Cryptococcal meningitis post autologous stem cell transplantation.

Disseminated Cryptococcus disease occurs in patients with defective T-cell immunity. Cryptococcal meningitis following autologous stem cell transplant (SCT) has been described previously in only 1 patient, 4 months post SCT and while off antifungal prophylaxis. We present a unique case of Cryptococcus meningitis pre-engraftment after autologous SCT, while the patient was receiving fluconazole prophylaxis. A 41-year-old man with non-Hodgkin's lymphoma underwent autologous SCT. Post-transplant prophylaxis consisted of fluconazole 400 mg daily, levofloxacin 500 mg daily, and acyclovir 800 mg twice daily. On day 9 post transplant, he developed fever and headache. Peripheral white blood cell count (WBC) was 700/µL. Magnetic resonance imaging of the brain showed lesions consistent with meningoencephalitis. Cerebrospinal fluid (CSF) analysis revealed a WBC of 39 with 77% lymphocytes, protein 63, glucose 38, CSF pressure 20.5 cmH2 O, and a positive cryptococcal antigen. CSF culture confirmed Cryptococcus neoformans. The patient was treated with liposomal amphotericin B 5 mg/kg intravenously daily, and flucytosine 37.5 mg/kg orally every 6 h. He was switched to fluconazole 400 mg daily after 3 weeks of amphotericin therapy, with sterilization of the CSF with negative CSFCryptococcus antigen and negative CSF culture. Review of the literature revealed 9 cases of cryptococcal disease in recipients of SCT. Median time of onset was 64 days post transplant. Only 3 meningitis cases were described; 2 of them after allogeneic SCT. Fungal prophylaxis with fluconazole post autologous SCT is recommended at least through engraftment, and for up to 100 days in high-risk patients. A high index of suspicion is needed to diagnose and treat opportunistic infections, especially in the face of immunosuppression and despite adequate prophylaxis. Infection is usually fatal without treatment, thus prompt diagnosis and therapy might be life saving.

Donor-derived fungal infections in organ transplant recipients: guidelines of the American Society of Transplantation, infectious diseases community of practice.

Donor-derived fungal infections can be associated with serious complications in transplant recipients. Most cases of donor-derived candidiasis have occurred in kidney transplant recipients in whom contaminated preservation fluid is a commonly proposed source. Donors with cryptococcal disease, including those with unrecognized cryptococcal meningoencephalitis may transmit the infection with the allograft. Active histoplasmosis or undiagnosed and presumably asymptomatic infection in the donor that had not resolved by the time of death can result in donor-derived histoplasmosis in the recipient. Potential donors from an endemic area with either active or occult infection can also transmit coccidioidomycosis. Rare instances of aspergillosis and other mycoses, including agents of mucormycosis may also be transmitted from infected donors. Appropriate diagnostic evaluation and prompt initiation of appropriate antifungal therapy are warranted if donor-derived fungal infections are a consideration. This document discusses the characteristics, evaluation and approach to the management of donor-derived fungal infections in organ transplant recipients.

False-positive Aspergillus galactomannan assay in solid organ transplant recipients with histoplasmosis.

Post-transplantation histoplasmosis may be acquired via inhalation, may result from endogenous reactivation, or may be derived from the allograft. The Histoplasma and Aspergillus enzyme-linked immunoassays are increasingly being relied upon for rapid diagnosis of fungal infections, especially in immunocompromised patients. We describe 4 cases of solid organ transplant recipients who had histoplasmosis and a falsely positive Aspergillus galactomannan (GM) obtained from the serum or bronchoalveolar lavage (BAL) fluid. We also report our experience, testing for Histoplasma antigen (Ag) in specimens positive for Aspergillus GM. From January 2007 through December 2010, of 2432 unique patients who had positive Aspergillus GM tests, 514 (21%) were tested for Histoplasma Ag, and 27 were found to be positive. Most specimens that tested positive for both Aspergillus and Histoplasma were obtained by BAL. False-positive tests for Aspergillus GM can occur in immunosuppressed patients who have histoplasmosis, and may obscure the correct diagnosis.

Effect of an oral probiotic nutraceutical containing Aspergillus-derived ingredients on a serum and urine galactomannan antigen assay in dogs.

A commercial Aspergillus galactomannan antigen (GMA) enzyme linked immunosorbent assay (ELISA) is used to support a diagnosis of systemic aspergillosis in dogs. In human patients, false positive results have been associated with administration of medications derived from molds. We sought to determine the effect of administration of a commercially available oral probiotic nutraceutical that contained Aspergillus-derived ingredients on serum and urine Aspergillus GMA levels in dogs by conducting a prospective, cross-over study. Galactomannan index (GMI) was measured on the solubilized probiotic nutraceutical and was positive (GMI ≥ 0.5) with a mean of 7.91. Serum and urine galactomannan indices were measured in 10 healthy dogs before (day 0) and after 1 week (day 7) of probiotic nutraceutical administration, then again 2 weeks after the probiotic nutraceutical was discontinued (day 21). Median (range) serum GMI were 0.19 (0.08-0.62), 0.22 (0.07-1.15) and 0.17 (0.14-0.63) at day 0, 7 and 21, respectively. Two of 10 dogs developed positive GMI (≥0.5) results after probiotic nutraceutical administration; however, no significant changes were noted over the study period. Median (range) urine GMI results were 0.06 (0.04-0.22), 0.07 (0.05-0.41) and 0.06 (0.03-0.16) at day 0, 7 and 21, respectively. A trend towards an increase urine GMI was noted between day 0 and 7 (P = 0.18), and decrease was noted between day 7 and 21 (P = 0.09). Administration of probiotics containing Aspergillus-derived ingredients to dogs did not reliably result in elevated Aspergillus GMA levels.

Diagnosis of acute pulmonary histoplasmosis by antigen detection.

BACKGROUND: Antigen detection, which has proven useful in diagnosis of disseminated histoplasmosis, has not been studied in acute pulmonary histoplasmosis (APH). Because treatment is indicated in most patients with moderately severe or severe APH, antigen detection for rapid diagnosis could be helpful. METHODS: Histoplasma antigen detection was evaluated in 130 patients with APH. RESULTS: Antigenuria was detected in 64.6%, antigenemia in 68.6%, and antibody in 64.3%. If both urine and serum specimens were tested, antigen was detected in 82.8%, of which 45.8% had antigenemia only; and if both antigen and antibody were measured, results were positive in 93.3%, of which antigen only was positive in 35.7%. CONCLUSIONS: Testing for antigenemia, antigenuria, and antibodies using the complement fixation test offers a sensitive, noninvasive method for diagnosis of APH.

Antigen Concentrations as an Indicator of Clinical Remission and Disease Relapse in Cats with Histoplasmosis.

BACKGROUND: Treatment monitoring is subjective and disease relapse is common in cats with histoplasmosis. The Histoplasma antigen enzyme immunoassay (EIA) is a noninvasive test used for determining disease remission and detecting disease relapse in humans with histoplasmosis. The utility of the antigen EIA for these purposes in cats remains unknown. HYPOTHESIS/OBJECTIVES: Those Histoplasma antigen concentrations in urine and serum would decline with antifungal treatment and that antigen elimination would be an indicator of clinical remission in cats with histoplasmosis treated with antifungal treatment. ANIMALS: Fifteen client-owned cats with histoplasmosis. METHODS: Masked observational study. Cats were monitored monthly during antifungal treatment. Time of clinical remission and serum and urine antigen elimination were determined for each cat. RESULTS: Twelve of 15 cats achieved clinical remission. At the time of diagnosis, antigen was detectable in urine in 14/15 (93%) cats and in serum in 11/15 (73%) cats. Both serum (P < .0005) and urine (P < .0001) antigen concentrations significantly decreased over time with effective treatment. Antigen elimination was sensitive [urine, 90.0% (95% CI 72.3-97.4%); serum, 90.4% (68.2-98.3%)] but less specific [urine, 64.6% (51.7-75.8%); serum, 52.1% (37.4-66.5%)] for disease remission. Urine antigen was positive in both cats and serum antigen was positive in 1 cat at the time of disease relapse. CONCLUSIONS AND CLINICAL IMPORTANCE: Measurement of Histoplasma antigen in urine and serum might be useful tests for determining disease remission and relapse in cats with histoplasmosis. Further research is needed to investigate the importance of low-level antigenemia and antigenuria.

Treatment of Disseminated Aspergillosis with Posaconazole in 10 Dogs.

BACKGROUND: Few effective treatments for disseminated Aspergillus infections in dogs are available. Posaconazole has potent and broad-spectrum activity against Aspergillus spp., but its use has not yet been sufficiently evaluated in dogs. HYPOTHESIS/OBJECTIVES: The aim of this study was to determine the safety and efficacy of posaconazole for the treatment of naturally occurring disseminated Aspergillus infections in dogs. ANIMALS: Ten client-owned dogs with disseminated aspergillosis. METHODS: Prospective, nonrandomized, noncontrolled study with posaconazole administered to dogs at dosage of 5 mg/kg p.o. q12h. The primary veterinarian or the veterinary specialist caring for the dogs provided patient data. RESULTS: The treatment response for dogs with disseminated disease while receiving posaconazole was defined as clinical remission (n = 4) and clinical improvement (n = 6). There was a high rate of relapse during treatment or after cessation of treatment in both groups, and most dogs died or were euthanized due to progressive disease. Excluding 1 dog concurrently treated with terbinafine that remains alive 5 years after diagnosis, the mean survival time for dogs was 241 days (range 44-516 days). Three other dogs lived >1 year after starting treatment. No clinically relevant adverse events or increases in serum liver enzyme activity occurred during treatment with posaconazole. CONCLUSIONS AND CLINICAL IMPORTANCE: Posaconazole appears to be safe and well-tolerated for treatment of disseminated Aspergillus infections in dogs. Long-term survival >1 year is possible with prolonged treatment, but relapse is common.

Diagnosis and management of central nervous system histoplasmosis.

Two cases of Histoplasma meningitis are presented, illustrating the difficulty in diagnosis and treatment. The first case occurred in a patient with acquired immunodeficiency syndrome as a relapse of disseminated histoplasmosis and resolved after prolonged treatment and ongoing antiretroviral therapy. The second case occurred in a cardiac allograft recipient as meningitis and focal brain lesions that responded to liposomal amphotericin B, but the patient died shortly after therapy was completed. Unfortunately, there are no prospective studies addressing the diagnosis and management of patients with histoplasmosis of the central nervous system from which to provide evidence-based guidelines for care. In the absence of such data, an approach will be presented on the basis of our experience and opinions.

Treatment of an amebic liver abscess with intravenous metronidazole.

A case of amebic liver abscess was treated in which the abscess was not visualized by hepatic ultrasonography, thus delaying the diagnosis and initiation of appropriate therapy. The abscess was surgically drained because of imminent rupture. Postoperatively, the patient was unable to take oral medications and was successfully treated with intravenously administered metronidazole. Hepatic ultrasonography should not be relied on to rule out liver abscesses. We suggest that parenteral metronidazole should be considered as an alternate therapy to dehydroemetine in patients who are not able to take oral medications.

Hematogenous vertebral osteomyelitis. Pasteurella multocida as the causative agent.

Human disease caused by Pasteurella multocida is well documented, and a wide variety of clinical syndromes have been described. We describe herein a patient with vertebral osteomyelitis, discitis, and paravertebral abscess caused by P multocida, a presentation that has not been described previously, to our knowledge.

Sarcoidlike manifestations of histoplasmosis.

We have evaluated 11 patients with sarcoidosis accompanied by laboratory evidence for histoplasmosis. Clinical findings were typical of those described in sarcoidosis. Eight patients were treated with corticosteroids and responded promptly without progression of histoplasmosis. One patient received a 35 mg/kg course of amphotericin B without clinical improvement, but responded appropriately to corticosteroid therapy. Another patient had positive sputum cultures for Histoplasma capsulatum 5 years after initial diagnosis of sarcoidosis, but showed no improvement in the pulmonary infiltrate after treatment with amphotericin B. Although histoplasmosis and sarcoidosis may be interrelated in several ways, we postulate that H capsulatum may have triggered a chronic inflammatory disease recognized as sarcoidosis in some of these patients, a hypothesis yet to be tested. Alternative explanations for the association of histoplasmosis and sarcoidosis include the coincidental occurrence of two separate illnesses in a "hyperendemic" area for histoplasmosis and false-positive serologic test results caused by the heightened humoral immune response observed in sarcoidosis.

Solid-phase radioimmunoassay for IgG antibodies to Staphylococcus epidermidis. Use in serious coagulase-negative staphylococcal infections.

A radioimmunoassay (RIA) for human IgG antibodies to Staphylococcus epidermidis was compared with an agar-gel-diffusion assay in patients with a variety of infections. The RIA was sensitive and reproducible and discriminated between endocarditis and uncomplicated bacteremias due to coagulase-negative staphylococci. Anti-S epidermidis antibodies by RIA were elevated in 16 (89%) of 18 patients with coagulase-negative staphylococcal endocarditis but in none of 28 patients with uncomplicated bacteremia (n = 18) or with blood culture contaminated with these organisms (n = 10). Cross-reacting IgG antibodies to S epidermidis antigens were also detected by RIA in 13 (76%) of 17 patients with Staphylococcus aureus endocarditis but in none of 17 patients with nonvalvular S aureus bacteremias and in none of 25 patients with endocarditis or bacteremia caused by other pathogens. Agar-gel-diffusion assay was less sensitive than RIA for detecting coagulase-negative staphylococcal endocarditis, being positive in nine (50%) of 18 such patients. This RIA may be useful in distinguishing patients with endocarditis from those with nonvalvular staphylococcemias or blood culture contamination.

Significance of Histoplasma antigen in the cerebrospinal fluid of patients with meningitis.

A radioimmunoassay was previously developed for detection of Histoplasma capsulatum antigen in the blood and urine of patients with disseminated histoplasmosis. In this investigation, cerebrospinal fluid (CSF) specimens from 14 episodes of Histoplasma meningitis occurring in 12 patients were tested by radioimmunoassay. Histoplasma capsulatum antigen was detected in the CSF of five patients. Cerebrospinal fluid cultures were positive for H capsulatum in three of these five patients. Antibodies to H capsulatum were found in nine of the 13 CSF specimens tested. The radioimmunoassay for Histoplasma antigen was also positive in the CSF in one of 11 patients with coccidioidal meningitis but not in 17 patients with cryptococcal meningitis. It was concluded that Histoplasma antigen is present in the CSF of some patients with histoplasmosis and chronic meningitis, but cross-reactions may occur in patients with coccidioidal meningitis.

Piperacillin and gentamicin v carbenicillin and gentamicin for treatment of serious gram-negative infections.

Piperacillin sodium, a new penicillin with remarkable in vitro activity against Pseudomonas aeruginosa and other Gram-negative bacilli, and gentamicin sulfate were compared with carbenicillin disodium and gentamicin in a prospective, randomized, double-blind comparison for treating serious Gram-negative infections. Of the 32 patients whose courses were "evaluable" for efficacy, 12 of 14 who received piperacillin and gentamicin and 13 of 18 who received carbenicillin and gentamicin had favorable outcomes. Of the 99 patients whose courses were evaluable for toxicity, nine of 51 recipients of piperacillin and gentamicin and 15 of 48 recipients of carbenicillin and gentamicin suffered clinical reactions possibly, probably, or definitely related to the penicillin. No statistically significant differences were found in the two groups in the frequencies of biochemical abnormalities, including hypokalemia, that occurred in 19 or 44 recipients of piperacillin and gentamicin and 16 of 45 recipients of carbenicillin and gentamicin. Thus, this study did not prove differences in efficacy of toxicity for piperacillin and gentamicin plus carbenicillin and gentamicin for serious Gram-negative infections.

Systemic salmonellosis in patients with disseminated histoplasmosis. Case for 'macrophage blockade' caused by Histoplasma capsulatum.

Five patients are described with disseminated histoplasmosis and systemic salmonellosis. Four of these patients were also immunocompromised because of the acquired immunodeficiency syndrome in two patients and renal transplantation in another two patients. Histologic studies in two patients showed histiocytes that were heavily laden with Histoplasma capsulatum yeast-phase organisms. We postulate that diffuse parasitization of the reticuloendothelial system (RES) by Histoplasma organisms may cause "RES blockade," which then predisposes to systemic salmonellosis, as reported in certain other infections and in sickle cell anemia.

Diabetic foot infections. Bacteriologic analysis.

Diabetic patients with foot infections were prospectively evaluated over a two-year period. Cultures from reliable specimens avoiding contamination with foot ulcers were obtained in 54 infectious episodes. Staphylococcus species, Enterococcus species, Corynebacterium species, and various species of Enterobacteriaceae were commonly isolated. Common anaerobic isolates included Peptostreptococcus magnus, Peptostreptococcus prevotii, and Bacteroides species. Results of cultures from 94 unreliable specimens were similar. Results of reliable and unreliable specimens obtained simultaneously in 26 patients agreed in seven (27%), but antibiotics selected for organisms isolated from unreliable specimens would have adequately covered pathogens found in the reliable culture in 24 (93%). Diabetic foot infections usually involve mixed bacterial flora, including aerobic, facultatively anaerobic, and anaerobic microorganisms. Specimens should be obtained from infected tissue that does not communicate directly with the foot ulcer if possible. If such specimens are not available, cultures of purulent exudate within the foot ulcer or soft-tissue sinuses may provide useful information on which to base decisions about antibiotic therapy. Broad-spectrum beta-lactam antibiotics or a combination of antibiotics active against facultatively anaerobic cocci and bacilli as well as anaerobes provide the best empirical antimicrobial coverage in these patients.

Histoplasmosis in renal allograft recipients. Two large urban outbreaks.

During two large outbreaks, ten episodes of histoplasmosis were documented in eight renal allograft recipients. Another episode occurred before the outbreaks. Associated infections with cytomegalovirus occurred in five patients and may have further impaired cellular immunity. Prolonged fever was the predominant clinical finding; and dissemination was observed in seven of our nine patients, including three with meningitis. Special stains of tissues and the histoplasmal complement fixation test provided useful diagnostic information rapidly, while cultures were eventually positive in seven patients. Treatment with amphotericin B resulted in prompt clinical improvement in all patients, but relapse occurred in two patients one year following therapy.

Infection and diabetes mellitus.

Most physicians believe that diabetic individuals are predisposed to infections and that infection complicates the control of the diabetes. However, only bacteriuria can be documented to occur with increased frequency in diabetic compared with nondiabetic patients. Although most bacteriuric diabetic patients are asymptomatic, severe infections such as emphysematous pyelonephritis, papillary necrosis, perinephric abscess, and candida pyelonephritis may occur. Tuberculosis, once a proven threat to diabetic individuals, is a less serious problem now that effective screening and chemoprophylaxis programs have been initiated. Several unusual infections such as malignant external otitis, rhinocerebral mucormycosis, emphysematous pyelonephritis, and emphysematous cholecystitis occur also exclusively in diabetics. Foot infections are very important in diabetic patients; successful treatment requires accurate assessment of the extent and etiology of the infections and often involves surgery as well as broad antibiotic coverage. The important problem of infection in diabetic patients deserves careful evaluation. Questions such as do diabetic individuals have a higher incidence of infection, why are diabetic patients predisposed to infection, why is necrosis common in several of the infections, what is the course of asymptomatic bacteriuria, who do diabetic patients develop foot infections, and how should foot infections be prevented and treated should be topics of clinical investigation.

Amphotericin B oral suspension for fluconazole-refractory oral candidiasis in persons with HIV infection. Adult AIDS Clinical Trials Group Study Team 295.

OBJECTIVE: To determine the efficacy and safety of amphotericin B oral suspension (ABOS) for the treatment of fluconazole refractory oral candidiasis in persons with HIV infection. DESIGN AND SETTING: A prospective, multicenter, open label trial at 25 study centers within the AIDS Clinical Trials Group. PATIENTS AND METHODS: Individuals with diffuse oral candidiasis after 14 days of treatment with 200 mg of fluconazole daily (more than five plaques or a single plaque > 3 cm largest length) were treated with ABOS, 100 mg/ml, 5 ml swish and swallow, four times daily for 14 days. Thereafter incomplete or non-responders received an additional 14 days of therapy and responders received maintenance ABOS twice daily for up to 6 months. Relapses during maintenance ABOS were treated by increasing the dose to four times daily. MAIN OUTCOME MEASURES: To demonstrate an ABOS clinical response rate > 33% and a treatment-limiting toxicity rate < 50%. Clinical response was defined as the absence of mouth pain and the presence of less than five oral plaques, the largest being < 3 cm largest dimension. RESULTS: Fifty-eight subjects with a median age of 39 years and a median CD4 count of 10 x 10(6) cells/l were enrolled. Four subjects were excluded from the analysis because of inadequate follow-up after randomization (n = 3) or the presence of active esophageal disease (n = 1). Of the remaining 54 subjects, 23 (42.6%; 95% lower confidence interval, 31.1%) were classified as responders after 28 days. Five subjects (9%) stopped treatment due to toxicity. Relapse occurred in 16 responders (70%). CONCLUSIONS: Amphotericin B oral suspension is well tolerated but has limited efficacy for the treatment of fluconazole refractory oral candidiasis.

Effects of treatment intensification with hydroxyurea in HIV-infected patients with virologic suppression.

BACKGROUND: Virologic rebound can result from suboptimal antiviral potency in combination antiretroviral therapy. DESIGN: Multicenter, partially blinded, prospective, randomized study of 202 HIV-infected subjects to determine whether therapy intensification improves long-term rates of virologic suppression. METHODS: Subjects had plasma HIV RNA < 200 copies/ml, CD4 cell count of > 200 x 10(6) cells/l, and treatment with indinavir (IDV) + zidovudine (ZDV) + lamivudine (3TC) for at least 6 months before randomization to stay on this regimen or to receive IDV + didanosine (ddI) + stavudine (d4T) plus or minus hydroxyurea (HU) (600 mg twice daily). Treatment failure was defined as either confirmed rebound of HIV RNA level to > 200 copies/ml or a drug toxicity necessitating treatment discontinuation. RESULTS: Treatment failure occurred more frequently in subjects randomized to the HU-containing arm (32.4%), than in those taking IDV + ddI + d4T (17.6%) or IDV + ZDV + 3TC (7.6%). The time to treatment failure was shorter for the HU-containing arm compared with the IDV + ZDV + 3TC (P < 0.0001) or IDV + ddI + d4T arms (P = 0.032). Dose-limiting toxicities rather than virologic rebound accounted for the differences between treatment failure among the study arms. Pancreatitis led to treatment discontinuation in 4% of subjects in treatment arms containing ddI + d4T. Three subjects with pancreatitis died, all randomized to the HU-containing arm. CONCLUSIONS: Switching to IDV + ddI + d4T + HU in patients treated with IDV + ZDV + 3TC was associated with a worse outcome, principally because of drug toxicity.