Biomedical subjects

J N Galgiani

Publications and source records attributed to J N Galgiani.

At least 37 records · Page 2Linked to original sources

PubMed1996

Cloning and sequence analysis of the cDNA for a protein from Coccidioides immitis with immunogenic potential.

We have cloned and sequenced the cDNA encoding an immunoreactive protein from the pathogenic fungus Coccidioides immitis which stimulates human T cells and has been associated with protective vaccines in mice. The transcript contained an open reading frame encoding 194 amino acids with a calculated molecular weight of 19.5 kDa, a 151 base 5' untranslated region (UTR), and a 468 base 3'UTR. A four member repeat motif, usually thr-ala-glu-pro, exists for amino acids 98 through 141. Deduced amino acid sequence derived from the cDNA was identical with previously determined internal amino acid sequence from the native protein, and goat antiserum raised against the purified fungal protein reacted with an inducible fusion protein translated from this cDNA. Using this cDNA to produce recombinant protein will allow direct testing of its role in human immunity to coccidioidomycosis and may lead to new diagnostic tests.

Amino Acid Sequence↗

PubMed1996

The role of understaffing in central venous catheter-associated bloodstream infections.

OBJECTIVE: To determine risk factors for central venous catheter-associated bloodstream infections (CVC-BSI) during a protracted outbreak. DESIGN: Case-control and cohort studies of surgical intensive care unit (SICU) patients. SETTING: A university-affiliated Veterans Affairs medical center. PATIENTS: Case-control study: all patients who developed a CVC-BSI during the outbreak period (January 1992 through September 1993) and randomly selected controls. Cohort study: all SICU patients during the study period (January 1991 through September 1993). MEASUREMENTS: CVC-BSI or site infection rates, SICU patient clinical data, and average monthly SICU patient-to-nurse ratio. RESULTS: When analyzed by hospital location and site, only CVC-BSI in the SICU had increased significantly in the outbreak period compared to the previous year (January 1991 through December 1991: pre-outbreak period). In SICU patients, CVC-BSI were associated with receipt of total parenteral nutrition [TPN]; odds ratio, 16; 95% confidence interval, 4 to 73). When we controlled for TPN use, CVC-BSI were associated with increasing severity of illness and days on assisted ventilation. SICU patients in the outbreak period had shorter SICU and hospital stays, were younger, and had similar mortality rates, but received more TPN compared with patients in the pre-outbreak period. Furthermore, the patient-to-nurse ratio significantly increased in the outbreak compared with the pre-outbreak period. When we controlled for TPN use, assisted ventilation, and the period of hospitalization, the patient-to-nurse ratio was an independent risk factor for CVC-BSI in SICU patients. CONCLUSIONS: Nursing staff reductions below a critical level, during a period of increased TPN use, may have contributed to the increase in CVC-BSI in the SICU by making adequate catheter care difficult. During healthcare reforms and hospital downsizing, the effect of staffing reductions on patient outcome (i.e., nosocomial infection) needs to be critically assessed.

Aged↗

PubMed1996

Cerebrospinal fluid antibodies detected by ELISA against a 33-kDa antigen from spherules of Coccidioides immitis in patients with coccidioidal meningitis. The National Institute of Allergy and Infectious Diseases Mycoses Study Group.

Antibodies against a 33-kDa antigen from Coccidioides immitis were detected by ELISA in patients' cerebrospinal fluid (CSF). Anti-33-kDa antibodies were detected at dilutions > 1:80 in only 1 (1.4%) of 73 patients without coccidioidal meningitis but in 74 (71.8%) of 103 with meningitis. Anti-33-kDa antibodies were detected in 53 (91.4%) of 58 patients whose anti-coccidioidal complement-fixing (CF) antibodies were detectable and in 21 (46.7%) of 45 patients whose CSF was negative by CF test (positive predictive value, 99%; negative predictive value, 71%; sensitivity, 72%; specificity, 99%). Anti-33-kDa antibodies, among which IgG1 was the dominant subclass, increased when infections worsened and decreased when patients' conditions improved. Antibody concentration appeared to be independent of most baseline findings, although only 1 of 5 patients coinfected with human immunodeficiency virus had initially detectable antibodies. Measurement of anti-33-kDa antibodies is a sensitive indicator of coccidioidal meningitis and of its clinical course.

Antibodies, Fungal↗

PubMed1996

Detection of coccidioidal antibodies by 33-kDa spherule antigen, Coccidioides EIA, and standard serologic tests in sera from patients evaluated for coccidioidomycosis.

During a 9-month study of patients being evaluated for coccidioidomycosis, 1 or more serum samples were obtained from 138 patients with an illness suggestive of recent infection. In this group, standard immunodiffusion tests of unconcentrated sera were positive for 25; 49 additional patients had at least 1 reactive test result by newer enzyme-linked serologic tests. At least 11 of these 49 patients had coccidioidomycosis as determined by culture or subsequent standard serologic tests. Patients with coccidioidomycosis identified only by newer tests had fewer or milder clinical abnormalities than did patients in whom the disease was detected by standard tests. For 31 other patients with illness of a chronic or undetermined duration, newer tests detected only 10 more than the 18 identified by standard tests, suggesting that later in the course of illness, standard testing gains in sensitivity for coccidioidal infection.

Antibodies, Fungal↗

PubMed1996

Cytokine production by peripheral blood mononuclear cells in human coccidioidomycosis.

The production and mRNA expression of the cytokines interferon-gamma (IFN-gamma) and interleukin (IL)-4, -10, and -12 by peripheral blood mononuclear cells (PBMC) after incubation with the coccidioidal antigen toluene spherule lysate (TSL) from various subjects were measured. The IFN-gamma concentration in PBMC supernatants incubated for 72 h from 8 subjects with disseminated coccidioidomycosis was significantly less than that from 7 healthy, coccidioidal-immune subjects (P = .015). No differences were seen among the subject groups in the concentrations of IL-4, -10, or -12. By use of competitive polymerase chain reaction, PBMC from subjects with disseminated coccidioidomycosis also expressed less mRNA for IFN-gamma and IL-12 than did cells from healthy, immune subjects. These data suggest that patients with disseminated coccidioidomycosis have a diminished T helper lymphocyte type 1 response.

Base Sequence↗

PubMed1996

Microdilution antifungal susceptibility testing of Candida albicans and Cryptococcus neoformans with and without agitation: an eight-center collaborative study.

The growth patterns observed in the trailing wells when fluconazole is being tested may give rise to readings that suggest resistance or increased MICs for known susceptible strains. We conducted a multicenter study to evaluate the intralaboratory and interlaboratory reproducibilities of a method that uses agitation to disperse these types of growth. Ten strains of Candida albicans and five strains of Cryptococcus neoformans were tested against fluconazole, flucytosine, and amphotericin B by using a microdilution adaptation of the proposed reference method of the National Committee for Clinical Laboratory Standards for yeasts (M27-T). The endpoint criterion used before agitation was consistent with the M27-T recommendation, while a criterion of 50% or more reduction of growth compared with the control was used after agitation. The results of this study showed that use of agitation and the modified endpoint criterion both improved intralaboratory and inter-laboratory agreement and increased the frequency of interpretable MICs. The MICs obtained by this method were comparable to those obtained by the broth macrodilution M27-T method. Like M27-T, this method was not able to definitely distinguish amphotericin B-susceptible from -resistant strains, although the MICs for the resistant strains were consistently higher than those for the susceptible ones. The findings imply that agitation should be seriously considered when antifungal agents, particularly fluconazole, are tested in a microdilution format.

Amphotericin B↗

PubMed1996

Susceptibility testing of fungi: current status of correlation of in vitro data with clinical outcome.

In summary, it is clear that in vitro susceptibility testing can predict outcome in selected clinical situations. The clearest data are from the fluconazole-treated AIDS patients with oropharyngeal candidiasis. In this setting, the homogeneity of the underlying immune defect, combined with the ease of identification and monitoring of the infection, creates a near-perfect test situation. In more complex scenarios, such as the heterogeneous population of patients enrolled in a recent study of candidemia, no such clear-cut correlation was present. The importance of host factors in the correlation of the MIC with outcome cannot be overemphasized. Examples of these parameters include patient status (underlying disease, the presence of intravascular catheters, and CD4+ T-cell number), drug pharmacokinetics (absorption and distribution), patient compliance, and drug-drug interactions. Identification of relevant factors can substantially improve the degree of the MIC-outcome correlation and thus improve the clinical utility of in vitro testing. An important feature in this entire process is the role of standardized susceptibility testing procedures. While not without flaws, the proposed NCCLS reference method has been invaluable in allowing multiple investigators to contribute data that can be used to clarify the correlation between the fluconazole MIC and outcome. While the development of simplified second-generation methods is eagerly anticipated, the role of the reference method as a common touchstone is critical. Only by use of either the reference method itself or methods with a known relationship to the reference method can this broad collaborative process really proceed. Current work is focusing on defining interpretive breakpoints for fluconazole and Candida species, refinement of the in vitro procedures used to measure susceptibility to amphotericin B, ketoconazole, and itraconazole, and the acquisition of a broad base of data on the relationship between the MIC and outcome for these three drugs. Although considerable work remains to be done, the available data suggest that solutions to each of these problems are possible and that routine susceptibility testing of fungi will become meaningful for clinical decision making in the foreseeable future.

Amphotericin B↗

PubMed1995

Autoantibodies against peptide-defined epitopes of T-cell receptors in retrovirally infected humans and mice.

Autoantibodies directed against peptide-defined epitopes of T-cell receptors occur in the serum of healthy humans with the levels and isotypic expression dependent upon physiological changes (aging, pregnancy) or upon the development of autoimmune disease. We carried out investigations of autoantibodies against Tcr peptide-defined epitopes in retroviral infections of humans (HIV-1) and mice (LP-BM5 strain of murine leukemia virus) to determine whether infection with these agents disrupted the regulation of the production of these antibodies. Retroviral infection in humans resulted in increased levels of autoantibody production against putative immunoregulatory regions of the Tcr beta chain (V beta CDR1 and Fr3), a result reflecting a disruption of regulation. In addition, antigenic mimicry was observed with a cross-reaction shared between the common portion of the V3 neutralizing loop of the HIV-1 gp120 molecule and the joining segment of T-cell receptors (J beta). Infection of mice with the defective retrovirus resulted in the induction of antibodies directed particularly against V beta CDR1 peptide-defined determinants. Analysis of the virally induced response to a set of 8 CDR1 peptide epitopes indicated a selectivity to the process. It was possible to partially reverse aberrant cytokine changes correlated with the onset of murine MAIDS by administration of T-cell receptor peptides in saline. These results show that retroviral infection in humans and mice has a profound dysfunctional effect on the regulation of autoantibodies to T-cell receptors. The function of these autoantibodies in the immunopathogenesis of acquired immunodeficiency remains to be determined.

Acquired Immunodeficiency Syndrome↗

PubMed1995

Fluconazole in the treatment of chronic pulmonary and nonmeningeal disseminated coccidioidomycosis. NIAID Mycoses Study Group.

PURPOSE: To determine the efficacy and safety of fluconazole as treatment for coccidioidomycosis. PATIENTS AND METHODS: This was a multicenter, open-label, single-arm study. Of 78 patients enrolled, 22 had soft-tissue, 42 had chronic pulmonary, and 14 had skeletal coccidioidomycosis. Forty-nine had at least one concomitant disease, 7 of whom had HIV infection. Patients were given oral fluconazole 200 mg/d. Nonresponders were increased to 400 mg/d. Treatment courses were long: a mean of 323 +/- 230 days at 200 mg and 433 +/- 178 days at 400 mg. Predefined assessment of disease-related abnormalities was performed at the time of enrollment and repeated at least every 4 months. A satisfactory response was defined as any reduction of baseline abnormality by month 4 and at least 51% reduction by month 8. RESULTS: Among 75 evaluable patients, a satisfactory response was observed in 12 (86%) of the 14 patients with skeletal, 22 (55%) of the 40 patients with chronic pulmonary, and 16 (76%) of the 21 patients with soft-tissue disease. Five patients (7%) required modification of treatment due to toxicity. Forty-one patients who responded were followed off drug. Fifteen (37%) of them experienced reactivation of infection. CONCLUSION: Fluconazole 200 or 400 mg/d is well tolerated and a moderately effective treatment for chronic pulmonary or nonmeningeal disseminated coccidioidomycosis. The relapse rate following therapy is high. Treatment trials with higher doses appear warranted. The relative efficacy of fluconazole versus other azoles or amphotericin B remains unknown.

Adult↗

PubMed1995

Persistent coccidioidal seropositivity without clinical evidence of active coccidioidomycosis in patients infected with human immunodeficiency virus.

We retrospectively identified 13 patients infected with human immunodeficiency virus (HIV) who had persistently positive coccidioidal serological tests without evidence of active coccidioidomycosis--to our knowledge, a heretofore undescribed phenomenon. The median duration of follow-up was 19 months. Five patients developed active coccidioidomycosis during this follow-up period; the median interval from the initial positive serological test to the development of active disease was 23 months. There were no significant differences between patients who developed active coccidioidomycosis and those who did not with regard to CD4 lymphocyte count or previous antifungal therapy. Moreover, when all 13 patients were compared with 21 patients who had HIV infection and active coccidioidomycosis, no differences were found with regard to age, race, risk factor for HIV infection, or initial CD4 lymphocyte count. In summary, persistently positive coccidioidal serological tests in HIV-infected patients appear to represent true coccidioidal infection and are associated with a significant risk of the development of active coccidioidomycosis.

Adult↗

PubMed1995

Coccidioidomycosis among visitors to a Coccidioides immitis-endemic area: an outbreak in a military reserve unit.

An outbreak of coccidioidomycosis occurred in a US Marine reserve unit based in Tennessee after a 3-week training exercise in California that involved substantial exposure to soil and dust. Interviews and serologic testing were done on three occasions (6, 11, and 15 weeks) after the men returned from California, and spherulin skin tests were done at 6 months. Of 27 men, 8 (30%) had evidence of recent coccidioidal infection. Of these, 7 (88%) had an illness consistent with coccidioidomycosis that, despite medical evaluation, was diagnosed incorrectly in 5 men (71%). Diagnosis of coccidioidal pneumonia outside an area in which Coccidioides immitis is endemic is unlikely unless the health care provider is aware that the patient traveled recently. Detection of coccidioidomycosis could be facilitated if organizations that regularly send people to C. immitis-endemic regions were to inform these persons about the risks of infection.

Adult↗

PubMed1995

Tumor necrosis factor-alpha and interleukin-1 beta in cerebrospinal fluid of patients with coccidioidal meningitis during therapy with fluconazole. National Institute of Allergy and Infectious Diseases Mycoses Study Group.

The levels of tumor necrosis factor-alpha (TNF-alpha) and interleukin (IL)-1 beta in the cerebrospinal fluid (CSF) of 66 patients with coccidioidal meningitis during therapy with fluconazole were measured by ELISA. The median concentration of TNF-alpha was 15.2 pg/mL for 322 samples; for IL-1 beta, it was 4.7 pg/mL for 316 samples. There were no significant changes in the level of either cytokine over 24 months of follow-up nor was there an association between the initial CSF concentrations of TNF-alpha and IL-1 beta and subsequent fluconazole treatment failure. Over time, concentrations of IL-1 beta were significantly associated with both clinical symptoms and white blood cell counts in CSF. These results indicate that CSF levels of TNF-alpha and IL-1 beta are relatively low compared with those associated with acute bacterial meningitis.

Coccidioidomycosis↗

PubMed1995

Differences in oxidant release by human polymorphonuclear leukocytes produced by stimulation with different phases of Coccidioides immitis.

Human polymorphonuclear leukocytes (PMNL) inhibit growth of arthroconidia and young spherules but not mature spherules of Coccidioides immitis. To evaluate these differences, oxidants were measured when PMNL were exposed to C. immitis or other particulate stimuli. Concentrations of arthroconidia, young spherules, mature spherules, and Candida glabrata were adjusted to result in equivalent superoxide release. Hydrogen peroxide and hypochlorous acid were stimulated by arthroconidia or young spherules but were undetectable after exposure to mature spherules. Levels of catalase in mature spherules were too low to account for the low levels of hydrogen peroxide and hypochlorous acid. When mature spherules were added to arthroconidia or zymosan, stimulation of hydrogen peroxide and hypochlorous acid occurred. The results suggest that mature spherules stimulate superoxide release but interfere with hydrogen peroxide and hypochlorous acid production. The low levels of these antimicrobial oxidants may contribute to resistance of C. immitis to human PMNL.

Coccidioides↗

PubMed1995

Detection of amphotericin B-resistant Candida isolates in a broth-based system.

Because of the limited ability of the National Committee for Clinical Laboratory Standards proposed M27P methodology to detect resistance to amphotericin B by Candida isolates, we sought to identify alternative media and pH conditions that could reliably identify resistant isolates. Antibiotic Medium 3 broth (also known as Penassay broth) buffered to pH 5 or pH 7 produced superior results and readily identified a series of resistant isolates.

Amphotericin B↗

PubMed1994

Decrease in nosocomial Clostridium difficile-associated diarrhea by restricting clindamycin use.

OBJECTIVE: To report the investigation and effective control of a nosocomial epidemic of Clostridium difficile-associated diarrhea. DESIGN: Concurrent surveillance for identification of new nosocomial cases, retrospective case-control analysis, and hospital formulary control of antibiotic use. SETTING: University-affiliated Veterans Affairs Medical Center located in southwestern United States. PATIENTS: Hospitalized patients who developed diarrhea submitted stool specimens for cytotoxin assay. Patients who were positive for cytotoxin were compared with control patients without infection. MEASUREMENTS: Isolates of C. difficile were typed by restriction endonuclease analysis. Antimicrobial agent use from hospital pharmacy records and selected patient data from chart review were correlated with frequency of specific laboratory abnormalities. RESULTS: For 13 months, the monthly incidence of C. difficile infection averaged more than five times that for the previous 21 months. Stool specimens from 34 patients (59%) contained a single strain (restriction enzyme analysis type J7). Clindamycin was statistically associated with the epidemic as shown by the following: clindamycin use at our center compared with national normal values, clindamycin use for years before compared with during the epidemic, monthly use of clindamycin compared with monthly frequency of infection, frequency of infection in patients receiving clindamycin compared with that in patients receiving other antimicrobial agents, and amount of clindamycin used by infected patients compared with that used by control patients. Restricting clindamycin use led to a prompt disease in infection rate and the type J7 organisms. CONCLUSION: A nosocomial epidemic of C. difficile diarrhea was controlled by analysis of antibiotic use patterns and by subsequent restriction of clindamycin.

Arizona↗

PubMed1994

Evaluation of hepatic injury arising during fluconazole therapy.

Previous reports have described hepatotoxicity associated with ketoconazole therapy. There is also concern that therapy with fluconazole might cause the same side effect as ketoconazole. We describe two patients who developed unexplained liver test abnormalities after beginning fluconazole therapy. To determine whether fluconazole might have been responsible, liver biopsies were performed. Specimens from both patients demonstrated an absence of hepatocyte necrosis, which, if present, would have necessitated discontinuation of fluconazole therapy. A critical review of other case reports of fluconazole-associated hepatitis also failed to produce a consistent picture. Our experience indicates that a liver biopsy may be useful in selected patients to exclude clinically relevant hepatotoxicity due to fluconazole therapy and to allow its continued use.

Adult↗

PubMed1994

NIAID Mycoses Study Group Multicenter Trial of Oral Itraconazole Therapy for Invasive Aspergillosis.

BACKGROUND: Invasive aspergillosis is the most common invasive mould infection and a major cause of mortality in immunocompromised patients. Response to amphotericin B, the only antifungal agent licensed in the United States for the treatment of aspergillosis, is suboptimal. METHODS: A multicenter open study with strict entry criteria for invasive aspergillosis evaluated oral itraconazole (600 mg/d for 4 days followed by 400 mg/d) in patients with various underlying conditions. Response was based on clinical and radiologic criteria plus microbiology, histopathology, and autopsy data. Responses were categorized as complete, partial, or stable. Failure was categorized as an itraconazole failure or overall failure. RESULTS: Our study population consisted of 76 evaluable patients. Therapy duration varied from 0.3 to 97 weeks (median 46). At the end of treatment, 30 (39%) patients had a complete or partial response, and 3 (4%) had a stable response, and in 20 patients (26%), the protocol therapy was discontinued early (at 0.6 to 54.3 weeks) because of a worsening clinical course or death due to aspergillosis (itraconazole failure). Twenty-three (30%) patients withdrew for other reasons including possible toxicity (7%) and death due to another cause but without resolution of aspergillosis (20%). Itraconazole failure rates varied widely according to site of disease and underlying disease group: 14% for pulmonary and tracheobronchial disease, 50% for sinus disease, 63% for central nervous system disease, and 44% for other sites; 7% in solid organ transplant, 29% in allogeneic bone marrow transplant patients, and 14% in those with prolonged granulocytopenia (median 19 days), 44% in AIDS patients, and 32% in other host groups. The relapse rates among those who completed therapy and those who discontinued early for possible toxicity were 12% and 40%, respectively; all were still immunosuppressed. CONCLUSION: Oral itraconazole is a useful alternative therapy for invasive aspergillosis with response rates apparently comparable to amphotericin B. Relapse in immunocompromised patients may be a problem. Controlled trials are necessary to fully assess the role of itraconazole in the treatment of invasive aspergillosis.

AIDS-Related Opportunistic Infections↗

PubMed1994

Comparative analysis of three antifungal susceptibility test methods against prospectively collected Candida species.

We performed antifungal susceptibility tests with cilofungin (LY121019), amphotericin B, and flucytosine against 38 strains of yeasts from patients with esophagitis or fungemia either before, during, or after treatment with cilofungin. Tests were performed using a macrobroth dilution method similar to that proposed by the National Committee for Clinical Laboratory Standards (M27-P) and two microbroth methods. For cilofungin and amphotericin B, minimum inhibitory concentrations from microbroth tests using Antibiotic Medium 3 (AM3) were systematically lower than results from the other two methods that utilized RPMI-1640 medium (RPMI). AM3 did not provide any greater degree of in vitro correlation with clinical results than did RPMI. We conclude that cilofungin and possibly other congeners of the echinocandin class of antifungal agents can effectively be studied using the proposed National Committee for Clinical Laboratory Standards method.

Amphotericin B↗