Epidemiology and outcomes of Clostridium difficile infection in allogeneic hematopoietic cell and lung transplant recipients.

BACKGROUND: Clostridium difficile infection (CDI) is a common complication of lung and allogeneic hematopoietic cell (HCT) transplant, but the epidemiology and outcomes of CDI after transplant are poorly described. METHODS: We performed a prospective, multicenter study of CDI within 365 days post-allogeneic HCT or lung transplantation. Data were collected via patient interviews and medical chart review. Participants were followed weekly in the 12 weeks post-transplant and while hospitalized and contacted monthly up to 18 months post-transplantation. RESULTS: Six sites participated in the study with 614 total participants; 4 enrolled allogeneic HCT (385 participants) and 5 enrolled lung transplant recipients (229 participants). One hundred and fifty CDI cases occurred within 1 year of transplantation; the incidence among lung transplant recipients was 13.1% and among allogeneic HCTs was 31.2%. Median time to CDI was significantly shorter among allogeneic HCT than lung transplant recipients (27 days vs 90 days; P = .037). CDI was associated with significantly higher mortality from 31 to 180 days post-index date among the allogeneic HCT recipients (Hazard ratio [HR] = 1.80; P = .007). There was a trend towards increased mortality among lung transplant recipients from 120 to 180 days post-index date (HR = 4.7, P = .09). CONCLUSIONS: The epidemiology and outcomes of CDI vary by transplant population; surveillance for CDI should continue beyond the immediate post-transplant period.

Endemic fungal infections in solid organ and hematopoietic cell transplant recipients enrolled in the Transplant-Associated Infection Surveillance Network (TRANSNET).

BACKGROUND: Invasive fungal infections are a major cause of morbidity and mortality among solid organ transplant (SOT) and hematopoietic cell transplant (HCT) recipients, but few data have been reported on the epidemiology of endemic fungal infections in these populations. METHODS: Fifteen institutions belonging to the Transplant-Associated Infection Surveillance Network prospectively enrolled SOT and HCT recipients with histoplasmosis, blastomycosis, or coccidioidomycosis occurring between March 2001 and March 2006. RESULTS: A total of 70 patients (64 SOT recipients and 6 HCT recipients) had infection with an endemic mycosis, including 52 with histoplasmosis, 9 with blastomycosis, and 9 with coccidioidomycosis. The 12-month cumulative incidence rate among SOT recipients for histoplasmosis was 0.102%. Occurrence of infection was bimodal; 28 (40%) infections occurred in the first 6 months post transplantation, and 24 (34%) occurred between 2 and 11 years post transplantation. Three patients were documented to have acquired infection from the donor organ. Seven SOT recipients with histoplasmosis and 3 with coccidioidomycosis died (16%); no HCT recipient died. CONCLUSIONS: This 5-year multicenter prospective surveillance study found that endemic mycoses occur uncommonly in SOT and HCT recipients, and that the period at risk extends for years after transplantation.

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.

Outcomes of antifungal prophylaxis in high-risk liver transplant recipients.

Antifungal prophylaxis for liver transplant recipients (LTRs) is common among patients considered at high risk of infection, but optimal prophylaxis duration and drug has not been defined. This study aimed to assess the effects of 14 days of antifungal therapy prophylaxis in reducing proven invasive fungal infections (IFI) in high-risk subjects. Eligible subjects who met 2 or more risk criteria were randomized 1:1 to the treatment arms (liposomal amphotericin B or fluconazole) and were followed for 100 days post transplantation for evidence of IFI. The study was designed to enroll 300 subjects, but was closed early for insufficient enrollment. A total of 71 subjects were enrolled and randomized. Two-thirds of subjects completed 14 days of study therapy. Ten subjects developed proven or probable IFI with Candida species (9 subjects) and Cryptococcus neoformans (1 subject); rates were similar in the 2 treatment arms. Eleven subjects died, but no death was attributed to study drug or IFI. In summary, high-risk LTRs tolerated antifungal prophylaxis well, and rates of IFI were lower than previously reported in untreated high-risk LTRs.

A vaccine to prevent herpes zoster and postherpetic neuralgia in older adults.

BACKGROUND: The incidence and severity of herpes zoster and postherpetic neuralgia increase with age in association with a progressive decline in cell-mediated immunity to varicella-zoster virus (VZV). We tested the hypothesis that vaccination against VZV would decrease the incidence, severity, or both of herpes zoster and postherpetic neuralgia among older adults. METHODS: We enrolled 38,546 adults 60 years of age or older in a randomized, double-blind, placebo-controlled trial of an investigational live attenuated Oka/Merck VZV vaccine ("zoster vaccine"). Herpes zoster was diagnosed according to clinical and laboratory criteria. The pain and discomfort associated with herpes zoster were measured repeatedly for six months. The primary end point was the burden of illness due to herpes zoster, a measure affected by the incidence, severity, and duration of the associated pain and discomfort. The secondary end point was the incidence of postherpetic neuralgia. RESULTS: More than 95 percent of the subjects continued in the study to its completion, with a median of 3.12 years of surveillance for herpes zoster. A total of 957 confirmed cases of herpes zoster (315 among vaccine recipients and 642 among placebo recipients) and 107 cases of postherpetic neuralgia (27 among vaccine recipients and 80 among placebo recipients) were included in the efficacy analysis. The use of the zoster vaccine reduced the burden of illness due to herpes zoster by 61.1 percent (P<0.001), reduced the incidence of postherpetic neuralgia by 66.5 percent (P<0.001), and reduced the incidence of herpes zoster by 51.3 percent (P<0.001). Reactions at the injection site were more frequent among vaccine recipients but were generally mild. CONCLUSIONS: The zoster vaccine markedly reduced morbidity from herpes zoster and postherpetic neuralgia among older adults.

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.

Protein malnutrition and the febrile response in the Fischer rat.

We assessed the effect of protein deprivation on the ability of peritoneal macrophages from Fischer rats to produce interleukin-1 (IL-1) after in vitro stimulation. Pyrogenic activity of supernatants was measured by an in vivo febrile response assay. Control rats were given a 23% casein diet and protein-malnourished rats were given an 8% casein diet for 4 weeks. IL-1-containing supernatants prepared from peritoneal macrophages were injected into assay rats, whose temperatures were measured for 6 hours (delta T6). Rats injected with IL-1-containing supernatants derived from peritoneal macrophage cultures of protein-deprived rats had significantly less fever (delta T6 = 0.20 +/- 0.09 degree C) than rats injected with IL-1 containing supernatants derived from peritoneal macrophage cultures of control rats (delta T6 = 0.56 +/- 0.09 degree C), P less than .01. Protein malnutrition leads to diminished pyrogenicity of macrophage culture supernatants and may be at least partly responsible for the decreased febrile response seen in the malnourished animals.

Monokine secretion in aging and protein malnutrition.

Aged and protein-malnourished hosts have diminished febrile responses and increased morbidity and mortality from infection that could be due to deficiencies in the production of certain monokines. In this study, the ability of peritoneal macrophages from aged and protein-malnourished rats to produce IL-1 and TNF was explored. Aged rats fed a standard diet produced less IL-1 and TNF, as measured by the thymocyte proliferation and L929 cytotoxicity assays, than young and middle-aged rats. Monokine production was not diminished by protein malnutrition in any age group. No synergistic decline in IL-1 or TNF production was seen with increasing age in malnourished rats. Diminished IL-1 and TNF production may partially explain the severity of infection seen in the elderly patient, but not the malnourished host. The role of other cytokines such as IL-6 and cytokine inhibitors in aging and malnutrition should be explored.

Persistent Strongyloides stercoralis in a blind loop of the bowel. Successful treatment with mebendazole.

Three courses of thiabendazole therapy, including one course given directly into a blind loop of the bowel, failed to eradicate Strongyloides stercoralis from a 55-year-old man who had undergone a Roux-en-Y operation. The patient responded to 1.5 g/day of mebendazole for 14 days, and the infection did not recur. Our case illustrates the difficulty of eliminating S stercoralis from a blind loop of the bowel and indicates that mebendazole therapy used in adequate doses is effective treatment for strongyloidiasis. The lack of toxicity of mebendazole makes it a desirable drug for Strongyloides infestation resistant to thiabendazole therapy.

Hospital-acquired infective endocarditis.

Nosocomial endocarditis occurred in 22 patients who were discharged from a university hospital, a veterans' hospital, and a community hospital during the period of January 1976 to December 1985. Nosocomial episodes were 14.3% of the total endocarditis cases seen. Fourteen (63.6%) of 22 nosocomial endocarditis episodes occurred in patients over the age of 60 years, compared with 39 (29.5%) of 132 episodes of community-acquired endocarditis during the same period. Nosocomial endocarditis was due predominantly to Staphylococcus aureus or coagulase-negative staphylococci (77.4%) and, less often, to streptococci (13.6%). Intravascular devices were the source of bacteremia in ten (45.5%) of the nosocomial endocarditis episodes. The overall mortality rate was 40.9%, 50% in patients over the age of 60 years. Improved care of intravascular devices or prophylaxis before procedures could probably have prevented endocarditis in 12 of the 22 patients.

Invasive fungal infections in patients with chronic mucocutaneous candidiasis.

Patients with chronic mucocutaneous candidiasis have persistent Candida infection of nails, skin, and mucous membranes, but rarely, if ever, does an invasive fungal infection develop. We describe two patients with chronic mucocutaneous candidiasis who died of fungal infection; one had C albicans meningitis and the second had Cryptococcus neoformans meningitis. The cases of four other patients with chronic mucocutaneous candidiasis and invasive fungal infection, three with crytococcosis and one with histoplasmosis, have been reported previously. Immunological profiles on these six patients revealed no differences from those of other patients with chronic mucocutaneous candidiasis without invasive fungal infection. Three of the four patients who received amphotericin B were cured of their infection; three patients died, including one patient with overwhelming cryptococcosis who had received intensive antifungal therapy and transfer factor.

Streptococcal endocarditis initially seen as septic arthritis.

Two patients were initially seen with culture-positive streptococcal arthritis as an early manifestation of bacterial endocarditis. The organisms were an alpha-hemolytic, nongroup D streptococcus and a beta-hemolytic, group b streptococcus. One patient had a persistent septic monarthritis; the other had migratory arthritis in which a positive synovial culture was followed by a negative culture from the same joint before antimicrobial treatment was started. This experience suggests that some sterile synovial aspirates encountered in patients with bacterial endocarditis may be explained by delay of arthrocentesis.

Efficacy of ketoconazole v nystatin in prevention of fungal infections in neutropenic patients.

A prospective randomized study was undertaken in neutropenic patients to evaluate the efficacy of prophylactic ketoconazole v nystatin in reducing yeast infections. Eighteen patients received 500,000 units of nystatin suspension four times daily, and 18 patients received 200 mg of ketoconazole daily. The nystatin group experienced nine local yeast infections (four thrush, three esophagitis, and two vaginitis); three patients receiving ketoconazole had thrush. No cases of disseminated candidiasis occurred in either group. Ketoconazole was better tolerated than nystatin and neither drug caused toxic effects. In addition to being nontoxic and better tolerated, ketoconazole appeared to be slightly more effective than nystatin in reducing locally severe yeast infections.

High-level aminoglycoside-resistant enterococci. Colonization of nursing home and acute care hospital patients.

Enterococci with high-level resistance (HLR) to gentamicin sulfate and other aminoglycosides have emerged as pathogens in recent years. More than half of all current isolates of enterococci at the Ann Arbor (Mich) Veterans Administration (VA) Medical Center are HLR strains. We determined the rate of colonization with HLR enterococci in patients in the acute care hospital, the attached nursing home, and a private nursing home. We also studied the factors related to colonization and the molecular relatedness of strains of HLR enterococci in these settings. In the VA facilities, 47.4% of patients in the nursing home and 36.1% of patients in the acute care hospital were colonized, compared with a 4.3% colonization rate in the private nursing home. Intravenous or Foley catheters and bedridden status were associated with colonization in the acute care setting; the need for advanced nursing care and prior antibiotic therapy were associated with colonization in the nursing home. Environmental surfaces were contaminated with HLR enterococci in both VA settings. Plasmid analysis of HLR strains revealed identity between both patient and environmental strains in the nursing home care unit and the acute care hospital. Nursing home patients, with their high rate of colonization with HLR enterococci and their frequent movement into the acute care hospital, may play a role as a reservoir for subsequent transmission of HLR enterococci.

The impact of culture isolation of Aspergillus species: a hospital-based survey of aspergillosis.

The term "aspergillosis" comprises several categories of infection: invasive aspergillosis; chronic necrotizing aspergillosis; aspergilloma, or fungus ball; and allergic bronchopulmonary aspergillosis. In 24 medical centers, we examined the impact of a culture positive for Aspergillus species on the diagnosis, risk factors, management, and outcome associated with these diseases. Most Aspergillus culture isolates from nonsterile body sites do not represent disease. However, for high-risk patients, such as allogeneic bone marrow transplant recipients (60%), persons with hematologic cancer (50%), and those with signs of neutropenia (60%) or malnutrition (30%), a positive culture result is associated with invasive disease. When such risk factors as human immunodeficiency virus infection (20%), solid-organ transplantation (20%), corticosteroid use (20%), or an underlying pulmonary disease (10%) are associated with a positive culture result, clinical judgment and better diagnostic tests are necessary. The management of invasive aspergillosis remains suboptimal: only 38% of patients are alive 3 months after diagnosis. Chronic necrotizing aspergillosis, aspergilloma, and allergic bronchopulmonary aspergillosis have variable management strategies and better short-term outcomes.

Steady-state pharmacokinetics of delavirdine in HIV-positive patients: effect on erythromycin breath test.

OBJECTIVE: The steady-state kinetics of delavirdine and desisopropyldelavirdine were evaluated in human immunodeficiency virus-positive patients after escalating oral doses and after repeated oral administrations at the same dose level. STUDY DESIGN: Patients (n = 8 males) were given escalating oral doses of delavirdine mesylate, in a sequential fashion, over 14 days for phases 1 (200 mg every 8 hours), 2 (300 mg every 8 hours), and 3 (400 mg every 8 hours). Control patients (n = 4 males) were given 300 mg oral doses of drug every 8 hours for all three phases. Hepatic CYP3A activity was evaluated with the erythromycin breath test (ERMBT). RESULTS: In the escalating-dose group, delavirdine displayed nonlinear kinetics as indicated by the decreasing oral clearance, maximum steady-state plasma concentration/minimum steady-state plasma concentration ratio, and log-linear terminal rate constant, as well as by increasing half-life at higher doses; the ratio of desisopropyl-delavirdine formation clearance to elimination clearance was also reduced. In the control group, the kinetics of delavirdine and desisopropyl-delavirdine were unchanged. Plasma protein binding was linear for delavirdine in the escalating-dose and control groups; on average, the fraction unbound was about 2.3% and 2.0%, respectively. Hepatic CYP3A activity was markedly reduced after short- and long-term exposure to all doses of delavirdine mesylate. Delavirdine could maximally inhibit 70% to 75% of predose ERMBT values, with an IC50 of about 0.9 mumol/L. CONCLUSION: Delavirdine is a potent and reversible inhibitor of hepatic CYP3A; it is also a substrate for this CYP450 isoform. It is likely that delavirdine will exhibit drug-drug interactions when coadministered with other CYP3A substrates.

Fever and malnutrition: endogenous pyrogen/interleukin-1 in malnourished patients.

The effect of protein-calorie malnutrition on the release of endogenous pyrogen/interleukin-1 (EP/IL-1), the protein responsible for the induction of fever, was investigated in 18 hospitalized patients with chronic malnutrition. Monocytes from the 18 patients and from 19 healthy controls were cultured overnight after stimulation with Staphylococcus epidermidis. The presence of EP/IL-1 was tested by injecting culture supernatants into rabbits and measuring the maximum febrile response (delta Tmax). Malnourished patients produced significantly less EP/IL-1 than controls (delta Tmax = 0.27 +/- 0.04 degrees C for patients vs 0.49 +/- 0.03 degrees C for controls, p less than 0.001). The poor febrile response in the malnourished patients was related to low serum albumin and retinol-binding protein, but not to thyroxine-binding albumin or lymphocyte number. This abnormality may help explain the poor febrile response often noted in hospitalized debilitated patients.

Comparison of cryptococcal and tuberculous meningitis.

Twenty-six patients had cryptococcal meningitis and 16 patients had tuberculous meningitis. Underlying conditions were mostly immunosuppressive diseases in patients with cryptococcosis and chronic debilitating diseases in patients with tuberculosis. There were few distinguishing charact eristics between the two infections with regard to symptoms and signs. The presence of a miliary pattern on chest roentgenogram and inappropriate secretion of antidiuretic hormone were nonspecific but helpful signs supporting a diagnosis of tuberculous meningitis; the presence of cryptococcal antigen was both a specific and sensitive indicator of cryptococcal meningitis. Acid-fast smears of CSF and the tuberculin skin test were of little help diagnostically, being positive in only 18% and 31%, respectively, of patients with tuberculous meningitis. Substantial delays in diagnosis and treatment were associated with increased mortality.

Salmonella meningitis. Occurrence in an adult.

Salmonella meningitis is predominantly a disease of infants. An adult patient is described who had meningitis due to S typhimurium following a traumatic fracture of the first lumbar vertebra. A review of previous cases of Salmonella meningitis in adults revealed a predominance of infection due to S typhi prior to 1940 with a variety of other serotypes isolated since then. Only one of nine patients survived prior to the antibiotic era, but three of five patients with Salmonella meningitis since 1940 have survived.

Infective endocarditis: clinical features in young and elderly patients.

The elderly constitute an increasing percentage of patients with infective endocarditis. The disease manifestations and outcomes in 53 episodes of endocarditis in patients over the age of 60 were reviewed and compared with 55 episodes of endocarditis in patients less than 40 years of age and 46 episodes of endocarditis in patients aged 40 to 60. The percentage of cases caused by staphylococci and streptococci were roughly equal in all groups. Enterococci, Streptococcus bovis, and coagulase-negative staphylococci were more common in the elderly. In the elderly, invasive vascular procedures were the most common source of infection. Endocarditis acquired nosocomially accounted for 23 percent of all episodes in older patients. The elderly reported fewer symptoms and showed a diminished febrile response. Errors in diagnosis were noted in 68 percent of elderly patients, and a delay in initiating appropriate therapy was more common in this age group. The mortality rate was significantly higher in the elderly (45.3 percent) than in the middle-aged (32.6 percent) and young (9.1 percent). Endocarditis in elderly patients is often nosocomially acquired, is difficult to diagnose, and is associated with a higher mortality than noted in younger patients.