Direct C-glycosylation of guanine analogues: the synthesis and antiviral activity of certain 7- and 9-deazaguanine C-nucleosides.

C-Glycosylation of two guanine analogues, 9-deaza- and 7-deazaguanine, has been achieved under Friedel-Crafts conditions, providing a direct synthetic route to 9-deazaguanosine (4; 2-amino-7-beta-D-ribofuranosyl-5H-pyrrolo[3,2-d]pyrimidin-4(3H)-one) and 8-beta-D-ribofuranosyl-7-deazaguanine (16), respectively. This electrophilic C-glycosylation was applied successfully to six guanine and substituted-guanine analogues resulting in yields of approximately 50%. This represents the first reported C-ribosylation of preformed nitrogen heterocycles isosteric with guanine. These C-nucleosides were evaluated for their ability to provide protection against a lethal Semliki Forest virus infection in mice, relative to 7-thia-8-oxoguanosine which was used as a positive control. Two of the C-nucleosides, 2-amino-6-chloro-5-methyl-7-beta-D-ribofuranosyl-5H-pyrrolo [3,2-d]pyrimidin-4(3H)-one (12) and the corresponding 6-bromo derivative (13), showed good prophylactic activity in this virus model system.

Comparison of the efficacy, safety and cost of cefixime, ceftriaxone and aztreonam in the treatment of multidrug-resistant Salmonella typhi septicemia in children.

An increase in the incidence of Salmonella typhi strains resistant to chloramphenicol, ampicillin and trimethoprim-sulfamethoxazole causing enteric fever in Egyptian children stimulated the evaluation of alternative drugs. Children with positive blood cultures were treated with cefixime, ceftriaxone or aztreonam, and the efficacy, safety and cost of these regimens were evaluated and compared. Cefixime (7.5 mg/kg) was given orally twice daily to 50 children for 14 days, ceftriaxone (50 to 70 mg/kg) was given im once daily for 5 days to 43 children and aztreonam (50 to 70 mg/kg) was given im every 8 hours for 7 days to 31 children. Children in the 3 groups were comparable with regard to age, sex, duration and severity of illness before admission. All children were cured. A significant difference (P < 0.05) in duration of treatment before becoming afebrile seemed to favor ceftriaxone (3.9 days) over aztreonam (5.5 days) and cefixime (5.3 days). During the 4-week follow-up period relapses occurred in 3 (6%) children in the cefixime group, in 2 (5%) in the ceftriaxone group and in 2 (6%) in the aztreonam group. Safety and efficacy were comparable for all 3 drugs. Ceftriaxone was most cost-effective on an inpatient basis, because of a more rapid clinical cure, and cefixime was the most cost-effective on an outpatient basis, because of drug cost.

Dexamethasone treatment for bacterial meningitis in children and adults.

Four hundred twenty-nine patients with bacterial meningitis were assigned on a nonselective alternating basis into one of two therapeutic regimens. Patients in Group I received dexamethasone in addition to standard antibacterial chemotherapy of ampicillin and chloramphenicol whereas those in Group II received antibacterial chemotherapy alone. Dexamethasone was given intramuscularly (8 mg to children younger than 12 years and 12 mg to adults every 12 hours for 3 days). Both treatment groups were comparable with regard to age, sex, duration of symptoms and state of consciousness at the time of hospitalization. A significant reduction in the case fatality rate (P less than 0.01) was observed in patients with pneumococcal meningitis receiving dexamethasone; only 7 of 52 patients died compared with 22 of 54 patients not receiving dexamethasone. A reduction in the overall neurologic sequelae (hearing impairment and paresis) was observed in patients receiving dexamethasone. This reduction was significant only in patients with Streptococcus pneumoniae meningitis; none of the 45 surviving patients receiving steroids had hearing loss whereas 4 of 32 patients not receiving dexamethasone had severe hearing loss (P less than 0.05). No significant difference was observed between the two groups with regard to time for patients to become afebrile or to regain consciousness or in the mean admission and 24- to 36-hour cerebrospinal fluid leukocyte count, glucose or protein content.

Dexamethasone adjunctive treatment for tuberculous meningitis.

During a 5-year period, 280 of 2010 patients admitted to the meningitis ward of a referral hospital in Cairo, Egypt, were clinically diagnosed as having tuberculous meningitis and were treated with either antituberculous chemotherapy and dexamethasone or antituberculous chemotherapy alone. Fatality rates and neurologic sequelae were compared for the 2 treatment groups in the 160 patients who had cerebrospinal fluid cultures positive for Mycobacterium tuberculosis. The overall mortality rate of 51% reflects the delay in receiving appropriate therapy (79% with symptoms for more than 2 weeks) and the severity of illness on admission (56% in coma, 39% drowsy). The fatality rate was significantly lower in the group receiving dexamethasone (43% vs. 59%, P less than 0.05), particularly in the drowsy patients (15% vs. 40% P less than 0.04), and in patients surviving long enough to receive at least 10 days of treatment (14% vs. 33%, P less than 0.02). Development of neurologic complications after initiation of therapy (4 vs. 10) and permanent sequelae (6 vs. 13) were significantly lower in the dexamethasone-treated group (P less than 0.02).

Azithromycin compared with rifampin for eradication of nasopharyngeal colonization by Neisseria meningitidis.

OBJECTIVES: To evaluate the efficacy and safety of azithromycin compared with rifampin for eradication of nasopharyngeal carriage of Neisseria meningitidis METHODS: Pharyngeal swabs were obtained from 500 students attending nursing school in Cairo, Egypt, to determine the colonization rate with N. meningitidis. Colonized individuals were randomized to receive azithromycin (500 mg once) or rifampin (600 mg twice daily for four doses). Subjects were then recultured 1 and 2 weeks posttreatment to determine the effectiveness of the antibiotic therapy for eradication of meningococcal nasopharyngeal colonization. RESULTS: Individuals treated with azithromycin had a 93% eradication rate at 1 and 2 weeks posttreatment comparable with 95 and 91%, respectively, for rifampin. No significant side effects were reported by any subjects treated with either antibiotic. CONCLUSION: Azithromycin is effective in the eradication of N. meningitidis from the nasopharynx of asymptomatic colonized individuals and deserves further evaluation for use as prophylaxis against N. meningitidis.

Potential interventions for the prevention of childhood pneumonia: geographic and temporal differences in serotype and serogroup distribution of sterile site pneumococcal isolates from children--implications for vaccine strategies.

Streptococcus pneumoniae is a leading cause of fatal bacterial pneumonia in young children. Pneumococcal polysaccharide vaccines have not been promoted for use in young children because many constituent serotypes are not immunogenic in children < 2 years old. Conjugating pneumococcal polysaccharide epitopes to a protein carrier would likely increase vaccine immunogenicity in children. We reviewed published and unpublished pneumococcal serotype and serogroup data from 16 countries on 6 continents to determine geographic and temporal differences in serotype and serogroup distribution of sterile site pneumococcal isolates among children and to estimate coverage of proposed and potential pneumococcal conjugate vaccine formulas. The most common pneumococcal serotypes or groups from developed countries were, in descending order, 14, 6, 19, 18, 9, 23, 7, 4, 1 and 15. In developing countries the order was 6, 14, 8, 5, 1, 19, 9, 23, 18, 15 and 7. Development of customized heptavalent vaccine formulas, one for use in all developed countries and one for use in all developing countries, would not provide substantially better coverage against invasive pneumococcal disease than two currently proposed heptavalent formulas. An optimal nanovalent vaccine for global use would include serotypes 1, 5, 6B, 7F, 9V, 14, 18C, 19F and 23F. Geographic and temporal variation in pneumococcal serotypes demonstrates the need for a species-wide pneumococcal vaccine.

Detection of IgM antibodies to Neisseria meningitidis group A polysaccharide in meningitis patients by direct and antibody capture enzyme-linked immunosorbent assays.

Serum specimens obtained from culture-positive group A meningococcal meningitis patients in Cairo, Egypt were tested for immunoglobulin M (IgM) antibodies to Neisseria meningitidis group A polysaccharide by direct and IgM capture enzyme-linked immunosorbent assays (ELISAs). Sera from patients with meningitis caused by other bacteria were used as negative control specimens. The IgM antibodies to this antigen were detected by direct ELISA in 93% of 58 specimens obtained from patients with group A meningococcal disease three or more days after hospital admission, and by IgM capture ELISA in 83% of 60 such specimens. Sixteen percent of 25 specimens obtained three or more days after admission from negative control patients were positive by direct ELISA, and 4% were positive by IgM capture ELISA. The correlation coefficient of the results with the two assays was 0.85.

Tuberculosis meningitis, Abbassia Fever Hospital-Naval Medical Research Unit No. 3-Cairo, Egypt, from 1976 to 1996.

A total of 1,430 patients with the presumptive diagnosis of tuberculous meningitis were admitted to the U.S. Naval Medical Research Unit No. 3/Abbassia Fever Hospital in Cairo, Egypt from January 1976 to January 1996. Diagnosis was confirmed by culture of the mycobacteria from the cerebrospinal fluid CSF of 857 patients and these patients are included in the final analysis. There were 497 males and 360 females. The patients ranged in age from five months to 55 years. The number of patients admitted during the months of March, April, and May were more than double those admitted during October, November, and December. The duration of symptoms prior to admission ranged from seven to 90 days (mean = 29.5 days). Upon admission, 4% of the patients were alert, 34% were drowsy, and 62% were in a coma. Of the 857 patients studied, 490 (57%) died, 256 (30%) recovered completely, and 11 (13%) recovered with sequelae. The mortality and neurologic sequelae were directly related to the stage of disease and duration of symptoms prior to admission. Mortality was significantly lower in patients admitted in stage II and or with short duration of disease compared with those in stage III and or with prolonged duration of symptoms prior to admission. The use of dexamethasone in patients with tuberculous meningitis significantly reduced the ocular complications that occur in these patients and also significantly reduced the fatality rate.

Reversal of hepatic fibrosis after praziquantel therapy of murine schistosomiasis.

We examined the effect of parasitologic cure of S. mansoni infection on liver fibrosis in mice. Praziquantel, 250 mg/kg body weight, was administered orally to mice 8 weeks after infection with 50 S. mansoni cercariae. We assessed liver fibrosis by chemical measurement of collagen content as measured by the estimation of hydroxyproline and by histologic examination at the time of treatment, and at 10 and 20 weeks post-treatment, in comparison with the same measurements in untreated S. mansoni-infected mice and age-matched normal control mice. The extent of infection was monitored by liver egg counts. Compared to normal uninfected mice, mice with untreated S. mansoni infection showed steady accumulation of liver collagen at the 3 measurement periods, reaching an average level of 15-fold greater than that found in normal mice at 28 weeks after infection. Mice treated with praziquantel showed a prompt decrease in S. mansoni liver egg load with no viable eggs 10 weeks after treatment. Liver fibrosis was modestly diminished in treated mice compared to untreated controls 10 weeks after treatment; fibrosis was arrested and liver collagen content had diminished to normal levels by 20 weeks after treatment. No praziquantel toxicity was noted. The survival of treated mice was markedly greater than that of untreated infected animals. We conclude that parasitologic cure of murine S. mansoni infection is followed by arrest and eventual partial reversal of liver fibrosis under the conditions employed.

Meningitis and encephalitis at the Abbassia Fever Hospital, Cairo, Egypt, from 1966 to 1989.

A total of 7,809 patients with meningitis or encephalitis were admitted to the Abbassia Fever Hospital in Cairo, Egypt from November 1, 1966 to April 30, 1989. The etiology was Neisseria meningitidis (mostly group A) in 27.3% of the patients, Mycobacterium tuberculosis in 19.7%, Streptococcus pneumoniae in 7.3%, and Haemophilus influenzae in 4.1%. Almost 27% of the cases had purulent meningitis but without detectable etiology; however, the epidemiologic data suggest that most of these had meningococcal meningitis. Encephalitis was suspected in 12.5% of the patients. Most of the meningococcal, pneumococcal, and Haemophilus cases occurred during the winter months. The number of meningococcal and culture-negative purulent cases per year reached a maximum three times during the 22.5 years of this study. There were more males than females in all etiologic groups, with the ratio for the total patient population being 1.6:1. The average age ranged between 11.7 and 16.5 years for all groups except for Haemophilus patients, who had a mean age of 2.5 years. The mortality rate was almost 55% for tuberculous patients and was approximately 40% for both pneumococcal and Haemophilus patients; it was 8.5% in patients with meningococcal disease.

A review of the treatment of bacterial meningitis.

This is review of our experience in the treatment of meningitis carried out at the Naval Medical Research Unit No. 3 (NAMRU-3), Cairo, Egypt since 1967. We have demonstrated that the serum and cerebrospinal fluid concentrations of ampicillin and its efficacy when used in the treatment of meningitis are comparable whether they are administered intravenously or intramuscularly. The third generation cephalosporin ceftriaxone was found to be very safe and effective when administered intramuscularly once a day in the treatment of the different types of acute bacterial meningitis. Aztreonam given intramuscularly was successful in the treatment of Gram-negative meningitis caused by multi-resistant organisms. The fatality rates and morbidity were significantly reduced in patients with meningitis when dexamethasone was given in conjunction with antibacterial chemotherapy.

Epidemiology, prevalence and clinical diagnosis of meningitis at Abbassia Fever Hospital, Cairo, 1966-1989.

The United States Naval Medical Research Unit No. 3 and the Abbassia Fever Hospital in Cairo, Egypt have together diagnosed and treated 7809 patients admitted to a meningitis ward since 1966. Aetiological diagnosis was based on clinical evaluation and laboratory studies. Marked increases in annual admissions in 1970-1972, 1980-1982 and 1987-1988 were related to increases in admissions due to meningococcal disease, while in 1977-1981 the increase was due to encephalitis related to Rift Valley fever. Better, rapid diagnostic procedures are needed to enable effective treatment to be given earlier and to reduce mortality rates.

Laboratory diagnosis of bacterial meningitis.

This overview summarizes studies conducted since 1970 on the laboratory diagnosis of bacterial meningitis at the Naval Medical Research Unit No. 3. These investigations demonstrated that counterimmunoelectrophoresis (CIE), agglutination of sensitized staphylococcal cells or latex particles, and enzyme-linked immunosorbent assay (ELISA) effectively detect and identify specific antigens in the cerebrospinal fluid of patients with meningococcal, pneumococcal, and Haemophilus meningitis. ELISA was the most sensitive of these methods and CIE the least sensitive. ELISA was also used to measure antibodies to meningococcal outer membrane protein antigens in patients. Finally, high rates of group A meningococcal nasopharyngeal carriage were found in group A meningococcal meningitis patients and populations associated with group A patients, but not in populations that were not associated with group A disease.

The use of dexamethasone in preventing ocular complications in tuberculous meningitis.

Twenty-seven patients with tuberculous meningitis (TBM) were treated with ethambutol, isonicotinic acid hydrazide, streptomycin and dexamethasone and 28 were treated with triple anti-tuberculous drugs only. Only two of the patients to whom steroids were given developed ocular complications as compared to seven of those not receiving dexamethasone. High dose dexamethasone apparently prevents optic atrophy in TBM. Controlled double-blind studies with and without dexamethasone are needed to confirm this postulation.

Cefixime in the treatment of enteric fever in children.

Cefixime in a dose 20 mg/kg/day, orally, divided into two doses 12 h apart for a minimum of 12 days, was administered to 50 children with proven S. typhi septicaemia. Forty four of the patients were infected with strains of S. typhi resistant to multiple antibiotics including chloramphenicol, ampicillin and trimethoprim-sulfamethoxazole. All patients responded rapidly to treatment and were cured clinically and bacteriologically. Fever subsided within a mean of 5.3 days (range 3-8 days). Only two of the 50 patients treated relapsed during the 8 week follow-up period. No serious adverse reactions attributable to the drug were observed. Cefixime proved to be an effective oral drug in this open treatment trial and was associated with minimal side effects. It may provide a therapeutic alternative to the treatment of Salmonella infection with organisms multi-resistant to the standard drug regimens. Its oral formulation may provide an efficient alternative to parenteral therapy in less severely ill patients who can tolerate oral feeding.

Aztreonam compared to chloramphenicol in the treatment of enteric fevers.

Fifty-seven patients, twenty-six males and thirty-one females, aged 6 to 50 years (mean 12.6 years) with proven Salmonella typhi or S. paratyphi A septicaemia, were treated in an open randomized parallel study with either aztreonam or chloramphenicol. Aztreonam was given intramuscularly at a level of 50 to 80 mg/kg body weight per dose every 8 h for 7 days to thirty patients. Chloramphenicol was given orally in a dose of 50 to 70 mg/kg body weight every 6 h for 12 days to twenty-seven patients. All patients responded rapidly to treatment, becoming afebrile and asymptomatic within 5.5 to 6.4 days. Only one patient on aztreonam relapsed following treatment, whereas three patients relapsed after chloramphenicol treatment. There were no serious side effects with either drug.

Ceftriaxone compared with a combination of ampicillin and chloramphenicol in the treatment of bacterial meningitis in adults.

Thirty patients, 25 males and 5 females, aged 16-30 years (mean 21.8 years) with bacterial meningitis were assigned randomly into one of two therapeutic regimens. Patients in Group I received ceftriaxone 100 mg/kg (max 4 g) intravenously (i.v.) once daily. Those in Group II received ampicillin i.v. 160 mg/kg/day plus chloramphenicol i.v. 100 mg/kg/day every 6 h. Of the 15 patients in Group I, N. meningitidis was isolated from 11 patients and S. pneumoniae from 4; and of the 15 patients in Group II, N. meningitidis was isolated from 10 patients and S. pneumoniae from 5. Response to therapy as measured by mortality, time taken for defervescence and for patients to regain full consciousness were comparable in the two groups. One patient in each group died; both died within 24 h of initiation of therapy. The mean no. of days taken to become afebrile were 3.4 and 3.5 and to regain full consciousness were 3.9 and 3.5 for Groups I and II respectively. Ceftriaxone given i.v. appears to be as effective as a combination of ampicillin and chloramphenicol in the treatment of adult patients with meningitis due to N. meningitidis and S. pneumoniae. However, the once-daily schedule of ceftriaxone is more convenient, saving nursing time and expense.

Ceftriaxone versus chloramphenicol in the treatment of enteric fever.

Fifty-five patients with culture-proven Salmonella typhi and paratyphi enteric fever were assigned to one of two therapeutic regimens. Group I received ceftriaxone 60-80 mg/kg/day intramuscularly for 5-7 days, those in group II received chloramphenicol 50-80 mg/kg/day orally in 4 divided doses for 12-14 days. both groups were comparable as regards age, sex, severity and duration of symptoms prior to admission. A significant reduction in the mean number of days taken for patients to become afebrile, disappearance of clinical signs and symptoms, duration of therapy and hospital stay were observed in patients receiving ceftriaxone as compared to those receiving chloramphenicol. None of the patients receiving ceftriaxone relapsed, while three patients receiving chloramphenicol relapsed. No major reactions were seen with either drug.

The use of the bromine partition test in the diagnosis and prognosis of tuberculous meningitis.

The bromine partition test was successfully used to differentiate cases of proven tuberculous meningitis from patients with aseptic and non-tuberculous meningitis. Forty patients, 22 males and 18 females aged 5 to 30 years (mean 13.5 +/- 6.2), were included in the study. Nineteen patients were confirmed to have tuberculous meningitis, 12 had aseptic meningitis, and 9 bacterial meningitis. All patients received 0.6 mci/kg of bromine 82 administered through a nasogastric tube as ammonium bromide dissolved in 5 ml of isotonic sodium chloride. The serum to CSF bromine ratio was then calculated 48 hours after the dose. The test was then repeated 8 days later in patients with bacterial meningitis and 8, 90, and 180 day later in patients with tuberculous meningitis. The test was very useful in quickly differentiating cases of aseptic from bacterial and tuberculous meningitis and was also a useful prognosticator in patients with severe tuberculous meningitis.

The value of the tuberculin skin test in patients with tuberculous meningitis.

To determine the clinical utility of the tuberculin purified protein derivative (PPD) skin test in patients suspected of having tuberculous meningitis (TBM), the test was applied on admission to 180 patients suspected of having tuberculous meningitis and to 50 patients with proven bacterial meningitis admitted to the Abbassia Fever Hospital, Cairo, Egypt, during the period 1987 to 1989. Admission tuberculin positivity in evaluated groups revealed the following: overall suspect TBM cases--17% (31/180), culture-confirmed TBM cases--19% (16/83), and culture-confirmed acute bacterial meningitis cases--14% (7/50). Repeat PPD skin test at 60 days in surviving presumptive/confirmed TBM cases revealed a significant increase in tuberculin positivity to 62% (58/93) from admission (p < 0.001). Evaluation of PPD positivity by clinical stage of TBM revealed 36% positivity in alert patients as compared to 12% positivity in comatose patients (p = 0.01). Admission tuberculin skin testing as a diagnostic aid for clinical management of tuberculous meningitis is of limited utility in our study population because of the high prevalence of tuberculin positivity in the Egyptian population (potential false positive correlation with the acute presentation) and the advanced stage of TBM at presentation to Egyptian public hospitals (potential false negative correlation).