One hundred ninety-four patients with cryptococcal meningitis were enrolled in a multicenter, prospective, randomized clinical trial to compare the efficacy and toxicity of four as compared with six weeks of combination amphotericin B and flucytosine therapy. Among 91 patients who met preestablished criteria for randomization, cure or improvement was noted in 75 percent of those treated for four weeks and in 85 percent of those treated for six weeks. The estimated relapse rate for the four-week regimen was higher--27 as compared with 16 percent--whereas the incidence of toxic effects for the two regimens was similar--44 as compared with 43 percent. Among 23 transplant recipients, 4 of 5 treated for four weeks relapsed, leading to the decision to treat the rest of the group for six weeks. Only 3 of the 18 treated for six weeks relapsed. In a third group of 80 patients, the protocol was not followed during the initial four weeks, and these patients were not randomized. Thirty-eight died or relapsed. Multifactorial analysis of pretreatment factors for all 194 patients identified three significant predictors (P less than 0.05) of a favorable response: headache as a symptom, normal mental status, and a cerebrospinal fluid white-cell count above 20 per cubic millimeter. These and other findings in this study are consistent with the view that the four-week regimen should be reserved for patients who have meningitis without neurologic complications, underlying disease, or immunosuppressive therapy; a pretreatment cerebrospinal fluid white-cell count above 20 per cubic millimeter and a serum cryptococcal antigen titer below 1:32; and at four weeks of therapy, a negative cerebrospinal fluid India ink preparation and serum and cerebrospinal fluid cryptococcal-antigen titers below 1:8. Patients who do not meet these criteria should receive at least six weeks of therapy.

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An experimental model of human fallopian tubes in organ culture was used to examine the ability of lipopolysaccharide (LPS) of Neisseria gonorrhoeae to damage the fallopian tube mucosa. Gonococcal LPS was purified by hot phenol-water extraction and sequential ultracentrifugation. This LPS was highly lethal for lead-sensitized mice and at a concentration as low as 6 pg/ml reproducibly gelled limulus amoebocyte lysate. Gonococcal LPS damaged fallopian tube mucosa in concentrations as low as 0.015 microgram/ml, a values less than the LPS concentration in organ culture medium surrounding fallopian tube mucosa that was damaged by gonococcal infection. The toxic effect of LPS was neutralized by polymyxin B. Gonococci were shown to elaborate blebs of outer membrane material that is likely to contain LPS. These studies suggest that gonococci elaborate LPS-containing material into their surrounding medium, that the LPS is capable of mediating damage to human fallopian tube mucosa, and that the production of mucosal damage requires the lipid A portion of the LPS molecule.

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Infection of human fallopian tubes in organ culture with Neisseria gonorrhoeae causes extensive damage of the mucosa. Filter-sterilized supernatant from gonococci-infected organ cultures produced similar damage in recipient uninfected organ cultures. This observation indicated the presence of one or more toxic factors. The toxic activity was unchanged after heating the supernatant to 85 C and was only partially diminished by dialysis. Toxic activity could not be detected in homogenates of uninfected organ cultures but was present in supernatants of gonococcal broth cultures. Toxic supernatants from organ cultures contained microgram quantities of gonococcal lipopolysaccharide (LPS). Amounts of this LPS and toxic activity for genital mucosa were both substantially reduced by absorption of the supernatant with limulus amoebocyte lysate. Thus, gonococcal LPS appears to be responsible for most of the toxicity of filter-sterilized supernatant from gonococci-infected human fallopian tubes in organ culture and may play an important role in the pathogenesis of gonococcal infection in vivo.