Phaeohyphomycosis fungal infections in solid organ transplant recipients: clinical presentation, pathology, and treatment.

BACKGROUND: Dematiaceous, or dark-pigmented, fungi are known to cause infections such as phaeohyphomycosis, chromoblastomycosis, and mycetoma. These fungi are becoming increasingly important opportunistic pathogens in solid organ transplant recipients (SOTR). We present a retrospective chart review of 27 SOTR who developed phaeohyphomycosis infections post transplant from 1988 to 2009. METHODS: Cases were reviewed for fungal species isolated, date and source of culture, immunosuppressive and fungal therapy used, and outcome. The majority of isolates obtained were from the skin and soft tissue, with 3 pulmonary and brain abscesses. RESULTS: The time from transplantation to onset of infection ranged from 2 months to 11 years. The species isolated were Exophiala (11), Ochroconis (3), Alternaria (2), Phoma (2), Wangiella (1), Cladosporium (1), Aureobasidium (1), Chaetomium (1), Coniothyrium (1), and non-sporulating fungi (2). An additional 4 patients had infections confirmed by pathology, but no cultures were done. Most of the affected skin lesions were surgically debrided and treated with itraconazole; 2 patients were treated with voriconazole and 2 with amphotericin D. Death from fungal disease occurred only in patients with pulmonary and brain abscesses. CONCLUSIONS: As the number of SOTR increases, so does the incidence of fungal infections in that population. Surgery, along with antifungal therapy and a reduction in immunosuppression, are the cornerstones of treatment.

Pulmonary cryptococcosis in patients without HIV infection: factors associated with disseminated disease.

Cryptococcus neoformans is an uncommonly recognized cause of pneumonia in HIV-negative patients. Because of its propensity to disseminate to the meninges and other sites, a lumbar puncture is recommended for patients with pulmonary cryptococcosis, regardless of other risk factors. This study explored clinical and laboratory features to help predict which patients had pulmonary disease alone versus those who had pulmonary plus extrapulmonary disease. A retrospective chart review at 15 medical centers was performed from 1990 to 2000 of all HIV-negative patients who had pulmonary cryptococcosis. Demographic, clinical, radiographic, and laboratory features were evaluated to determine factors that differentiated those patients who had extrapulmonary disease. Among 166 patients who had pulmonary cryptococcosis, 122 had pulmonary infection only and 44 had pulmonary plus extrapulmonary (disseminated) disease. A negative serum cryptococcal antigen titer was more common in patients with pulmonary disease alone (p < 0.01). Multivariate analysis demonstrated that patients who had disseminated disease were more likely than those who only had pulmonary disease to have cirrhosis (p = 0.049), headache (p < 0.001), weight loss (p = 0.003), fever (p = 0.035), altered mental status (p < 0.001), and to be receiving high-dose corticosteroids (p = 0.008). In this large cohort of HIV-negative patients with pulmonary cryptococcosis, there were easily distinguished clinical and laboratory features among patients with pulmonary disease alone versus those with pulmonary plus extrapulmonary disease. These findings may be helpful in the evaluation of HIV-negative patients with pulmonary cryptococcosis with regard to the need for lumbar puncture or to search for disseminated disease.

Clinical relevance of bacteriostatic versus bactericidal mechanisms of action in the treatment of Gram-positive bacterial infections.

The distinction between bactericidal and bacteriostatic agents appears to be clear according to the in vitro definition, but this only applies under strict laboratory conditions and is inconsistent for a particular agent against all bacteria. The distinction is more arbitrary when agents are categorized in clinical situations. The supposed superiority of bactericidal agents over bacteriostatic agents is of little relevance when treating the vast majority of infections with gram-positive bacteria, particularly in patients with uncomplicated infections and noncompromised immune systems. Bacteriostatic agents (e.g., chloramphenicol, clindamycin, and linezolid) have been effectively used for treatment of endocarditis, meningitis, and osteomyelitis--indications that are often considered to require bactericidal activity. Although bacteriostatic/bactericidal data may provide valuable information on the potential action of antibacterial agents in vitro, it is necessary to combine this information with pharmacokinetic and pharmacodynamic data to provide more meaningful prediction of efficacy in vivo. The ultimate guide to treatment of any infection must be clinical outcome.

Cryptococcosis in human immunodeficiency virus-negative patients in the era of effective azole therapy.

We conducted a case study of human immunodeficiency virus (HIV)-negative patients with cryptococcosis at 15 United States medical centers from 1990 through 1996 to understand the demographics, therapeutic approach, and factors associated with poor prognosis in this population. Of 306 patients with cryptococcosis, there were 109 with pulmonary involvement, 157 with central nervous system (CNS) involvement, and 40 with involvement at other sites. Seventy-nine percent had a significant underlying condition. Patients with pulmonary disease were usually treated initially with fluconazole (63%); patients with CNS disease generally received amphotericin B (92%). Fluconazole was administered to approximately two-thirds of patients with CNS disease for consolidation therapy. Therapy was successful for 74% of patients. Significant predictors of mortality in multivariate analysis included age > or =60 years, hematologic malignancy, and organ failure. Overall mortality was 30%, and mortality attributable to cryptococcosis was 12%. Cryptococcosis continues to be an important infection in HIV-negative patients and is associated with substantial overall and cause-specific mortality.

Deep dermatophytosis: report of 2 cases and review of the literature.

Skin infections due to dermatophytes are common and generally associated with a low degree of morbidity in normal hosts. Rare cases have been reported in which the dermatophyte invaded the deep dermis, subcutis, or even internal organs. Two patients, each of whom had clinical and histological findings of a deep or locally invasive dermatophyte infection, are described. This condition typically presents as a nodular eruption that is characterized histologically by suppurative granulomatous inflammation and deposition of organisms in the reticular dermis. Recognition of the potential of dermatophytes for local invasion in susceptible hosts will help ensure proper diagnosis and timely intervention in these cases.

Resolution of rhinocerebral zygomycosis associated with adjuvant administration of granulocyte-macrophage colony-stimulating factor.

We successfully treated 3 consecutive patients who had nonneutropenic rhinocerebral zygomycosis, by use of subcutaneous granulocyte-macrophage colony-stimulating factor therapy combined with traditional surgical and medical treatment. All patients are currently free of disease. Granulocyte-macrophage colony-stimulating factor should be considered as adjuvant therapy for rhinocerebral zygomycosis; however, optimum dose and length of therapy are unknown.

Practice guidelines for diseases caused by Aspergillus. Infectious Diseases Society of America.

Aspergillosis comprises a variety of manifestations of infection. These guidelines are directed to 3 principal entities: invasive aspergillosis, involving several organ systems (particularly pulmonary disease); pulmonary aspergilloma; and allergic bronchopulmonary aspergillosis. The recommendations are distilled in this summary, but the reader is encouraged to review the more extensive discussions in subsequent sections, which show the strength of the recommendations and the quality of the evidence, and the original publications cited in detail. Invasive aspergillosis. Because it is highly lethal in the immunocompromised host, even in the face of therapy, work-up must be prompt and aggressive, and therapy may need to be initiated upon suspicion of the diagnosis, without definitive proof (BIII). Intravenous therapy should be used initially in rapidly progressing disease (BIII). The largest therapeutic experience is with amphotericin B deoxycholate, which should be given at maximum tolerated doses (e.g., 1-1.5 mg/kg/d) and should be continued, despite modest increases in serum creatinine levels (BIII). Lipid formulations of amphotericin are indicated for the patient who has impaired renal function or who develops nephrotoxicity while receiving deoxycholate amphotericin (AII). Oral itraconazole is an alternative for patients who can take oral medication, are likely to be adherent, can be demonstrated (by serum level monitoring) to absorb the drug, and lack the potential for interaction with other drugs (BII). Oral itraconazole is attractive for continuing therapy in the patient who responds to initial iv therapy (CIII). Therapy should be prolonged beyond resolution of disease and reversible underlying predispositions (BIII). Adjunctive therapy (particularly surgery and combination chemotherapy, also immunotherapy), may be useful in certain situations (CIII). Aspergilloma. The optimal treatment strategy for aspergilloma is unknown. Therapy is predominantly directed at preventing life-threatening hemoptysis. Surgical removal of aspergilloma is definitive treatment, but because of significant morbidity and mortality it should be reserved for high-risk patients such as those with episodes of life-threatening hemoptysis, and considered for patients with underlying sarcoidosis, immunocompromised patients, and those with increasing Aspergillus-specific IgG titers (CIII). Surgical candidates would need to have adequate pulmonary function to undergo the operation. Bronchial artery embolization rarely produces a permanent success, but may be useful as a temporizing procedure in patients with life-threatening hemoptysis. Endobronchial and intracavitary instillation of antifungals or oral itraconazole may be useful for this condition. Since the majority of aspergillomas do not cause life-threatening hemoptysis, the morbidity and cost of treatment must be weighed against the clinical benefit. Allergic bronchopulmonary aspergillosis (APBA). Although no well-designed studies have been carried out, the available data support the use of corticosteroids for acute exacerbations of ABPA (AII). Neither the optimal corticosteroid dose nor the duration of therapy has been standardized, but limited data suggest the starting dose should be approximately 0.5 mg/kg/d of prednisone. The decision to taper corticosteroids should be made on an individual basis, depending on the clinical course (BIII). The available data suggest that clinical symptoms alone are inadequate to make such decisions, since significant lung damage may occur in asymptomatic patients. Increasing serum IgE levels, new or worsening infiltrate on chest radiograph, and worsening spirometry suggest that corticosteroids should be used (BII). Multiple asthmatic exacerbations in a patient with ABPA suggest that chronic corticosteroid therapy should be used (BIII). Itraconazole appears useful as a corticosteroid sparing agent (BII). (ABSTRACT TRUNCATED)

Hepatitis E seroconversion in United States travelers abroad.

Sporadic cases of symptomatic hepatitis E virus (HEV) infection have been reported in United States travelers to developing countries, including Mexico and Pakistan. To evaluate the risk of exposure in United States travelers, 356 patients seen in our Travel Clinics were tested for antibodies to HEV before and 6 weeks after traveling. Samples obtained 6 months after traveling were available for 211 travelers. IgG and IgM antibodies to HEV were assayed with HEV ELISA diagnostic kits containing 3 recombinant antigens expressed in Escherichia coli representing immunodominant epitopes within open reading frames 2 and 3 of HEV. Nine patients were IgG seropositive in specimens obtained before travel. Four individuals seroconverted. In all 4 patients, IgG seroconversion was demonstrated in samples obtained at least 6 months after return. Samples obtained 6 weeks after return were seronegative for HEV in all 3 patients for whom such samples were available. Travel destinations were diverse: Thailand, China, Russia, and Peru. These data are consistent with an infection acquired while traveling. None of the seropositive subjects reported any symptoms of hepatitis before or after travel. In the absence of overt disease, these results imply that exposure to HEV resulted in subclinical infections.

Central nervous system lesions in liver transplant recipients: prospective assessment of indications for biopsy and implications for management.

BACKGROUND: Precise diagnosis of central nervous system (CNS) lesions in liver transplant recipients remains problematic. Brain biopsies are often not feasible as a result of coagulopathy. We sought to determine whether selected clinical or radiologic characteristics can predict the likely etiology of CNS lesions in liver transplant recipients and thus obviate the need for diagnostic brain biopsies. METHODS: A 4-year prospective, observational, cohort study was conducted at liver transplant centers at four geographically diverse medical institutions. A total of 1730 consecutive liver transplant recipients were evaluated for CNS lesions; 60 patients with radiologically documented CNS lesions comprised the study sample. RESULTS: Vascular events (52%, 31/60), infections (181%, 11/60), immunosuppressive associated leukoencephalopathy (12%, 7/60), central pontine myelinolysis (8%, 5/60), and malignancy (3%, 2/60) were the predominant etiologies of CNS lesions. CNS lesions were most likely to occur within 30 days of transplantation (43%, 26/60); central pontine myelinolysis, subdural hematoma, acute infarcts, and Aspergillus brain abscesses were the predominant etiologies during this time. All brain abscesses were fungal; 73% (8/11) of these patients concurrently had documented extraneural (pulmonary) infection as a result of the same fungal pathogen. Thus, a diagnostic brain biopsy is not warranted in these patients. Patients on dialysis were more likely to have ischemic or infectious CNS lesions (P=0.03). Vascular events were more likely to occur in repeat transplant recipients (P=0.03). Twenty-five percent (15/60) of the CNS lesions occurred more than 1 year after transplantation; small vessel ischemic lesions, malignancy, or non-Aspergillus fungal brain abscesses accounted for all such lesions. CONCLUSIONS: A presumptive etiologic diagnosis can be established in a vast majority of CNS lesions in liver transplant recipients based on identifiable presentation that includes time of onset, unique risk factors, and neuroimaging characteristics. Empiric therapy of brain abscesses in liver transplant recipients should include antifungal and not antibacterial agents.

Strongyloides hyperinfection in a renal transplant recipient receiving cyclosporine: possible Strongyloides stercoralis transmission by kidney transplant.

Strongyloides hyperinfection and dissemination are recognized complications in kidney allograft recipients; however, the development of strongyloidiasis in renal transplant recipients receiving cyclosporine A (CyA) has not been described, nor has the development of strongyloidiasis in other organ transplant recipients. The former observation has been attributed to the antiparasitic activity of CyA seen in animal studies; the latter has no explanation yet. We report the first case of Strongyloides hyperinfection in a renal transplant patient occurring immediately after CyA was discontinued. From the unique characteristics of this case, it appears that the anti-Strongyloides activity of CyA in animals may also be found in humans.

Invasive aspergillosis in liver transplant recipients in the 1990s.

Invasive aspergillosis occurred in 26 liver transplant recipients since 1990 at five liver transplant centers. The median time to onset was 17 days after transplantation. Twenty-seven percent of the patients had undergone retransplantation. Invasive aspergillosis occurred significantly earlier after transplantation in smokers than in nonsmokers (P=0.017). Patients with late-onset aspergillosis (occurring after posttransplant day 90) were more likely to have had prior cytomegalovirus infection than those with early-onset aspergillosis (occurring within 90 days of transplantation) (67% vs. 10%, respectively, P=0.013). Only 8% of the patients had received additional corticosteroids or OKT3, which suggests that augmented immunosuppression may not be a relevant risk factor for invasive aspergillosis in the 1990s due to less frequent use of these agents. The median serum bilirubin level of the patients was 21.8 mg/dl, 85% of the patients had renal insufficiency, and 54% were on dialysis before the onset of invasive aspergillosis, which suggest that overall severity of illness, including poorly functioning hepatic allograft and renal failure may be the major determinants of disease occurrence. Overall mortality was 92% (24/26). No difference in mortality could be shown for the patients who received amphotericin B versus liposomal amphotericin B preparations (100% vs. 89%); however, the mean time to death after the initiation of therapy was 20 days in patients who received amphotericin B and 43 days in those who received liposomal amphotericin B preparations.

Comparison of the amplified Mycobacterium tuberculosis (MTB) direct test, Amplicor MTB PCR, and IS6110-PCR for detection of MTB in respiratory specimens.

Several nucleic acid amplification techniques (NAAT) have been developed for rapid and direct detection of Mycobacterium tuberculosis (MTB) from clinical specimens. This study compared the performances of the Gen-Probe Amplified MTB Direct Test (AMDT), Roche Amplicor MTB PCR test, and an IS6110-PCR assay with acid-fast smear and culture in the detection of MTB from 428 respiratory specimens from 259 patients. Patients' charts were reviewed for clinical correlation. Of 98 specimens that were clinically positive for MTB, acid-fast smear was positive in 50% of cases, culture in 93%, IS6110-PCR in 83%, AMDT in 84%, and Amplicor MTB PCR in 80%. Of 337 specimens that were negative for MTB, 117 (35%) were positive for nontuberculous mycobacteria. Specificities were as follows: smear, 89%; culture, 100%; IS6110-PCR, 99%; AMDT, 98%; and Amplicor MTB PCR, 96%. The accuracies of the tests were 80%, 98%, 96%, and 92%, respectively. MTB culture-positive specimens that were smear-negative were detected by AMDT and IS6110-PCR in 77% of cases and by Amplicor MTB PCR in 70%. NAAT was less sensitive than was culture for detection of MTB, but all these techniques had acceptable accuracy and were completed within hours. NAAT may be useful for rapid screening of respiratory specimens to distinguish MTB from nontuberculous mycobacteria infection in order to isolate patients.

Multicenter, phase IV evaluation of intravenous ciprofloxacin as initial therapy in patients with lower respiratory tract, urinary tract, and skin/skin structure infections.

A prospective, open-label, multicenter, Phase IV study of the efficacy and safety of intravenous (IV) ciprofloxacin (400 mg by 60-minute infusion every 12 hours) in the treatment of lower respiratory tract infections (LRTIs), urinary tract infections (UTIs), and skin/skin structure infections (SSSIs) in hospitalized patients was conducted in 1991. After a minimum of 3 days of IV therapy, patients could be switched to oral therapy with any antimicrobial. Of 360 patients who were valid for investigator assessment of clinical outcome at the end of IV therapy, a favorable outcome (cure and improvement in infection) was reported in 337 (94%) patients and failure was reported in 23 (6%) patients. Of 330 patients valid for investigation assessment of clinical outcome at the end of all therapy (IV treatment alone or IV treatment followed by an oral antimicrobial), a favorable outcome was noted in 311 (94%) patients, and failure occurred in 19 (6%) patients. Adverse events were noted in 72 (9%) of 782 patients and led to premature discontinuation of IV therapy in 23 (3%) patients. IV ciprofloxacin appears to be effective and safe in the management of mild-to-moderate LRTI and SSSI and mild, moderate, or severe UTI in hospitalized patients.

Dermatologic manifestations of nontuberculous mycobacterial diseases.

Various nontuberculous mycobacteria can cause infection of skin and soft tissues. These organisms are also known as atypical mycobacteria, anonymous mycobacteria, and mycobacteria other than tuberculosis. These organisms are much more common causes of cutaneous infection than Mycobacterium tuberculosis. Infections caused by nontuberculous mycobacteria are frequently misdiagnosed because clinicians fail to include them in the differential diagnosis of chronic skin infection.

Optimum outpatient therapy of skin and skin structure infections.

Skin and skin structure infections appear in a variety of ways with multiple aetiologies. Optimum therapy is accomplished with a good understanding of both skin anatomy and common resident or transient bacterial flora present on the skin surface. Primary and secondary infections occur in both immunocompetent and immunocompromised patients, each of which require unique decision-making skills on the part of the prescriber. Deciding when culture and sensitivity should be performed or therapy should be begun empirically is often difficult and can be frustrating. This is complicated by the ever-increasing number of antimicrobial agents available today and their variable costs. Choosing the best antibiotic agent, based on evidence of which is the most effective agent for a particular lesion, the easiest dosage schedule and the most economical drug, is a goal that will best serve both the patient and the physician.

Infections in orthotopic heart transplant patients at the Ochsner Medical Institutions.

Ninety-five orthotopic heart transplants were performed at the Ochsner Foundation Hospital. Twenty-nine of 62 patients followed for 1 year had 48 major infections, including 20 bacterial, 15 viral, 7 fungal, and 6 parasitic. Eighty-six percent of all patients survived 1 year, but infections caused five of the nine deaths. Improved diagnosis and therapy of disseminated aspergillosis could have prevented two deaths.

Temafloxacin: an overview.

Temafloxacin (6-fluoro-7-piperazino-4-quinolone) is a new fluoroquinolone with a 7-8 hour half-life and rapid gastrointestinal absorption. These characteristics make it an ideal antimicrobial for once- or twice-daily oral dosing. With the exception of the central nervous system (CNS), temafloxacin has excellent tissue and body fluid penetration and concentration. Temafloxacin has broad antimicrobial activity against gram-positive and gram-negative bacteria, including improved in vitro activity against Streptococcus pneumoniae, Mycoplasma hominis, and anaerobic bacteria, including Bacteroides fragilis. Temafloxacin is as effective as beta-lactam therapy and superior to ciprofloxacin in the treatment of S. pneumoniae lower respiratory infections. It has been clinically effective when given in a short 3-day regimen for the treatment of uncomplicated urinary tract infections. Multiple clinical trials indicate that temafloxacin is also clinically effective, well tolerated, and safe for use in adult patients for the treatment of other lower respiratory tract, genitourinary tract, and skin and skin-structure infections.

Diagnosis of disseminated cytomegalovirus infection and pneumonitis in a heart transplant recipient by skin biopsy: case report.

A pulmonary infection caused by both Toxoplasma gondii and cytomegalovirus (CMV) developed in a heart transplant recipient. A presumptive diagnosis of CMV pneumonitis was made on the basis of a skin biopsy finding demonstrating CMV inclusions. This diagnosis was later supported by a positive pleural fluid culture for CMV, a greater than fourfold increase in CMV IgG antibody, and a response to therapy with ganciclovir sodium. Biopsy of skin lesions in patients at risk for CMV infections may represent an important early diagnostic tool.