Clark R. Gregg

Treatment of Cryptococcal Meningitis with Combination Amphotericin B and Flucytosine for Four as Compared with Six Weeks

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.

Treatment of Systemic Mycoses with Ketoconazole: Emphasis on Toxicity and Clinical Response in 52 Patients: National Institute of Allergy and Infectious Diseases Collaborative Antifungal Study

The pharmacology, in vitro mycologic activity, toxicity, and efficacy of ketoconazole were studied in a Phase-II evaluation by the National Institutes of Health and National Institute of Allergy and Infectious Disease Mycoses Study Group. This report emphasizes the toxicity and clinical response data in 52 patients with the following systemic mycoses: blastomycosis in 16 patients; nonmeningeal coccidioidomycosis in 13; histoplasmosis in 8; nonmeningeal cryptococcosis in 7; sporotrichosis in 7; and both blastomycosis and nonmeningeal coccidioidomycosis in 1. Maximum daily doses of ketoconazole were 100 mg in 1 patient; 200 mg in 23; 400 mg in 12; and 600 mg in 16. In 52% of the patients, duration of therapy ranged from less than 1 to 6 months, whereas in 35%, duration ranged from 7 to 12 months, and in 13%, from 12 to 22 months. In 35 patients (67%), evidence of toxicity was not seen. Nausea, anorexia, or vomiting occurred in 21%. Cure or marked improvement was shown in 27 patients (52%), whereas failure of the primary course was seen in 14 (27%) and relapse after ketoconazole was discontinued in 11 (21%). Although this evaluation did not provide clear-cut clinical response data, our results indicate that ketoconazole, in the dosage regimens used, was more effective in patients with histoplasmosis and nonmeningeal cryptococcosis than in patients with blastomycosis and nonmeningeal coccidioidomycosis, and least effective in patients with sporotrichosis.

The Problem of Bacillus Species Infection with Special Emphasis on the Virulence of Bacillus cereus

Although Bacillus cereus is an uncommon ocular pathogen, infection with it usually results in loss of the eye. Although previous reports have emphasized endogenous infection, our recent experience indicates the importance of B cereus infection following trauma. Management is hampered by ineffectiveness of current empirical antibiotic regimens. This microorganism is resistant to both the penicillins and the cephalosporins. Although B cereus is susceptible to gentamicin, our studies indicate that gentamicin by itself is inadequate to eradicate the infection. B cereus, however, is susceptible to clindamycin and combined therapy with gentamicin and clindamycin appears to offer the best approach. Early diagnosis is the key to successful treatment. We believe the clinical circumstances likely to lead to B cereus infection, as well as the manifestations of the disease itself, are sufficiently distinctive to alert the ophthalmologist to the possibility of this infection. Prompt recognition of the infection should allow institution of appropriate therapy before permanent structural changes occur.

Protease inhibitor-based therapy is associated with decreased HIV- related health care costs in men treated at a veterans administration hospital

BACKGROUND Protease inhibitor (PI) therapy for HIV infection is associated with decreased rates of opportunistic infections and death. Statistical models predict that decreased complications will be associated with decreased hospitalization costs. A recent report suggested that the decrease in the HIV hospitalization costs were offset by increases in demand for outpatient services. We performed a study of hospital use and HIV-associated health care costs in our center to determine the following: whether PI therapy is associated with decreased inpatient use; whether PI therapy is associated with decreased outpatient use and costs; whether decreased HIV health care costs are associated with increased use of nucleoside analogues. METHODS The Dallas Veteran Affairs Medical Center provides comprehensive inpatient and outpatient HIV care and thus can evaluate the relation between inpatient and outpatient costs. The mean monthly number of hospital days, Infectious Diseases clinic visits, emergency department visits, other outpatient clinic visits, inpatient costs, outpatient costs, and PI costs were determined from January 1, 1995 through July 31, 1997. This time period was then divided into three intervals. Comparisons of PI use and HIV-related health care costs were during the three intervals was performed using analysis of variance (ANOVA). Significant differences between the baseline characteristics were further analyzed through multiple linear regression. RESULTS A decrease in hospital days, and all outpatient visits including emergency visits, and HIV clinic visits was determined. No difference was found in the rate of use of other outpatient services. The per patient costs of HIV care decreased from a monthly average of

Gonococcal infection of human fallopian tube mucosa in organ culture: Relationship of mucosal tissue TNF-α concentration to sloughing of ciliated cells

1905 U.S. in the first interval to

Drug interactions and anti-infective therapies

1122 U.S. in the last interval (p < .01). Linear regression demonstrated an inverse relation between PI use and total HIV costs (B=-0.67, p=.00, adjusted R2=0.52) but no relation between nucleoside use, stage of disease or financial class. CONCLUSIONS PI therapy is associated with decreased hospital days and use of outpatient services. Total patient costs decreased, but a concomitant rise in outpatient costs took place. This increase was primarily a result of increased costs of acquiring PI. Increases in the number of nucleoside agents prescribed were not associated with decreased costs.

Campylobacter Bacteremia, Cholecystitis, and the Acquired Immunodeficiency Syndrome

BACKGROUND AND OBJECTIVES An experimental model consisting of gonococcal infection of human fallopian tube mucosa in organ culture has proven useful in studying the molecular pathogenesis of acute gonococcal salpingitis and postsalpingitis sequelae. Gonococcal infection of human fallopian tube mucosa in organ culture results in the sloughing of ciliated epithelial cells from the mucosa. This damage to the mucosa can be quantified on fallopian tube pieces by an assay of the percent of the periphery that has ciliary activity (PPCA) remaining at specific time points after infection. Although assay of the PPCA has been quite valuable, it is labor-intensive, somewhat subjective, and requires that the observers have training and experience. A more practical assay for genital mucosal damage is desirable for further investigations that employ the fallopian tube experimental model. Gonococcal infection of fallopian tube mucosa in organ culture also results in the production of easily quantified tumor necrosis factor-alpha (TNF-alpha) by the mucosa. Furthermore, treatment of the organ cultures with recombinant human TNF-alpha (rHuTNFalpha) alone also causes sloughing of ciliated cells from the mucosa. These findings strongly suggest that TNF-alpha is a mediator of the mucosal damage that attends gonococcal infection. GOALS OF THE STUDY To determine: (1) whether the PPCA values and the TNF-alpha concentrations in fallopian tube mucosal tissues correlate closely enough to allow prediction of the PPCA from a measurement of the mucosal tissue TNF-alpha concentration; and (2) whether the correlation of the TNF-alpha mucosal tissue concentration with the sloughing of ciliated cells (measured by the PPCA) supports the hypothesis that induction of TNF-alpha by gonococcal infection, with resultant sloughing of ciliated cells, is likely to be a major pathogenic mechanism of gonococcal salpingitis and might mediate postsalpingitis infertility and ectopic pregnancy. STUDY DESIGN A metaanalysis was performed on studies from three research groups (two laboratories in the United States and one in the United Kingdom, using identical techniques for quantifying the PPCA, TNF-alpha, or both. RESULTS There was a close and statistically significant correlation between the TNF-alpha mucosal tissue concentration and the proportion of ciliated cells lost from the mucosa as measured by the PPCA (r = 0.95, p < 0.001). Therefore, as the mucosal tissue concentration of endogenous TNF-alpha increased, the loss of ciliated cells from the epithelium increased proportionately. CONCLUSIONS During gonococcal infection of human fallopian tube mucosa in organ culture, the mucosal tissue concentration of TNF-alpha can be used to predict the PPCA, and therefore, the extent of mucosal damage. This finding should facilitate studies of the molecular pathogenesis of infectious diseases involving human genital mucosa. Further, the close correlation of mucosal TNF-alpha concentration with genital mucosal damage, evaluated by the PPCA, supports the hypothesis that induction of the proinflammatory cytokine, TNF-alpha, by gonococcal infection, with resultant inflammation and sloughing of ciliated cells, is an important pathogenic mechanism of gonococcal salpingitis and may mediate postsalpingitis infertility and ectopic pregnancy as well.

Attachment of pathogenic Neisseria to human mucosal surfaces: Role in pathogenesis

Drug interactions are an important and often underappreciated cause of adverse clinical outcomes. This review considers the mechanisms for several clinically important drug interactions that involve the major classes of anti-infective agents. This approach is intended to complement the use of text-based references and computer databases so that physicians and pharmacists can avoid prescribing and dispensing drugs that have adverse interactions.

Gonococcal lipopolysaccharide: A toxin for human fallopian tube mucosa☆

Excerpt To the editor: We read with interest the reports of Kavin and colleagues (1) of acalculous cholecystitis and of Margulis and colleagues (2) of biliary tract disease in patients with AIDS. W...

Disseminated cryptococcosis in an AIDS patient diagnosed by examination of a peripheral blood smear

Studies of the interaction betweenNeisseria gonorrhoeae and human fallopian tube mucosa in organ culture suggest that attachment of gonococci is important, not only to secure the organism in the host, but also to initiate the disease process. The steps observed in gonococcal infection of fallopian tube organ cultures are: 1) attachment of gonococci to microvilli of nonciliated cells; 2) release from gonococci of lipopolysaccharide and possibly other toxic moities to cause mucosa damage; 3) engulfment or phagocytosis of gonococci by nonciliated cells; 4) transport of phagocytic vacuoles containing gonococci to the base of the nonciliated cells; and 5) exocytosis of gonococci within phagocytic vacuoles into the subepithelial tissues.In vivo, these steps might result in extensive local disease (e. g. salpingitis) or in the invasion of blood vessels to cause disseminated disease. Preliminary studies of human nasopharyngeal tissue in organ culture infected withNeisseria meningitidis indicate that meningococci attach to microvilli of nonciliated cells and are phagocytized by these cells. Meningococci subsequently appear in subepithelial tissues, though the route they take is not yet certain. These observations suggest at least some of the ways in which attachment may play a role in disease caused byN. gonorrhoeae andN. meningitidis. Mechanisms to block this attachment may provide new approaches to the prevention of infections caused by the pathogenicNeisseria. Untersuchungen zur Wechselwirkung zwischenNeisseria gonorrhoeae und menschlicher Tubenschleimhaut in Organkultur lassen annehmen, daß das Anheften der Gonokokken den Erreger im Wirtsorganismus schützt und außerdem den Krankheitsprozeß in Gang setzt. In Organkulturen von Tubengewebe lassen sich folgende Schritte der Gonokokkeninfektion beobachten: 1) Die Gonokokken lagern sich an die Microvilli zilienfreier Zellen an; 2) Gonokokken setzen Lipopolysaccharide und möglicherweise auch andere toxische Verbindungen frei, die die Schleimhaut schädigen; 3) zilienfreie Zellen verschlingen oder phagozytieren Gonokokken; 4) phagozytäre Vakuolen mit Gonokokken werden an die Basis der zilienfreien Zellen transportiert; 5) Gonokokken in den phagozytären Vakuolen treten in das subepitheliale Gewebe aus.In vivo könnten diese Vorgänge zu einem ausgedehnten, lokalisierten Krankheitsprozeß (beispielsweise einer Salpingitis) führen oder zur Invasion in Blutgefäße mit disseminierter Erkrankung. Frühere Untersuchungen anN. meningitidis-infiziertem menschlichen Nasopharyngealgewebe zeigen, daß Meningokokken sich an Microvilli nichtzilientragender Zellen anheften und von diesen Zellen phagozytiert werden. Anschließend erscheinen Meningokokken im subepithelialen Gewebe; der Weg der Ausbreitung ist allerdings noch ungewiß. Aus diesen Beobachtungen lassen sich zumindest einige der Vorgänge ableiten, über die Adhäsion in der Pathogenese von Gonokokken- und Meningokokkenerkrankungen eine Rolle spielt. Mechanismen, die das Anheften der Bakterien verhindern, bieten möglicherweise neue Ansätze für die Prävention von Erkrankungen, die durch pathogene Neisserien verursacht werden.