMS: To establish and evaluate a system of two seminested polymerase chain reaction (PCR) assays to identify and discriminate between agents of aspergillosis and mucormycosis in paraffin wax embedded tissue samples. METHODS: DNA of 52 blinded samples from five different centres was extracted and used as a template in two PCR assays targeting the mitochondrial aspergillosis DNA and the 18S ribosomal DNA of zygomycetes. RESULTS: Specific fungal DNA was identified in 27 of 44 samples in accordance with a histopathological diagnosis of zygomycosis or aspergillosis, respectively. Aspergillus fumigatus DNA was amplified from one specimen of zygomycosis (diagnosed by histopathology). In four of 16 PCR negative samples no human DNA was amplified, possibly as a result of the destruction of DNA before paraffin wax embedding. In addition, eight samples from clinically suspected fungal infections (without histopathological proof) were examined. The two PCR assays detected a concomitant infection with Absidia corymbifera and A fumigatus in one, and infections with Rhizopus arrhizus and A fumigatus in another two cases. CONCLUSIONS: The two seminested PCR assays described here can support a histopathological diagnosis of mucormycosis or aspergillosis, and can identify the infective agent, thereby optimising antifungal treatment.

An unusual case of Aspergillus endocarditis in a kidney transplant recipient.

The incidence of aspergillosis in kidney transplant recipients is low and most commonly occurs in the early posttransplantation period. We report an unusual case of a 52-year-old female patient with Aspergillus endocarditis as a late complication after kidney transplantation, presumably spread from a necrosis in the gut, associated with previous cytomegalovirus colitis. As complications, the patient experienced septic embolization into the coronary and pulmonary arteries, and an infarction of the right parietal cortex and insula. The patient died as a result of global heart failure after a 10-day course of antimycotic therapy with amphotericin B plus 5-flucytosine during surgical valve replacement.

Clinicopathological features of cutaneous histoplasmosis in human immunodeficiency virus-infected patients in Zimbabwe.

Reports of disseminated Histoplasma infection in African AIDS patients are scanty. In Zimbabwe, 12 patients presented in 1994-2000 with facial nodular/papular cutaneous lesions, which became umbilicated and finally ulcerated. Histology revealed non-granulomatous inflammation and macrophages stuffed with Histoplasma. Recognition of these clinical features may lead to more rapid diagnosis of disseminated histoplasmosis in Africa.

Influence of antimicrobial treatment on mortality in septicemia.

OBJECTIVE: To determine the influence of antimicrobial therapy and of predisposing illness on the septicemia mortality rate. METHOD: All blood-culture-positive episodes of septicemia in the Department of Medicine at the University Hospital in Frankfurt between 1989 and 1993 were entered on a database. Underlying illnesses were classified as immunocompromising diseases (hematological malignancies, AIDS and others), severe chronic and chronic illnesses and no predisposing illnesses. Therapy was judged on the basis of the in-vitro-susceptibility of the organism ('appropriate') and the interval (no. of days) between the onset of septicemia and start of appropriate treatment noted. For mortality all deaths within 28 days after the onset of septicemia were counted. RESULTS: Overall mortality due to septicemia was 18.1%, ranging from 9.4% (organ transplantation) to 50% (liver cirrhosis) according to the underlying illness. Mortality in patients receiving appropriate treatment (83.1%) was 16% as opposed to 28%, if no appropriate treatment was given (p<0.001). Comparison of appropriate treatment started within and after 48 hours revealed a reduction in mortality from 30.9% to 15.4% for early appropriate therapy in patients with hematological malignancies (p<0.002). For septicemia in patients with AIDS and chronic illnesses mortality was significantly higher (p<0.05) if treatment remained inappropriate (AIDS 28.6%, chronic illness 33.3%), but was similar when early and delayed appropriate therapy were compared (AIDS: 13% vs. 12.8%, chronic illness 11.8% vs. 11.1%). CONCLUSION: First-line treatment regimens for septicemia in patients with hematological malignancies should include the greatest possible part of the spectrum of causative organisms. In contrast to that it may be acceptable to rely to some extent on a change of treatment, when treating septicemia in patients with chronic illnesses or AIDS. These considerations are of value in the debate on rising health care costs. Several other facts, such as the stable mortality rate of 8 - 12% in previously healthy patients and the range of mortality from 9.4 - 50%, if predisposing illnesses are present, indicate the existence of adverse factors influencing the outcome of septicemia in spite of appropriate therapy. These pathophysiological factors will have to be studied in detail in order to improve the prognosis of septicemia further.

Successful treatment of disseminated mucormycosis with a combination of liposomal amphotericin B and posaconazole in a patient with acute myeloid leukaemia.

The combination of resection of infected tissue and antifungal therapy is the treatment of choice in mucormycosis. In disseminated mucormycosis, where surgery is impossible, the mortality is almost 90%. We report the first case of disseminated mucormycosis that was cured with a combination therapy of liposomal amphotericin B and posaconazole without surgical intervention.

Diagnosis of invasive aspergillosis and mucormycosis in immunocompromised patients by seminested PCR assay of tissue samples.

Aspergillosis and mucormycosis are the most common mold infections in patients with hematological malignancies. Infections caused by species of the genus Aspergillus and the order Mucorales require different antifungal treatments depending on the in vitro susceptibility of the causative strain. Cultures from biopsy specimens frequently do not grow fungal pathogens, even from histopathologically proven cases of invasive fungal infection. Two seminested PCR assays were evaluated by amplifying DNA of zygomycetes and Aspergillus spp. from organ biopsies of 21 immunocompromised patients. The PCR assays correctly identified five cases of invasive aspergillosis and six cases of mucormycosis. They showed evidence of double mold infection in two cases. Both assays were negative in five negative controls and in two patients with yeast infections. Sequencing of the PCR products was in accordance with culture results in all culture-positive cases. In six patients without positive cultures but with positive histopathology, sequencing suggested a causative organism. Detection of fungal DNA from biopsy specimens allows rapid identification of the causative organism of invasive aspergillosis and mucormycosis. The use of these PCR assays may allow guided antifungal treatment in patients with invasive mold infections.

[Therapy of candidiasis and cryptococcosis in AIDS]. / Die Therapie der Candidose und Cryptococcose bei AIDS.

Fungal infections figures large in HIV-infected patients. Candida infections of the mucous membranes belong to the main manifestations of immunodeficiency in HIV infection. For therapy and prophylaxis of oropharyngeal candidosis mainly systemically acting azoles as ketoconazole, fluconazole and itraconazole are applied; antimycotics to be administered topically regularly fail to act in patients with progressing disease. Ketoconazole tablets were used with good success in previous years of the AIDS epidemics. Application of ketoconazole in liquid formulation led to a significant increase in efficacy. Subsequently fluconazole proved to be a triazole with evidently better pharmacological properties leading to good clinical efficacy. Presently it represents the drug of first choice in acute and maintenance therapy of recurrent oropharyngeal and oesopharyngeal candidosis. In the case of therapy failure with fluconazole the administration of itraconazole in liquid cyclodextrine formulation can replace or at least delay the administration of amphotericin B plus flucytosine, a therapy rich in toxic side effects. The standard therapy of disseminated cryptococcosis--particularly of cerebral manifestation--is still the administration of amphotericin B combined with flucytosine. Alternative drugs are represented by fluconazole and itraconazole. However, an azole monotherapy seems to be legitimate only in primary cryptococcosis of the lungs or in early stages of secondary extrapulmonary infection. Cryptococcal meningitis requires an intense initial therapy. New therapy strategies were developed combining azoles with standard antimycotic drugs. The value of amphotericin B in liposomal or lipid complex formulations is still undetermined due to the up to now low number of AIDS patients treated.(ABSTRACT TRUNCATED AT 250 WORDS)

[Therapy of systemic mycoses in immunodeficiency]. / Therapie von Systemmykosen bei Abwehrschwäche.

Fungal infections have gained importance recently. The major reason for this is the increasing number of patients with immunodeficiency. Systemic treatment of invasive fungal infections up to now has been based on relatively few antimycotic agents (amphotericin B, flucytosine, as well as the azole derivatives fluconazole and itraconazole). Only a few number of fungi cause the majority of opportunistic fungal infections. Candida albicans leads to severe mucosal infections in cases of immunodeficiency. Systemic mycoses usually present as endogenous infections or are caused by an infected central venous catheter with dissemination into multiple organs. Less severe candida infections should be treated with fluconazole. A more severe candida infection still requires treatment with amphotericin B plus flucytosine. Aspergillus fumigatus, a ubiquitous mold, is the most frequent pathogen in patients with granulocytopenia. First choice treatment also is amphotericin B and flucytosine; treatment should be started despite lacking proof of pathogen in patients with immunodeficiency and typical clinical signs. Itraconazole, the azole derivative active against aspergillus, may be administered only in mild cases of aspergillus infections in immunocompromised patients. Infections with Cryptococcus neoformans, which hardly ever occur, have been observed frequently in AIDS patients. The manifestation of cryptococcosis mainly presents as chronical meningitis. Presently various treatment concepts are being clinically tested. An initial combination of amphotericin B, flucytosine, and fluconazole, followed by long-term treatment with fluconazole, is recommended.

Prevalence of Aspergillus fumigatus and other fungal species in the sputum of adult patients with cystic fibrosis.

Aspergillus fumigatus is often found in the respiratory tract secretions of patients with cystic fibrosis (CF), although the role of the fungus for progression of pulmonary disease remains unclear. This study aimed to investigate the frequency of A. fumigatus and other fungi in sputum of adult CF patients using different methods for culture and microscopy. Results from the analysis of 369 samples from 94 patients showed that A. fumigatus could be isolated in 45.7% of patients. Other moulds were rare, but the yeast Candida albicans was another frequent isolate, detected in 75.5% of patients. A comparison of different culture media showed no difference between a selective medium developed to specifically inhibit Pseudomonas aeruginosa and a standard fungal culture medium for growth of A. fumigatus, although both were more efficient for detection of fungi than other bacterial culture media. Fluorescent microscopy with calcofluor white was more sensitive for detection of fungal hyphae in undiluted sputum than standard methylene blue staining. This study shows that A. fumigatus and C. albicans have a high frequency in adult CF patients. Microbiological analysis should routinely include methods for specific identification of fungi to monitor for potential complications arising from fungal disease in these patients.

Primary cytomegalovirus infection in an outpatient setting--laboratory markers and clinical aspects.

BACKGROUND: Occasionally, primary cytomegalovirus (CMV) infection may give rise to more or less severe clinical illness in immunocompetent adults. We retrospectively analyzed cases of acute CMV infection in medical outpatients. PATIENTS AND METHODS: Over a 6-year period, we identified 22 patients with a febrile illness and hepatitis suffering from primary CMV infection. This was diagnosed on the basis of a strongly positive CMV IgM antibody test result and/or CMV IgG seroconversion. Clinical features as well as relevant laboratory results were analyzed. We also tested available samples for CMV glycoprotein B-specific antibodies and CMV IgG avidity and analyzed results of Epstein-Barr virus (EBV)-specific antibody assays. In addition, current age-specific CMV IgG seroprevalence rates were determined using 9,870 routine patient samples. RESULTS: At presentation, all patients complained of malaise and fever higher than 38 degrees C, and many also complained of cephalgia. Most patients who underwent abdominal ultrasonography had an enlargement of the spleen. Most patients had a relative lymphocytosis but only three had a mild leukocytosis. C-reactive protein was only slightly elevated in 13 patients; all 22 patients had elevated levels of alanine aminotransferase (ALT) and lactate dehydrogenase (LDH). Half the patients reported travel to areas outside western Europe, mostly to tropical and subtropical areas, within 3 weeks before onset of illness. Primary CMV infection was confirmed by negative anti-gB antibody test results and the absence of high-avidity CMV antibodies. In contrast, despite past EBV infection demonstrated by positive anti-EBNA-1 results, 15 out of 21 patients tested for EBV markers had positive or nonspecific IgM test results. The overall CMV IgG seroprevalence rate in the routine samples was 64.4%, with marked age-dependent increases. CONCLUSION: CMV is a relevant differential diagnosis in feverish illnesses accompanied by hepatitis in otherwise healthy adults, about 40% of whom are CMV-naïve. Half our patients seem to have acquired their CMV infection abroad, so that a diagnosis of CMV infection needs to be taken into account in travelers, in addition to infectious illnesses more commonly considered in this context, such as dengue or hepatitis A. For diagnosis, both CMV and EBV antibody studies should be performed and the inclusion of assays able to demonstrate past infection is helpful for achieving a definite diagnosis.

A randomized study of imipenem compared to cefotaxime plus piperacillin as initial therapy of infections in granulocytopenic patients.

The objective of the presented, randomized study was to compare the efficacy of antimicrobial monotherapy with imipenem (3 x 0.5g/d) to a combination therapy with cefotaxime (3 x 2g/d) plus piperacillin (3 x 4g/d) for empirical treatment of infections in neutropenic patients. In 165 patients, 237 infectious episodes were evaluable. The overall response rate of patients treated with cefotaxime plus piperacillin was 67/115 (58%), of those treated with imipenem 66/122 (54%). In patients not responding to the initial therapy regimen within 2 or 3 days, the antimicrobial therapy was modified. After therapy modification 85/100 patients were cured. Fever of unknown origin (FUO) showed the most favourable course compared to other infection types, with a response in 46/59 (78%) and in 35/50 (70%) cases, respectively. In comparison, pneumonias were successfully treated in only 3/21 (14%) and 7/37 (19%) cases. Even including patients with modified therapy, only 66% (21/32) of pneumonia episodes responded. The unfavourable results in pneumonias is mainly due to the high rate of 13 systemic mycoses in this group (22%). Overall, a similar response was observed in patients treated with cefotaxime plus piperacillin in comparison with imipenem. In primary bacteremias however, an advantage was observed in patients treated with imipenem (20/27; 74%) compared with cefotaxime plus piperacillin (11/23; 48%).

[Itraconazole suspension in the treatment of HIV-infected patients with fluconazole-resistant oropharyngeal candidiasis and esophagitis]. / Itraconazol-Suspension in der Behandlung HIV-infizierter Patienten mit Fluconazol-resistenter oropharyngealer Candida-Infektion und Soorösophagitis.

Forty AIDS patients suffering from fluconazole-resistant oropharyngeal candidosis were treated with oral itraconazole solution (200-800 mg/day). In 39/49 patients the disease could be initially cured or significantly improved. In contrast to the good clinical results, however, only in six patients a yeast count reduction was observed, and in four patients unchanged high yeast counts persisted. The main pathogen was C. albicans. Even in longtime treatment itraconazole solution was well tolerated. In two patients only the therapy had to be stopped due to the increase of transaminases. Considerable individual deviations in serum concentrations of itraconazole or hydroxy-itraconazole, respectively, were observed which correlated only to a minor degree with clinical and mycological results. Application of itraconazole in a soluble preparation caused an increase in efficacy due to simultaneous local and systemic action. In the case of resistance to fluconazole the itraconazole solution is a valuable alternative to the administration of amphotericin B which is rich in adverse reactions.

Characterization of amphotericin B aerosols for inhalation treatment of pulmonary aspergillosis.

In recent years, the incidence of invasive pulmonary aspergillosis has increased in patients receiving immunosuppressive therapy and/or organ transplantation. For prophylaxis against Aspergillus infections, amphotericin B may be a useful drug when inhaled as aerosol. In this study, the aerosolization of amphotericin B was investigated using eight different medical nebulizers under various operating conditions and with different amphotericin B concentrations in the solution. The output of each nebulizer was characterized by the mass flow of spray (drug) leaving the mouthpiece and by the size distribution of the droplets. An effective prevention of pulmonary aspergillosis via amphotericin B inhalation requires a high pulmonary deposition of the drug within an acceptable time of administration associated with a low deposition in the oropharyngeal region. To evaluate the dosages of drug delivered by various types of nebulizers to different regions of the respiratory tract, a semi-empirical deposition model was applied which is based on experimental aerosol deposition data from over 20 normal adults. The main results of the study are: Solutions with amphotericin B concentrations up to 10 mg/ml can be converted into sprays by means of medical nebulizers without any problems. For most nebulizers, the slight foaming of the amphotericin B solution has no effect on the production of the aerosol. To optimize amphotericin B treatment of the lungs via inhalation, sprays with mass flows above 100 mg/min and with mass median aerodynamic diameters (MMAD) below 3 microns should be slowly inhaled by the subject. Applying these criteria to the nebulizers investigated, three out of eight devices have proved suitable for amphotericin B treatment via inhalation.

Case report. Successful therapy of disseminated histoplasmosis in AIDS with liposomal amphotericin B.

A 36-year-old HIV-infected male patient presented with relapsing fever episodes to 39 degrees C, night sweats and weight loss. Computerized tomography of the abdomen showed enlarged multiple lymph nodes. After surgical resection of multiple lymph nodes, disseminated infection with Histoplasma capsulatum was diagnosed. Amphotericin B desoxycholate was initiated for 24 days. Fourteen days after therapy was discontinued, the patient suffered similar symptoms again. Subsequent treatment with liposomal amphotericin B led to rapid improvement within 3 days. Upon discharge, maintenance therapy with 600-mg itraconazole capsules was initiated and decreased to 400-mg 14-days later. Itraconazole therapy was continued until the patient died more than 2 years later because of complications of the underlying disease. At autopsy there were no signs of histoplasmosis.

Cryptococcus myelitis: atypical presentation of a common infection.

Cryptococcus neoformans is associated with as much as 45% of meningitis in patients admitted for hospital care in Zimbabwe, and it is an important opportunistic infection in patients infected with the human immunodeficiency virus. Cases of cryptococcosis presenting as a spinal cord syndrome have been reported from Zimbabwe and South Africa, but these were all cases of Cryptococcus vertebral osteomyelitis. We describe 3 unusual patients who presented with a myelitis-like syndrome without vertebral osteomyelitis.

Travel-acquired dengue infection: clinical spectrum and diagnostic aspects.

BACKGROUND: Dengue fever is increasingly recognized in travelers returning from endemic areas with acute febrile illness; however, its true burden in nonendemic countries is unknown. Only few studies focus on clinical manifestations and serological findings in primarily nonimmune individuals. PATIENTS AND METHODS: We analyzed the epidemiology, clinical manifestations and virological results in patients with imported acute dengue infection who presented at our travel clinic in Frankfurt am Main, Germany, between September 1998 and November 2000. An immunochromatographic test and an immunofluorescence assay were used for antibody testing. RESULTS: Dengue fever was confirmed in 13 patients, thus being the second commonest tropical infection after malaria in patients with fever and a travel history to a tropical country (18 cases per 1,000 patient visits per year). Most patients had only spent a short time abroad, either in South Central or South East Asia or in the Caribbean. CONCLUSION: The clinical features considered typical for dengue were not always present. Antibody assays were typically negative early in the course of disease, with seroconversion occurring only after cessation of clinical symptoms. A high index of suspicion is needed in these patients who often present without typical features of dengue and whose early antibody tests may be negative.

Fluconazole in the treatment of oropharyngeal candidosis in HIV-positive patients.

106 HIV-positive patients with 129 episodes of oropharyngeal Candida infection were treated with fluconazole (50-300 mg/d). Treatment lasted from 4 to 23 days. The majority of patients were in more advanced stages of HIV infection (82% AIDS cases). Therapy with fluconazole led to complete healing or improvement of clinical symptoms in 93% of all treatment courses. However, according to cultural findings, an elimination or recession of pathogens was achieved in only 70% of cases. Cultural monitoring showed a slow reduction of pathogens, as opposed to a fairly rapid clinical improvement. Candida albicans was the most frequently isolated Candida species (n = 128); the most selected Candida species during treatment were C. glabrata, C. krusei, and C. inconspicua. It is remarkable that C. glabrata, a low-grade pathogen, caused enanthema in 2 patients and a typical oral thrush in 1 patient. Fluconazole was well-tolerated, and apart from mild gastro-intestinal symptoms in 1 patient, no severe side effects were observed.

Itraconazole for prophylaxis of systemic mycoses in neutropenic patients with haematological malignancies.

The efficacy of oral itraconazole 2 x 200 mg capsules daily for prevention of systemic mycoses was investigated in granulocytopenic patients with haematological malignancies. Of 241 patients, 197 were evaluable for prophylactic efficacy, and 214 for adverse events. Patients with similar characteristics receiving oral amphotericin B as antifungal prophylaxis, observed over 15 months before introduction of itraconazole, served as control group (n = 223). With itraconazole prophylaxis, 13 cases of aspergillosis (9 proven, 1 probable, 3 possible; 7%) and no systemic yeast infection occurred, compared with 14 episodes of aspergillosis (9 proven, 2 probable, 3 possible; 6%) and 3 proven systemic yeast infections (Candida albicans, Candida norvegensis, Trichosporon beigelii) in the historical group. Adverse events were observed in 13% of evaluable patients receiving itraconazole. In four patients with acute lymphoblastic leukaemia receiving itraconazole and vincristine simultaneously, severe vinca alkaloid-induced neurotoxicity occurred. Plasma concentrations of itraconazole and hydroxyitraconazole were measured in 64 patients. After eight days of itraconazole the median drug concentration was adequate (700 ng/mL), but there was a marked individual variation (229-2861 ng/mL). In comparison with a historical group, antifungal prophylaxis with itraconazole reduced the incidence of systemic yeast infections, but the frequency of aspergillosis was similar. However, a general increasing incidence of aspergillus infections at our hospital over the last four years should be considered in the assessment of study results.