Peggy Miniter

Hospital epidemiologic surveillance for invasive aspergillosis : Patient demographics and the utility of antigen detection

OBJECTIVE To monitor the epidemiology of invasive aspergillosis at a university hospital during a period of hospital construction. To compare the efficacy of active epidemiologic surveillance for invasive aspergillosis using Aspergillus cultures with the efficacy of surveillance using Aspergillus antigen detection. DESIGN A prospective surveillance study. SETTING An 850-bed, tertiary-care, university-based hospital. PATIENTS A convenience sample of 153 patients with Aspergillus antigen testing and culture. RESULTS 24 cases were identified over a 12-month period; 7 were nosocomial, and 17 were community-acquired. Cases occurred primarily in patients with hematologic malignancy, but also occurred in patients with solid tumor, steroid treatment, cardiac transplant, and acquired immunodeficiency syndrome. Culture techniques identified only 14 (58%) of 24 cases, whereas Aspergillus antigen was positive in 19 (79%) of 24 cases tested. Epidemiological surveillance using either antigen or culture positivity detected 22 (92%) of 24 cases. In addition, antigen detection was 98% specific for the detection of aspergillosis, as compared to 91% for culture and 88% for antigen and culture combined. CONCLUSIONS Hospital surveillance for aspergillosis should include determination of whether cases are nosocomial or community-acquired, because many may be the latter. Patients at risk for aspergillosis include patients without hematologic malignancies. Enhanced case detection occurred with active surveillance of patients considered to be at risk using both fungal serology and traditional microbiological techniques. Antigen detection was more sensitive and specific for the detection of invasive aspergillosis and may improve epidemiological surveillance for aspergillosis.

Immunopathogenesis of chronic pyelonephritis

Immunopathologic responses to urinary Tamm-Horsfall protein in the development of chronic pyelonephritis were examined by four different approaches. First, in a rabbit model, tubulointerstitial nephritis developed in 64 of 102 rabbits injected intravenously with urine or rabbit Tamm-Horsfall protein as compared with only one of 17 rabbits in two control groups. Circulating cytotoxic lymphocytes plus immunoglobulin G (IgG) antibodies against Tamm-Horsfall protein were found in 51 percent of challenged (urine or Tamm-Horsfall protein) rabbits with tubulointerstitial nephritis as compared with only 8 percent of those without it (p less than 0.001). Second, in a porcine model of reflux nephropathy, 16 of 21 pigs with pyelographic findings indicative of reflux had elevated serum titers of anti-Tamm-Horsfall protein antibody as compared with 0 of 13 with normal pyelograms. Five of 10 refluxing pigs tested also had circulating lymphocytes that were cytotoxic in the presence of Tamm-Horsfall protein as compared with 0 of 13 with normal pyelograms. Third, in human studies, 12 of 49 patients with recurrent nephrolithiasis demonstrated abnormal elevations in anti-Tamm-Horsfall protein antibody; 13 of 49 had an abnormality in one of two assays of cell-mediated immunity to Tamm-Horsfall protein as compared with 0 of the normal control subjects. These abnormalities were not associated with overt obstruction or bacteriuria, but appeared to be more common in patients with recent onset and active recurrent nephrolithiasis. Lastly, an inhibitor of the binding reaction between human Tamm-Horsfall protein and its IgG antibody was detected in extracts of three uropathic coliforms. The inhibitors were partially purified by chromatographic means. Preliminary immunoautoradiographic studies revealed three or less protein-containing subunits of Escherichia coli that cross-reacted with anti-Tamm-Horsfall protein antibody. These studies suggest that autoimmune responses to Tamm-Horsfall protein may occur after exposure to Tamm-Horsfall protein by intravenous challenge, urinary reflux, or recurrent nephrolithiasis. This autoimmune response to Tamm-Horsfall protein may be the pathogenetic mechanism by which these factors, including bacteriuria, contribute to chronic pyelonephritis.

Activity of LY146032 in vitro and in experimental enterococcal pyelonephritis.

The efficacy of LY146032 (LY), a new lipopeptide antibiotic, was compared with that of vancomycin, ciprofloxacin, ceftriaxone, imipenem, and gentamicin and combinations of LY-ceftriaxone, LY-imipenem, and LY-gentamicin against 15 strains of Streptococcus (Enterococcus) faecalis by microtiter dilution and checkerboard techniques. LY was effective within a very narrow range of drug concentrations (from 0.125 to 2.0 micrograms/ml) and was more active than other agents tested against S. faecalis. Enhanced inhibition of S. faecalis was seen more frequently with combinations of either penicillin or ampicillin and an aminoglycoside than with combinations of LY and gentamicin, imipenem, or ceftriaxone. The in vivo efficacy of LY was compared with that of vancomycin and ampicillin alone and combinations of vancomycin-gentamicin, ampicillin-gentamicin, and LY-gentamicin in a rat model of chronic enterococcal pyelonephritis. At a dose of 10 mg/kg given twice daily, LY reduced the number of organisms per kidney significantly compared with that in infected untreated controls within 48 h after the initiation of therapy. At 20 mg/kg given once a day, LY was less effective but reduced colony counts significantly after 4 days of therapy, and its activity was comparable to that of vancomycin or vancomycin-gentamicin given twice daily. LY may be a promising agent for the treatment of enterococcal infections.

Efficacy of SCH 39304 in treatment of experimental invasive aspergillosis.

The efficacy of SCH 39304 (SCH) against Aspergillus fumigatus was assessed with an immunosuppressed, temporarily leukopenic rabbit model of invasive aspergillosis. Therapy with SCH at 10 or 15 mg/kg of body weight per day was begun 24 h after lethal challenge and compared with therapy with amphotericin B at 1.5 mg/kg/day. Compared with untreated controls, SCH reduced mortality and also reduced the tissue burden of A. fumigatus 100- to 1,000-fold in liver, kidney, and lung tissues. SCH at 15 mg/kg/day and amphotericin B eliminated A. fumigatus in liver, kidney, and lung tissues. In addition, both dosages of SCH significantly eliminated the organism from brain tissues, compared with controls. Both SCH and amphotericin B decreased or eliminated circulating aspergillus antigen. These results show that new azoles can be as effective as amphotericin B in eradicating the organism from tissues and offer promise in improving the treatment of invasive aspergillosis.

Saperconazole therapy in a rabbit model of invasive aspergillosis.

The efficacy of orally and intravenously administered saperconazole against Aspergillus fumigatus was assessed in an immunosuppressed temporarily leukopenic rabbit model of invasive aspergillosis and compared with that of amphotericin B. Oral saperconazole at dosages of 5, 10, and 15 mg/kg of body weight per day improved survival compared with that of controls. In addition, saperconazole at 10 and 15 mg/kg/day reduced the tissue burden and reduced levels of circulating antigen, which correlated with increasing dosages of saperconazole. Intravenous saperconazole produced levels in serum more than 10-fold that of oral therapy. Intravenous saperconazole not only improved survival and reduced antigen levels but also significantly eradicated A. fumigatus from tissues compared with those of controls and was as effective as amphotericin B in these studies. Saperconazole was effective in the treatment of experimental invasive aspergillosis and demonstrates the potential of the newer azoles in therapy for invasive aspergillosis.

An experimental model to determine the level of antibiotics in irradiated tissues

An experimental study was designed using male Sprague-Dawley rats treated with a single dose of 1800 rads to an area of skin and soft tissue of the back measuring 2 X 3 cm. This dose was estimated to produce changes equivalent to 6000 rads in divided doses over 6 weeks. At intervals of 5, 10, and 15 weeks after irradiation, punch biopsies were taken from both irradiation, and nonirradiated skin areas of each animal 30 minutes after the intraperitoneal administration of gentamicin. Skin homogenates were prepared, and the antibiotic levels in these samples were determined by a bacterial growth inhibition assay. The antibiotic levels were found to be equal (16.1 +/- 6 micrograms/ml vs. 16.0 +/- 5 micrograms/ml) in both irradiated and nonirradiated skin at 5 weeks after radiation. However, at 10 and 15 weeks after radiation, the antibiotic levels had dropped to 9.9 +/- 3 micrograms/ml in irradiated skin compared with 14.1 +/- 4 micrograms/ml in normal skin (p less than 0.001) and with 5.4 micrograms/ml in irradiated skin vs. 11.8 +/- 5 micrograms/ml in nonirradiated skin (p less than 0.001), respectively. Results demonstrate that in spite of adequate gentamicin levels in the circulation and nonirradiated tissue in rats, gentamicin has a decreasing ability to diffuse into irradiated tissues with increasing intervals after therapeutic doses of radiation.