Severe soft-tissue injury following intravenous infusion of phenytoin. Patient and drug administration risk factors.

From April 8, 1982, through June 1984, 11 patients in a single hospital experienced 17 episodes of limb edema and discoloration after the intravenous (IV) administration of phenytoin sodium (Dilantin). One patient required a below-the-elbow amputation; all other patients recovered. No single drug lot was implicated. A case-control study was performed using three controls for each case; controls received IV infusions of phenytoin and were hospitalized close in time to the case patients. Compared with controls, patients with reactions were more often female and elderly and had underlying cardiovascular disease. Affected patients also received phenytoin through an IV catheter smaller than 20 gauge (50% vs 6%), at a rate greater than 25 mg/min (63% vs 19%), and in two or more IV infusions of phenytoin given "IV push" at the same site (81% vs 24%). High-risk patients require careful monitoring and stricter guidelines for the IV administration of phenytoin.

Secondary bacterial infections in HIV-infected patients: an alternative ambulatory outpatient treatment utilizing intravenous cefotaxime.

The purpose of this study was to determine the safety and efficacy of home intravenous antibiotic therapy in treating secondary bacterial infections in patients infected with the human immunodeficiency virus (HIV). This study was a subset analysis of 22 patients with HIV, enrolled in two centers of a multicenter, open-label, prospective study. When necessary, patients were stabilized as inpatients, followed by home therapy. Enrolled patients had diagnoses of pneumonia, skin and soft-tissue infections, bacteremia/septicemia, or other infections requiring parenteral therapy. A third-generation cephalosporin, cefotaxime, 1-2 g every 8 hours, was delivered intravenously using an ambulatory delivery system (ADS). Home therapy with cefotaxime/ADS produced a clinical response rate of 95% and bacteriologic response of 88.2%. The requirement for and duration of inpatient therapy was markedly reduced compared with diagnosis-related group (DRG) allotments. In conclusion, home intravenous antibiotic therapy with cefotaxime in patients infected with HIV is effective and safe. It may improve quality of life by reducing the length of hospital stay.

Immune responses in histoplasmosis, a prototype of respiratory mycoses.

The cellular and molecular mechanisms of host defenses to histoplasmosis, a prototype of respiratory fungal infections are described. Although, cell-mediated acquired immunity is considered as a hallmark of protective immunity to histoplasmosis, the recent findings provide mounting evidence on the importance of natural cellular immunity in host resistance to fungal infections. The natural immunity to Histoplasma capsulatum infection is primarily mediated by natural killer cells, endothelial cells and platelets but mechanisms of intercellular communication and their interactions with the pathogen are not clearly defined.

Uptake and degradation of Pneumocystis carinii by macrophages in vitro.

Pneumocystis carinii organisms, isolated from lungs of rats with glucocorticoid-induced pneumocystosis, were ingested and degraded in vitro by alveolar and peritoneal macrophages obtained from healthy rats and mice. Uptake of the organisms was inhibited at 4 degrees C and by treatment of macrophages with iodoacetate. Neither uptake nor degradation was inhibited by pretreatment of macrophages with hydrocortisone sodium phosphate in vitro. Although peritoneal macrophages of any age in vitro were capable of ingesting Pneumocystis, alveolar macrophages that had been cultivated in vitro for less than 2 days were incapable of phagocytosis of the organism, a functional defect that corrected itself spontaneously during cultivation in vitro.

Protective effect of poly-2-vinylpyridine-N-oxide on susceptibility of silica-treated mice to experimental histoplasmosis.

We have studied the ability of poly-2-vinylpyridine-N-oxide (PVNO), a lysosomal stabilizing agent, to abrogate the cytotoxic effects of silica on macrophages. Male C3H/HeN mice were pretreated with PVNO and inoculated intravenously with silica particles. At 24 h after silica injection, silica-treated and -untreated mice were challenged intravenously with varying doses of live yeast cells of Histoplasma capsulatum. All mice receiving silica died when challenged with 5 X 10(5) yeast cells of Histoplasma sp. compared with no deaths in PVNO-pretreated animals and 10% mortality in controls not receiving PVNO or silica. When animals were given 2.5 X 10(5) yeast cells (a sublethal dose), the protective effect of PVNO was seen by a reduction in splenomegaly and viable Histoplasma sp. present in the spleen. Furthermore, PVNO alone showed a significant protective effect (P less than 0.05) against a lethal challenge with Histoplasma sp. Prior treatment with PVNO also protected mouse peritoneal macrophages from the cytotoxic effects of silica particles in vitro. These results indicate that PVNO abrogates the cytotoxicity of silica particles on macrophages and also increases the resistance of mice to histoplasmosis.

Blastogenic responses of lymphocytes from mice immunized by sublethal infection with yeast cells of Histoplasma capsulatum.

Blastogenic responses of spleen cells to histoplasmin and ribosomal antigens and to the mitogens concanavalin A. phytohemagglutinin, and lipopolysaccharide were studied in normal and immunized mice (10(5) live yeast cells of Histoplasma capsulatum given by the subcutaneous route). Cells (10(6) per well) were cultured with and without antigens and mitogens in microtiter plates with RPMI 1640-5% heat-inactivated normal mouse serum for 72 h at 37 degrees C. Cells were harvested after a 16- to 18-h pulse with 1 microCi of [3H]thymidine (6.7 Ci/mol), and thymidine incorporation was measured by scintillation counting. The initial blastogenic response to concanavalin A (54 X 10(3) cpm) was suppressed (P less than 0.001) from 4 to 14 days post-immunization and returned to control levels on day 21. The response to phytohemagglutinin was suppressed up to 21 days. Lipopolysaccharide responses, however, were affected to a lesser degree. Blastogenic responses to histoplasmin and H. capsulatum ribosomes were similar on day 0 in normal and immune lymphocytes, but by day 4 cells from immunized mice were more responsive (P less than 0.01). The maximum response to H. capsulatum antigens was detected on day 42 and was 9- to 16-fold higher than in controls. These results demonstrate in vitro responses of primed lymphocytes on exposure to H. capsulatum antigens and suppressed responses to mitogens during early stages of the immune response.

Evaluation of an ELISA for the detection of anti-Histoplasma ribosomal and antihistoplasmin antibodies in histoplasmosis.

We have developed an indirect sandwich enzyme-lined immunosorbent assay (ELISA) for the detection of antibodies to Histoplasma ribosomes and histoplasmin; we used this test for demonstration of these antibodies in sera from proven cases of histoplasmosis and other infections. Serum dilutions from five negative controls used in each experiment were normalized against 50 normal sera, and a factor of the mean absorbance was used to establish a positive reaction. Antiribosomal antibodies were detected in 97% of the known histoplasmosis patients with ELISA titers ranging from 1:100 to over 1:12,800. In contrast, antibodies to histoplasmin were detected in only 75% of these sera; titers ranged from 1:100 to 1:12,800. Cross-reactions with sera from other fungal infections (blastomycosis, coccidioidomycosis, paracoccidioidomycosis, cryptococcosis, candidiasis, and aspergillosis) were seen in 46% of the cases with ribosomes and 37% with histoplasmin. Fifty percent of the sera from tuberculosis patients gave positive reactions with ribosomes and 29% with histoplasmin. These results warrant further studies on the significance of antibodies to ribosomes and histoplasmin in immunity to histoplasmosis.

Effect of silica on the susceptibility of mice to experimental histoplasmosis.

The role of macrophages in the innate immunity of mice to histoplasmosis was investigated using silica, which selectively inactivates macrophages. Mice given silica IV 1 day prior to challenge with live yeast cells of Histoplasma capsulatum were more susceptible to infection than were untreated controls. This increased susceptibility to Histoplasma was observed when mice were given silica at 1, 14, and 21 days prior to infection but not at 3 and 7 days. Silica treated mice that survived 30 days after challenge with a sublethal dose of Histoplasma had 23 times more viable organisms in their spleens than in those of untreated controls. The blastogenic response of spleen cells to concanavalin A and phytohemagglutinin was unaffected at 12 hr after silica injection but was significantly depressed between 1 and 21 days. In contrast, silica treatment did not affect the blastogenic response of spleen cells to lipopolysaccharide. Silica particles were cytotoxic for mouse peritoneal macrophages but not to lymphocytes in vitro. These results indicate that macrophages play an essential role in natural immunity to histoplasmosis.