A randomized, double-blind comparative trial evaluating the safety of liposomal amphotericin B versus amphotericin B lipid complex in the empirical treatment of febrile neutropenia. L Amph/ABLC Collaborative Study Group.

In this double-blind study to compare safety of 2 lipid formulations of amphotericin B, neutropenic patients with unresolved fever after 3 days of antibacterial therapy were randomized (1:1:1) to receive amphotericin B lipid complex (ABLC) at a dose of 5 mg/kg/d (n=78), liposomal amphotericin B (L Amph) at a dose of 3 mg/kg/d (n=85), or L Amph at a dose of 5 mg/kg/d (n=81). L Amph (3 mg/kg/d and 5 mg/kg/d) had lower rates of fever (23.5% and 19.8% vs. 57.7% on day 1; P<.001), chills/rigors (18.8% and 23.5% vs. 79.5% on day 1; P<.001), nephrotoxicity (14.1% and 14.8% vs. 42.3%; P<.01), and toxicity-related discontinuations of therapy (12.9% and 12.3% vs. 32.1%; P=.004). After day 1, infusional reactions were less frequent with ABLC, but chills/rigors were still higher (21.0% and 24.3% vs. 50.7%; P<.001). Therapeutic success was similar in all 3 groups.

Online support for caregivers. Analysis of an Internet Alzheimer mailgroup.

Alzheimer's disease affects more than four million Americans and ranks as the fourth leading cause of death in adults. To deal with the stresses of constant caregiving, family members of patients with Alzheimer's disease are encouraged to participate in support groups. However, geographic and time constraints combined with lack of substitute caregivers may preclude attendance at traditional support groups. Internet-based groups offer caregivers the opportunity to interact with other caregivers for guidance, information, and encouragement. This project examines the content and themes of 532 messages posted on a public Alzheimer mailgroup during 20 days of 1998. Members used the mailgroup to find and proffer information, share experiences and opinions, and provide encouragement. By becoming aware of the potential advantages that online support groups offer to caregivers, nurses can encourage Alzheimer caregivers to use online groups as an empowering and practical adjunct to traditional caregiver support.

Amphotericin B with and without itraconazole for invasive aspergillosis: A three-year retrospective study.

BACKGROUND: Treatment of invasive aspergillosis is frequently unsuccessful, so innovations in therapy are needed. Clinical studies demonstrate that itraconazole may be an effective alternative to amphotericin B. Itraconazole also has been combined with amphotericin B in animal models of aspergillosis, but this regimen produced antagonistic effects. OBJECTIVES: To determine the role of itraconazole in the adjunctive treatment of invasive aspergillosis. METHODS: A review was conducted of all patients with definite or probable aspergillosis from January 1995 to December 1997 who were treated with conventional amphotericin B alone or in combination with itraconazole. RESULTS: Of 21 patients, 10 received amphotericin B and 11 received the combination. The two groups of patients were comparable clinically at baseline (including similar mean APACHE III scores). Both groups received similar doses and days of amphotericin B treatment. Of the patients who received combination therapy, nine (82%) were cured or improved, and of those who received only amphotericin B, five (50%) were cured or improved. CONCLUSIONS: This study demonstrates that itraconazole and amphotericin B given together are not clinically antagonistic and that the promise of combination therapy for aspergillosis should be evaluated further in a randomized clinical trial.

Randomized, double-blind clinical trial of amphotericin B colloidal dispersion vs. amphotericin B in the empirical treatment of fever and neutropenia.

We conducted a prospective, randomized, double-blind study comparing amphotericin B colloidal dispersion (ABCD) with amphotericin B in the empirical treatment of fever and neutropenia. Patients with neutropenia and unresolved fever after > or = 3 days of empirical antibiotic therapy were stratified by age and concomitant use of cyclosporine or tacrolimus. Patients were then randomized to receive therapy with ABCD (4 mg/[kg.d]) or amphotericin B (0.8 mg/[kg.d]) for < or = 14 days. A total of 213 patients were enrolled, of whom 196 were evaluable for efficacy. Fifty percent of ABCD-treated patients and 43.2% of amphotericin B-treated patients had a therapeutic response (P = .31). Renal dysfunction was less likely to develop and occurred later in ABCD recipients than in amphotericin B recipients (P < .001 for both parameters). Infusion-related hypoxia and chills were more common in ABCD recipients than in amphotericin B recipients (P = .013 and P = .018, respectively). ABCD appeared comparable in efficacy with amphotericin B, and renal dysfunction associated with ABCD was significantly less than that associated with amphotericin B. However, infusion-related events were more common with ABCD treatment than with amphotericin B treatment.

Nocardiosis after bone marrow transplantation: a retrospective study.

To evaluate the spectrum of nocardiosis after marrow transplantation, we reviewed the medical records of 27 patients with nocardiosis who were treated at three centers, and we reviewed the findings of three cases reported in the literature. Nocardial involvement was defined as invasive nocardiosis (n = 25), colonization (n = 4), or contamination (n = 1). The median time to the diagnosis of nocardiosis after marrow transplantation was 210 days. Nocardia asteroides complex accounted for 96% of isolates. All 25 invasive infections occurred in allogeneic marrow recipients. Ten (40%) of 25 patients with invasive nocardiosis were receiving double-strength oral trimethoprimsulfamethoxazole twice weekly as prophylaxis for Pneumocystis carinii pneumonia. Treatment regimens for nocardiosis included sulfonamides; synergistic agents were also often added. The overall survival rate at 6 years was 34%; survival from the infection itself was 84%. Two of four nocardiosis-related deaths also involved other pathogens. The incidence of nocardiosis among allogeneic marrow recipients averaged 0.3% over 25 years. We conclude that nocardiosis is a rare infection that occurs later after marrow transplantation than other infections and that is marginally associated with increased mortality among long-term survivors of allogeneic marrow transplantation.

Amphotericin B colloidal dispersion vs. amphotericin B as therapy for invasive aspergillosis.

To assess the efficacy and safety of amphotericin B colloidal dispersion (ABCD), 82 patients with proven or probable aspergillosis who were treated in clinical trials with ABCD were compared retrospectively with 261 patients with aspergillosis who were treated with amphotericin B at six cancer or transplant centers from January 1990 to June 1994. The groups were balanced in terms of underlying disease; ABCD recipients were younger and more likely to have preexisting renal insufficiency than were amphotericin B recipients (40.7% vs. 8.7%, respectively), and amphotericin B recipients were more likely to be neutropenic at baseline than were ABCD recipients (42.5% vs. 15.9%, respectively). Response rates (48.8%) and survival rates (50%) among ABCD-treated patients were higher than those (23.4% and 28.4%, respectively) among amphotericin B-treated patients (P < .001 for both comparisons). Renal dysfunction developed less frequently in ABCD recipients than in amphotericin B recipients (8.2% vs. 43.1%, respectively; P < .001). Multivariate analysis revealed that treatment group was the best predictor of response, mortality, and nephrotoxicity (ABCD: relative risk [RR] = 3.00, P = .002; RR = 0.35, P < .001; and RR = 0.13, P = .001; respectively). This retrospective study suggests that in the treatment of aspergillosis ABCD causes fewer nephrotoxic effects than amphotericin B and the efficacy of ABCD is at least comparable with that of amphotericin B.

A national survey of immunization practices following allogeneic bone marrow transplantation.

OBJECTIVES: To describe the frequency and patterns of use of routine childhood and hepatitis B, pneumococcal, influenza, and meningococcal vaccines following allogeneic bone marrow transplantation (BMT). DESIGN, SETTING, AND PARTICIPANTS: Survey of all US transplantation centers participating in the National Marrow Donor Program (NMDP) during 1994. MAIN OUTCOME MEASURES: Use, timing, and total doses of selected vaccines given to patients younger than 7 years and patients aged 7 years or older following allogeneic BMT. RESULTS: Of 66 centers associated with the NMDP, 45 (68%) responded. A total of 97% of centers performing transplants on patients younger than 7 years and 88% of centers performing transplants on patients aged 7 years or older gave either the diphtheria-tetanus vaccine or the diphtheria-tetanus-pertussis vaccine compared with 77% and 58% usage, respectively, of Haemophilus influenza type b conjugate vaccine (P=.03 and .003, respectively). Centers were more likely to administer inactivated poliovirus and measles-mumps-rubella vaccines to patients younger than 7 years than to the older age group (94% vs 73% for poliovirus, P=.02; and 94% vs 70% for measles-mumps-rubella, P=.01). About one half of centers routinely administer hepatitis B vaccine and approximately three quarters immunize with pneumococcal and influenza vaccines. Few programs, regardless of age of bone marrow recipient, use multiple vaccine (> or =2) doses. The number of schedules reported for specific vaccines varied widely (3-11 schedules per vaccine). CONCLUSIONS: Despite convincing evidence that patients lose protective antibodies to vaccine-preventable diseases following allogeneic BMT and accumulating data showing the safety and efficacy of many vaccines after BMT, vaccines are underutilized and schedules vary widely at US transplant centers. National guidelines for optimal doses and timing of vaccines after BMT are warranted.

Fungal disease in the immunocompromised host.

A variety of superficial and deep mycoses may affect the immunocompromised patient. Among the superficial mycoses, candidal infections are common in all groups, but dermatophyte and pityrosporum infections may also be found. Although not primarily dangerous, they may lead to secondary bacterial infections and morbidity. Of the systemic mycoses, candidiasis, aspergillosis, and mucor-mycosis are frequently lethal and require early diagnosis and aggressive antifungal treatment. Endemic mycoses, such as histoplasmosis and coccidioidomycosis, may result in severe and often fatal infections in those patients with cellular immune alterations. The identification and prophylaxis of high-risk patients and the development of more effective antifungal therapies are beginning to have an impact on the control of fungal disease in this population.

Efficacy of prophylactic aerosol amphotericin B lipid complex in a rat model of pulmonary aspergillosis.

Invasive pulmonary aspergillosis remains an important cause of morbidity and mortality among transplant recipients and patients receiving cancer chemotherapy. The lipid-associated formulation of amphotericin B (AmB), AmB lipid complex (ABLC), was evaluated for its prophylactic efficacy when it was administered as an aerosol in a rat model of pulmonary aspergillosis. Aerosol ABLC (aero-ABLC), in doses from 0.4 to 1.6 mg/kg of body weight given 2 days before infection, significantly delayed mortality compared to the mortality of rats given placebo (P < 0.001). At day 10 postinfection, 50% of rats in the 0.4-mg/kg group and 75% of rats in the 1.6-mg/kg group were alive, while all control animals had died. In a second trial aero-ABLC was more effective than an equivalent dose of aerosol AmB (aero-AmB) in prolonging survival, with 100% survival at day 14 postinfection in the ABLC group, compared to 62.5% survival in the AmB group. Mean concentrations of AmB in lungs were 3.7 times higher at day 1 (P < 0.002) and almost six times higher at day 7 (P < 0.001) after treatment with aero-ABLC than after treatment with a similar dose of aero-AmB. We conclude that aero-ABLC provided higher and more prolonged levels of the parent compound in the lungs than aero-AmB and was more effective in delaying mortality from aspergillosis in this model.

Mycobacterium haemophilum: microbiology and expanding clinical and geographic spectra of disease in humans.

Reports of the association of Mycobacterium haemophilum with disease in humans have greatly increased. At least 64 cases have now been reported, with symptoms ranging from focal lesions to widespread, systemic disease. The organism is now known to cause primarily cutaneous and subcutaneous infection, septic arthritis, osteomyelitis, and pneumonitis in patients who are immunologically compromised and lymphadenitis in apparently immunocompetent children. Underlying conditions in the compromised patients have included AIDS; renal, bone marrow, and cardiac transplantation; lymphoma; rheumatoid arthritis; marrow hypoplasia; and Crohn's disease. Reports have originated from diverse geographic areas worldwide. The epidemiology of M. haemophilum remains poorly defined; there appears to be a genetic diversity between strains isolated from different regions. The organism is probably present in the environment, but recovery by sampling has not been successful. M. haemophilum has several unique traits, including predilection for lower temperatures (30 to 32 degrees C) and requirement for iron supplementation (ferric ammonium citrate or hemin). These may in the past have compromised recovery in the laboratory. Therapy has not been well elucidated, and the outcome appears to be influenced by the patient's underlying immunosuppression. The organisms are most susceptible to ciprofloxacin, clarithromycin, rifabutin, and rifampin. Timely diagnosis and therapy require communication between clinician and the laboratory.

Infectious complications of autologous bone marrow and peripheral stem cell transplantation for refractory leukemia and lymphoma.

We aimed to characterize the infectious complications of autologous bone marrow (AuBMT) and peripheral stem cell transplantation (PSCT) in patients with refractory leukemia and lymphoma. We performed a retrospective analysis of all patients (n = 56) with refractory leukemia or lymphoma treated with AuBMT or PSCT at Memorial Sloan-Kettering Cancer Center from January 1993 to July 1994. Records were available in 55, of whom 33 (60%) received AuBMT and 22 (40%) PSCT. Fifteen (27%) developed complicated infections, including 13 (39%) treated with AuBMT and two (9%) with PSCT. Complicated infections were caused by bacterial (11 episodes), fungal (four episodes), and viral (four episodes) pathogens. Five (9%) infections were fatal. In a multivariate model, only duration of neutropenia was significantly associated with development of complicated infection (P = 0.006). Thus, 27% of patients with refractory leukemia or lymphoma treated with AuBMT or PSCT developed complicated infections and 9% died of infection. Prolonged neutropenia was significantly associated with development of infection. Patients receiving PSCT had significantly lower rates of complicated infection, presumably due to the associated shorter duration of neutropenia. Future studies are needed to define the role of PSCT as treatment for refractory neoplastic disease.

Is vulvovaginal candidiasis an AIDS-related illness?

Early in the AIDS epidemic, retrospective studies reported that vaginal candidiasis occurred more frequently in women who were infected with human immunodeficiency virus (HIV) than in those who were not infected. Some investigators suggested that new onset or recurrent vaginal candidiasis might identify HIV-infected individuals and predict the course of AIDS in women already known to be infected. In this article, studies of vaginal candidiasis in HIV-infected women are examined, and several observations are made. First, early studies were small and likely reflected biased populations. Second, adherence to previously accepted diagnostic criteria for vaginal candidiasis was not consistent in these studies. Finally, conclusions about the increased risk of recurrent or chronic candidal vaginitis in HIV-infected women have been promulgated in the medical literature and may have influenced clinical practice even though such statements are not supported epidemiologically. Prospective trials with uninfected community controls should determine the true impact of HIV infection on vulvovaginal candidiasis.

Prevention and reversal of renal allograft rejection by antibody against CD45RB.

Rejection continues to be the single largest impediment to successful organ transplantation. Antilymphocyte globulin, which contains antibodies that react with the leukocyte common antigen known as CD45, has proved to be one of the most effective agents for preventing rejection. We have shown earlier that a monoclonal antibody directed against the RB isoform of CD45 substantially inhibits the alloreactivity of human CD4+ lymphocytes in vitro. Here we investigate whether CD45RB could be an appropriate target for preventing renal allograft rejection in mice. Mice treated with two injections of a monoclonal antibody (MB23G2) raised against CD45RB protein all survived and had normal renal function. Furthermore, this antibody reversed acute rejection when therapy was delayed until day 4, and the mice survived for their natural lifespan. The immunosuppression achieved may find application in the prevention and treatment of transplant rejection in man.

Gender differences in gating of the auditory evoked potential in normal subjects.

Central nervous system (CNS) inhibitory mechanisms hypothesized to "gate" repetitive sensory inputs have been implicated in the pathology of schizophrenia. The present study investigated gender differences in inhibitory gating of evoked brain responses to repeated stimuli in normal subjects (30 women and 30 men) using an auditory conditioning-testing paradigm. Pairs of click stimuli (S1 and S2) were presented with a 0.5 s intrapair and a 10 s interpair interval. The amplitudes and latencies of the P50, N100, P180 components of the auditory evoked response to the conditioning (S1) and test response (S2) were measured, and the gating ratios were computed (T/C ratio = S2/S1 * 100). The amplitudes to S1 were not significantly different between men and women at P50, N100, or P180. However, women had significantly higher amplitudes to S2 at P50 (p = 0.03) and N100 (p = 0.04). The T/C ratios for women were higher (i.e., less suppression of response to S2) for P50 (p = 0.08) and N100 (p = 0.04) compared to men. The results suggested that differences in auditory gating between men and women were not due to biological differences in the P50 and N100 generators but possibly to differential influence of inhibitory mechanisms acting on the generator substrates of these evoked responses.

Mycobacterium haemophilum infections in bone marrow transplant recipients.

The purpose of this study was to describe the clinical presentation, treatment, and outcome of Mycobacterium haemophilum infection in patients undergoing bone marrow transplantation at a cancer center. Bone marrow transplant recipients with M haemophilum infection were identified upon culture of the organism by implementing the organism's unique requirements for growth. This report of the patients' clinical and immunologic course is based on a retrospective chart review. Two distinctly different presentations of M haemophilum infection were observed. Three patients presented with cutaneous lesions, typical of those seen in previous reports of the infection. Two others developed pulmonary disease only. All patients received directed therapy against M haemophilum, but respiratory failure developed in the patients with pneumonia and they died. The remaining 3 patients survived and are free of infection. These are the only reported cases of M haemophilum infection in bone marrow transplant recipients. Early diagnosis obtained through biopsy and special request for culture conditions conducive to the growth of the organism may decrease morbidity and mortality, particularly in patients with pulmonary disease.

Genital ulcer disease in women infected with human immunodeficiency virus.

OBJECTIVE: The purpose of this study was to determine the prevalence and microbiologic characteristics of genital ulcer disease in a population of human immunodeficiency virus-infected women. STUDY DESIGN: A retrospective cohort study was performed in university-affiliated, hospital-based women's human immunodeficiency virus clinics. A total of 307 women with human immunodeficiency virus infection were followed up during 20 months. There were no interventions. Age, race, CD4+ cell counts, bacteriologic and virologic analyses in cases of ulcers, serologic testing for syphilis, and histopathologic examination in selected cases (n = 6). RESULTS: Among 307 women followed up over a 20-month period, 43 ulcers were detected with a prevalence of 14%. Among the ulcer cases the average absolute CD4+ lymphocyte number was 210/mm3. Diagnostic evaluation yielded no proven etiologic agent in 26 (60%) of the cases. Twelve of the 43 cases (28%) were positive for herpes simplex-2. Five cases (12%) yielded unusual or mixed bacteriologic types. No cases were attributable to primary syphilis infection. One case each of an ulcer infected with cytomegalovirus, Chlamydia trachomatis, and Gardnerella vaginalis, as well as three unusual presentations of herpetic ulcers, is analyzed in detail. CONCLUSION: These cases exemplify the often dramatic presentation of human immunodeficiency virus-related genital ulcers and the clinical complexity of both diagnosis and management. The frequent lack of an infectious or neoplastic cause in human immunodeficiency virus-infected women with genital ulcer disease suggests that human immunodeficiency virus may play a local role in causation or exacerbation. Biopsies of atypical genital ulcers should be considered to aid diagnosis. Further studies are needed to elucidate the pathogenesis of genital ulcer disease in human immunodeficiency virus-infected women.

Increasing awareness of sleep hygiene in rotating shift workers: arming law-enforcement officers against impaired performance.

Research into the effects of rotating shift work on health, social, and performance indices suggests significantly more health concerns and judgement errors and poorer sleep patterns in shift workers on rotating versus nonrotating schedules. 31 male and 7 female law-enforcement officers voluntarily participated in a training session on sleep hygiene practices. On the Sleep Hygiene Awareness and Practice Scale administered prior to and after training were significant increases in awareness of sleep hygiene and knowledge of nicotine, caffeine, and hypnotics. We predicted that use of this knowledge would increase sleep satisfaction. However, 1-mo. follow-up scores on the Post-sleep Inventory of Webb, et al. reflected no change. It appears that scheduling demands, coupled with feelings of low self-efficacy toward managing those demands, resulted in little or no practice of sleep hygiene. A more productive approach may be to incorporate a comprehensive behavioral program within departments to instill and reinforce better practice of sleep hygiene.

Cryptococcosis.

Cryptococcal disease is the most common life-threatening fungal infection in patients with AIDS. The most common manifestation, meningitis, has an indolent presentation that may lead to a delay in diagnosis. Although clinical trials have demonstrated efficacy with fluconazole in some patients, amphotericin B, with or without flucytosine, is the treatment of choice. Lifelong suppression of cryptococcal disease after initial therapy, however, is best achieved with fluconazole. Prognostic staging systems and primary prophylaxis of cryptococcal disease are also discussed.

Prevention of infections in patients with neoplastic disease: use of a historical model for developmental strategies.

Infections associated with neoplastic disease and its treatment are well described. Associations between specific infections and particular immune defects have also been defined. Despite the awareness that certain patient populations are at risk, potential prophylactic regimens for many of these infections have not been studied. The development of isoniazid for the prevention of tuberculosis is reviewed. The requirements for the study of prophylactic antibiotics in patients with neoplastic disease are discussed based on this example. Specific infections associated with neoplastic disease are suggested as candidates for multicenter controlled trials of prophylactic regimens.