A phase I/II randomized, double-blind, placebo-controlled, dose-ranging study evaluating the efficacy, safety and pharmacokinetics of ravuconazole in the treatment of onychomycosis.

OBJECTIVE: To determine the effectiveness and safety of ravuconazole in the treatment of toenail onychomycosis. DESIGN: A phase I/II randomized, double-blind, double-dummy, placebo-controlled, dose-ranging study. Four 12-week dosing regimens were used: 200 mg/day; 100 mg/week; 400 mg/week and placebo. Subjects returned at weeks 2, 4, 6, 8, 10, 12, 14, 16, 24, 36 and 48 for assessment. Subjects were enrolled at 10 dermatology practices (seven in the United States, one in Canada, two in France). SUBJECTS: Adults with distal subungual onychomycosis of one great (hallux) toenail (minimum area of 25%), and at least 2 mm of proximal nail clear of disease were selected. Onychomycosis was confirmed by direct microscopy and/or fungal culture. Subjects with conditions known to produce abnormal-appearing nails were excluded. One hundred and fifty-one subjects were randomized in a 2:2:2:1 ratio to the treatments above. MAIN OUTCOME MEASURES: Primary efficacy was the effective cure rate at week 48 (mycological cure, and clinical cure or > 30% improvement). RESULTS: Effective cure was found in 56% of subjects using 200 mg/day. Effective cure was 10% in subjects receiving 100 mg/week, 8% of subjects using 400 mg/week, and 15% of subjects using placebo. Mycological cure was seen in 59% of subjects in the 200-mg/day group, which was significantly higher than the rates found in the other groups. Drug-related adverse events were infrequent in all treatment arms. Headache was the most frequently reported event. Abnormal laboratory tests were infrequent over the 12 weeks of dosing. Abnormal laboratory findings with increases beyond normal of Grade 2, 3 or 4 were found in 8/148 subjects (5.4%). Only the 200 mg daily regimen had a mean plasma steady state concentration of ravuconazole exceeding the MIC(90) adjusted for 98% protein binding (3000 ng/mL). CONCLUSIONS: For the treatment of onychomycosis, ravuconazole 200 mg/day for 12 weeks is the most effective of the regimens investigated. The safety of all regimens was acceptable. The concentrations of ravuconazole in the plasma compared to the adjusted MIC(90) may be useful in predicting the clinical and mycologic response of therapy.

Five days of cefprozil versus 10 days of clarithromycin in the treatment of an acute exacerbation of chronic bronchitis.

BACKGROUND: Shorter than traditional 7- to 14-day treatment regimens have demonstrated efficacy in treatment of an acute exacerbation of chronic bronchitis (AECB). OBJECTIVE: Perform a clinical efficacy study comparing 5 days of cefprozil therapy to 10 days of clarithromycin in treating an AECB. METHODS: A multicenter, randomized, double-blind study comparing efficacy and safety of cefprozil, 500 mg twice daily, for 5 days with clarithromycin, 500 mg twice daily, for 10 days in treatment of 295 subjects with AECB. Concomitantly, among all treated subjects, 39% (115 of 295) had a history of chronic obstructive pulmonary disease/emphysema; 21% (62 of 295) had a history of asthma/reactive airway disease; and 31% (90 of 295) had environmental allergies. RESULTS: There were no statistically significant differences among clinically evaluable subjects' cure rates; 82% (109 of 133) treated with cefprozil versus 85% (105 of 123) treated with clarithromycin were cured at test-of-cure visit (95% confidence interval, -12.0 to 5.1%). Clinical cure rates at end of study were 80% and 81%, respectively (95% confidence interval, -10.8 to 7.9%). Before treatment, 99% (85 of 86) of Gram-positive organisms isolated were susceptible to cefprozil and 78% (67 of 86) were susceptible to clarithromycin. A total of 84% (96 of 114) of Gram-negative organisms were susceptible to cefprozil and 63% (72 of 114) were susceptible to clarithromycin. Of clinically evaluable Streptococcus pneumoniae-infected subjects, 100% (11 of 11) of cefprozil subjects and 93% (14 of 15) of clarithromycin subjects experienced clinical cure. The most frequently reported adverse effects were nausea, 5% (7 of 150), and diarrhea, 9% (14 of 150), for cefprozil. For clarithromycin, the adverse effects were nausea, 8% (11 of 145); diarrhea, 12% (18 of 145); taste perversion, 8% (11 of 145); and dry mouth, 5% (7 of 145). CONCLUSIONS: Five days of cefprozil is as effective as 10 days of clarithromycin for treatment of an AECB.

Patient decision-making behavior: an emerging paradigm for nursing science.

BACKGROUND: As healthcare technology and medical therapies proliferate, healthcare providers have more options to offer and patients have more options from which to choose. Active patient participation in healthcare decision making is a relatively new phenomenon that has been born of sociocultural, ethical, and legal influences. Patients, however, often find healthcare decisions bewildering, stressful, and anxiety-provoking. OBJECTIVES: The purpose of this review is to provide a framework for those interested in pursuing patient decision-making investigations and suggest ways in which current knowledge can be extended to develop a scientific platform upon which to build decision support interventions. METHOD: Literature review. DISCUSSION: This review (a) provides a context for understanding patient decision making; (b) explicates the state of the science of patient decision making; (c) identifies significant theoretical, methodological, and measurement issues; and, (d) identifies gaps in patient decision-making knowledge and propose areas for further investigation.

Pharmacodynamics of fluoroquinolones against Streptococcus pneumoniae in patients with community-acquired respiratory tract infections.

Fluoroquinolone antibiotic agents have demonstrated efficacy in the treatment of respiratory tract infections. This analysis was designed to examine the relationship between drug exposure, as measured by the free-drug area under the concentration-time curve at 24 h (AUC(24))/MIC ratio, and clinical and microbiological responses in patients with community-acquired respiratory tract infections involving Streptococcus pneumoniae. The study population included 58 adult patients (34 males, 24 females) who were enrolled in either of two phase III, randomized, multicenter, double-blind studies of levofloxacin versus gatifloxacin for the treatment of community-acquired pneumonia or acute exacerbation of chronic bronchitis. Clearance equations from previously published population pharmacokinetic models were used in conjunction with dose and adjusted for protein binding to estimate individual patient free-drug AUC(24)s. In vitro susceptibility was determined in a central laboratory by broth microdilution in accordance with NCCLS guidelines. Pharmacodynamic analyses were performed on data from all evaluable patients with documented S. pneumoniae infection using univariate and multivariable logistic regression; pharmacodynamic breakpoints were estimated using Classification and Regression Tree analysis. A statistically significant (P = 0.013) relationship between microbiological response and the free-drug AUC(24)/MIC ratio was detected. At a free-drug AUC(24)/MIC ratio of <33.7, the probability of a microbiological response was 64%, and at a free-drug AUC(24)/MIC ratio of >33.7, it was 100% (P < 0.01). These findings may provide a minimum target free-drug AUC(24)/MIC ratio for the treatment of infections involving S. pneumoniae with fluoroquinolone antibiotics and provide a paradigm for the selection of fluoroquinolones to be brought forward from drug discovery into clinical development and dose selection for clinical trials. Further, when target free-drug AUC(24)/MIC ratios are used in conjunction with stochastic modeling techniques, these findings may be used to support susceptibility breakpoints for fluoroquinolone antibiotics and S. pneumoniae.

Health care utilization and satisfaction concerning gender-specific health problems among military women.

There is growing concern regarding the quality of gender-specific health care for military women in general and for female veterans of the Persian Gulf War in particular. This paper reports on health care utilization rates for gender-specific problems and describes differences in these rates among age, rank, and component groups of a randomly selected sample of military women. Study findings provide preliminary evidence for a closer examination of health care services for women within the armed forces, particularly within specific cohorts, to better target both services and policy.

Physical and emotional health of Gulf War veteran women.

BACKGROUND: Numerous questions have been raised about the health consequences to veterans of the Gulf War but most particularly to issues concerning women, who were deployed in unprecedented numbers. Little is known about the health consequences to women of wartime stressors, in general, or the environmental and job-related exposures specific to the theater of the Gulf War. METHODS: A stratified sample of 525 women participated in the study following the war and again in a follow-up study 2 yr later. The sampling frame was stratified on component of the U.S. Air Force (active, guard or reserve), deployment (in the theater or elsewhere), and parental status (parent or nonparent). Measures included items concerning general physical health, gender-specific health, the "Gulf War Syndrome," and the emotional responses to war, including symptoms of post-traumatic stress disorder (PTSD). RESULTS: Multiple statistical analyses were used to describe women's physical and emotional health at two time points following the war. Women deployed to the theater reported significantly more general as well as gender-specific health problems than did women deployed elsewhere. A cluster of common health problems included: skin rash, cough, depression, unintentional weight loss, insomnia, and memory problems. Women serving in the theater also reported a significant increase in several gender-specific problems compared to women deployed elsewhere. CONCLUSIONS: Findings suggest the need for follow-up of a cluster of specific health effects, including those concerning gynecologic and reproductive health.

When the patient chooses: describing unaided decisions in health care.

Patients make health care decisions in a complex and alien environment with little, if any, insightful aid from health care professionals; such professionals may be well intentioned but naive about how to provide decisional support. The search for information is unstructured, and once information is obtained, it is not easily understood by the layperson who may have difficulty understanding ambiguous and uncertain information. This paper addresses issues and concerns pertaining to the representation of unaided decision making in clinical practice among patients in two clinical contexts (breast cancer and cardiovascular disease). An analysis of qualitative clinical interviews provides indicators of naturalistic rule-based approaches patients use when making a medical decision. The relative salience of the alternatives plays a key role in discriminating rapid, intuitive decisions from those that are more deliberative. Empirical descriptions of real-world decision-making processes support a theoretical model of unaided decisions in health care.

Altered in vitro handling of Mycobacterium avium complex by monocytes and serum from HIV(+) patients.

In patients with acquired immunodeficiency syndrome (AIDS), mycobacterial diseases are leading opportunistic infections. The reasons for the peculiar propensity for disseminated infection with Mycobacterium avium complex (MAC) remain unclear. We have previously examined, in detail, the ability of monocytes from healthy donors to take up and kill MAC under both nonopsonic and opsonic conditions. We have now evaluated the in vitro ability of peripheral blood monocytes from HIV(+) patients to take up and kill MAC organisms, and have discovered a reduced ability under both nonopsonic and opsonic conditions. This reduction is due to: 1) apparent defect(s) in the phagocytes themselves, and 2) substance(s) in the HIV(+) serum which actively suppresses phagocyte activity.

Prevalence of viremia in human immunodeficiency virus-infected patients with renal disease.

BACKGROUND: The prevalence of viremia and its relationship to the pathogenesis of nephropathy in human immunodeficiency virus (HIV)-infected patients with renal disease is unknown. To assess the prevalence of plasma viremia in HIV-infected patients with chronic renal disease, we performed a cohort study in two urban university medical centers. METHODS: Samples of blood from 11 HIV-infected patients with renal failure who were treated with hemodialysis were analyzed concurrently with control samples from three non-HIV-positive patients receiving hemodialysis treatment. Samples from four HIV-infected patients with chronic renal insufficiency were evaluated concurrently. Thirty-three HIV-infected patients with serum creatinine levels of less than 132 mumol/L (1.5 mg/dL), and trace or absent dipstick proteinuria served as controls for the population with renal disease. The patients infected with HIV were staged by CD4 cell counts and the presence of opportunistic infections. Blood samples were analyzed for plasma HIV p24 antigenemia by antigen capture enzyme-linked immunosorbent assay. Blood samples were analyzed for the presence of viremia by infection of normal stimulated peripheral blood mononuclear cell cultures with plasma samples and detection of HIV p24 antigen in culture supernatants. RESULTS: Two of the 11 patients treated with hemodialysis had evidence of HIV p24 antigenemia, while seven of the 11 had evidence of plasma viremia. The proportion of hemodialysis patients with detectable antigenemia and viremia was similar to that in patients with chronic renal insufficiency. A significantly greater proportion of HIV-infected patients with renal disease had plasma viremia and antigenemia, compared with HIV-infected patients without renal disease. In logistic regression analysis, race, CD4 cell count (either on a continuous scale or dichotomized at 0.2 x 10(9)/L), and treatment with zidovudine were not significantly associated with the presence of plasma viremia, but patient age and the presence of renal disease were factors independently associated with viremia. CONCLUSIONS: The similar proportions of HIV-infected patients with viremia in groups of patients with chronic renal insufficiency and with renal disease treated with hemodialysis suggest that dialysis treatment does not increase the prevalence of plasma viremia in HIV-infected patients with renal disease. The similar proportions of HIV-infected hemodialyzed patients and patients with chronic renal insufficiency with plasma viremia, and the greater prevalence of viremia in patients with renal disease compared with HIV-infected patients without clinical renal disease suggest that plasma viremia and renal dysfunction are related. Whether this represents a cause and effect relationship is unknown. The greater prevalence of viremia in HIV-infected patients with renal disease has implications for the pathogenesis of HIV-related renal diseases and for caregivers in clinical settings and dialysis units.

Diagnosis of intracranial lymphoma in patients with AIDS: value of 201TI single-photon emission computed tomography.

OBJECTIVE: Although the prevalence of intracranial lymphoma is high among patients with AIDS, current imaging techniques are not reliable for differentiating this tumor from other common nonneoplastic lesions, such as those seen in toxoplasmosis. The purpose of this study was to prospectively investigate the use of 201Tl single-photon emission computed tomography (SPECT) in identifying intracranial lymphoma in patients with AIDS. SUBJECTS AND METHODS: Thirteen patients with AIDS and intracranial masses underwent 201Tl imaging with a three-headed SPECT camera. Sic of the 13 were subsequently proved to have lymphoma. Studies were interpreted prospectively as showing tumor if uptake of 201Tl was increased in the region where the lesion was seen on MR images. A lesion-to-nonlesion uptake ratio (counts/pixel) was calculated retrospectively. RESULTS: The SPECT images of six patients were interpreted prospectively as showing no lymphoma. Uptake ratios in these six patients were 0.77-1.95 (mean, 1.45). In each, tumor was excluded as a final diagnosis (four had toxoplasmosis, one had progressive multifocal leukoencephalopathy, and one had venous angioma). Among the seven patients with SPECT images interpreted as showing lymphoma, six were later proved to have lymphoma (uptake ratio: mean, 3.65; range, 2.95-4.30; p < .005). The SPECT findings in the seventh patient were classified as false-positive for tumor on the basis of the prospective interpretation of the images; three concurrent infections were found at autopsy. The uptake ratio in this patient was low (1.81), suggesting that quantification might have diagnostic usefulness for improving accuracy. CONCLUSION: This preliminary study indicates that 201Tl SPECT might be a useful, noninvasive method for differentiating intracranial lymphoma from nonneoplastic lesions in patients with AIDS.

Anti-lipopolysaccharide antibody levels in patients with AIDS at the onset of Pseudomonas aeruginosa bacteremia.

Lipopolysaccharide (LPS) in the cell wall of the P. aeruginosa is a major factor in the pathogenicity and virulence of this organism. Immunotype-specific serum antibodies to this LPS antigen (ALPS) are usually elevated with the onset of the bacteremia, act as opsonins, are protective in high levels, and are significantly associated with improved survival. In the present study, the ability of 11 patients with AIDS to mount a specific ALPS response with the onset of P. aeruginosa bacteria was evaluated prospectively. Of the 11 patients with AIDS only one had a substantial ALPS response, six mounted only a marginal ALPS response, and four had no ALPS response to the infecting strain of the P. aeruginosa. These data suggest most patients with AIDS do not exhibit a marked antigen-specific humoral response at the onset of P. aeruginosa bacteremia; this has important prognostic and therapeutic significance, as high ALPS titers are associated with survival.

Serum antibody for somatostatin-14 and prodynorphin 209-240 in patients with obsessive-compulsive disorder, schizophrenia, Alzheimer's disease, multiple sclerosis, and advanced HIV infection.

Patients with obsessive-compulsive disorder (OCD) demonstrated significant levels of antibody for somatostatin-28, its C-terminal fragment somatostatin-14, and prodynorphin. In contrast there were lower levels of reactivity for somatostatin-28(1-14) (the N-terminal fragment of somatostatin-28) and negligible reactivity for several other peptides including beta-endorphin and corticotropin. Healthy volunteers and disease controls [schizophrenia, Alzheimer's disease, multiple sclerosis, and subjects with advanced human immunodeficiency virus (HIV) infection] exhibited negligible reactivity. These data raise the consideration of an autoimmune mechanism for some OCD.

Chemotherapy for patients with pulmonary Kaposi's sarcoma: benefit of filgrastim (G-CSF) in supporting dose administration.

Kaposi's sarcoma (KS) is common in individuals infected with the human immunodeficiency virus (HIV-1). Although KS is frequently indolent, it can also be aggressive and life-threatening, especially in patients with pulmonary involvement (PKS), who have poor survival rates when untreated. In an effort to develop treatment regimens for PKS that would prolong life or reduce clinical symptoms, we used combination chemotherapy to treat 18 patients who had AIDS and PKS; 13 (72%) of them had a history of previous opportunistic infections. Doxorubicin, bleomycin, vinblastine, vincristine, actinomycin D, and dacarbazine were used in 3-week cycles with concomitant zidovudine, zalcitabine (dideoxycytidine), or didanocine (dideoxyinosine). Antiviral therapy was continued with chemotherapy. A partial or complete response to chemotherapy was obtained in 15 of the 18 patients (83%), as characterized by clearing of infiltrates on chest films and resolution of dyspnea and cough. Only 2 patients had opportunistic infections during treatment. Median survival was 9 months; patients who received dose reductions in less than three cycles of chemotherapy survived more than 1 year. Most deaths were related to unresponsive PKS. These results indicate that patients with symptomatic PKS can be safely and effectively treated with combination chemotherapy while receiving myelosuppressive drugs such as zidovudine. Such patients receive substantial relief from dyspnea and cough. Survival for treated patients exceeds survival for untreated historical controls.

Mycoplasma penetrans infection in male homosexuals with AIDS: high seroprevalence and association with Kaposi's sarcoma.

Antibodies to Mycoplasma penetrans were found at an unusually high frequency in male homosexuals with AIDS (55 of 149; 37%) and in human immunodeficiency virus (HIV)-infected asymptomatic homosexuals (13 of 49; 26.5%) but not in intravenous drug users (3 of 308; 1%) and hemophiliacs (1 of 165; 0.6%) with or without HIV-1 infection. Thus, both M. penetrans and Kaposi's sarcoma (KS) occur primarily in male homosexuals and rarely in other groups of patients at high risk of AIDS. Among 414 HIV-1-infected patients, statistical analysis revealed those with M. penetrans antibody were 11.7 times more likely to develop KS. Furthermore, among 198 HIV-infected homosexuals (149 with AIDS and 49 without AIDS), those with KS had M. penetrans-specific antibody at a significantly higher frequency (28 of 47; 59.6%) than did those without KS (27 of 102 with AIDS [26.5%] as well as 13 of 49 without AIDS [26.5%]; odds ratio = 4.1, P < .001). M. penetrans is apparently transmitted sexually through homosexual activity and is epidemiologically linked to formation of KS in homosexual men with AIDS. Parallel tests with M. genitalium revealed no similar link to KS in the same study sample.

Differential lobe lavage for diagnosis of acute Pneumocystis carinii pneumonia in patients receiving prophylactic aerosolized pentamidine therapy.

The diagnostic yield of bronchoalveolar lavage (BAL) for Pneumocystis carinii pneumonia (PCP) in patients infected with human immunodeficiency virus has been reported to be 95 percent, but falls to 62 percent in patients receiving aerosolized pentamidine. Because aerosolized pentamidine appears to be preferentially deposited in the middle and lower lobes, we postulated that an upper lobe lavage would have a higher diagnostic yield than the standard middle/lower lobe lavage in patients receiving aerosolized pentamidine. Twenty-five patients receiving aerosolized pentamidine suspected of having acute PCP underwent separate BAL of an upper lobe and lower lobe as well as transbronchial biopsy. Fifteen of the 25 (60 percent) were diagnosed as having PCP. Of the 15, one had the samples inadvertently combined. In the remaining 14, BAL was positive for P carinii organisms in 12 lavages of the lower lobe and 14 of the upper lobe. Upper lobe lavage had statistically significantly more P carinii organisms by semiquantitative technique than the lower lobe. In patients receiving aerosolized pentamidine, who develop acute PCP, an upper lobe lavage may have a higher diagnostic yield than the standard middle/lower lobe lavage. In addition, the transbronchial biopsy specimen offered no treatable diagnosis that was not made by lavage alone in the 25 patients. This raises the question of the utility of transbronchial biopsies in these patients.

Adhesion onto and invasion into mammalian cells by mycoplasma penetrans: a newly isolated mycoplasma from patients with AIDS.

The newly identified mycoplasma, Mycoplasma pentrans shows remarkable pathobiologic properties: it adheres to cell surfaces, deeply penetrates into the cell, strongly hemadsorbs human red blood cells, and cytadsorbs human CD4+ lymphocytes and monocytes. These in vitro biologic activities of mycoplasmas have been previously shown to be associated with pathogenic virulence in vivo. Both adhesion and invasion clearly involve the organism's unique tip-like structure. Invading mycoplasmas often have their tip-like structure deeply buried in the cytoplasm of infected mammalian cells. Extensive invasion of the mycoplasma into the cytoplasm may kill the cells. The same pathobiologic processes of adhesion and invasion using the specialized tip-like structure are found on the epithelium in the patient's urogenital tract infected by M. penetrans. Both in vitro and in vivo findings suggest a possible pathogenic role of this newly discovered human mycoplasma and call for careful evaluation of its role in human diseases.