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Objectives: To evaluate the pharmacokinetics, tolerance, safety and antiviral activity of the HIV protease inhibitor, saquinavir, formulated as soft gelatin capsules (SQV-SGC), given in combination with nucleoside antiretroviral agents (NRTIs) with or without nelfinavir in HIV-infected children., Methods: This was an open label study of HIV-infected children ages 3 to 16 years, conducted in two parts. In Part 1 of the study 14 children were treated orally with SQV-SGC (initially given in three 33-mg/kg doses daily; dosage adjusted to 50 mg/kg three times daily based on initial pharmacokinetics) and two NRTIs. Addition of nelfinavir was permitted for children who did not achieve a predetermined steady state target plasma saquinavir exposure. In Part 2 a new group of 13 children received SQV-SGC (33 mg/kg three times daily) in combination with nelfinavir and one or two NRTIs. Pharmacokinetics were assessed after the first dose and 4 weeks into treatment (steady state). Patients were treated for 72 and 48 weeks in Parts 1 and 2, respectively., Results: Most adverse events were mild; the most commonly reported were diarrhea, abdominal discomfort and headache. Two children were withdrawn from the study because of adverse events (one each of nausea and dysphagia) related to the study treatment. There were no deaths or serious adverse events attributed to the study medication. Steady state saquinavir area under the plasma concentration vs. time curves (AUC24) were 6,210 and 11,010 ng/h/ml for Parts 1 and 2, respectively. Compared with baseline measurements median changes in plasma HIV RNA concentrations were -2.12 log10 copies/ml [5 of 14 (36%) with HIV RNA <50 copies/ml) (Week 72)] and -2.58 log10 copies/ml [8 of 13 (62%) <50 copies/ml) (Week 48)] in Parts 1 and 2, respectively. The median changes in CD4+ lymphocyte count were +292 and +154 cells/microl for Parts 1 and 2, respectively. Genotypic resistance assays revealed a low frequency of saquinavir-associated resistance mutations after 48 weeks of therapy, with only 2 of 27 children having substitutions at positions 48V and/or 90M., Conclusions: Combination therapy with SQV-SGC was well-tolerated and safe in HIV-infected children, and antiviral activity was observed. Saquinavir plasma concentrations were lower than expected, particularly for Part 1 (SQV-SGC plus NRTIs), but addition of nelfinavir increased saquinavir exposures.

Objective: To evaluate the safety and antiviral and immunologic effects of hydroxyurea given with didanosine (ddI) and/or stavudine (d4T) to symptomatic HIV-infected children., Methods: HIV-infected children with a history of long term nucleoside antiretroviral therapy were treated orally with hydroxyurea (initial dose, 10 to 20 mg/kg once daily; final dose, 30 mg/kg once daily), added to existing therapy that included ddI and/or d4T., Results: Sixteen children were enrolled (mean age, 6.7 years; range, 1.8 to 13.4 years). Antiretroviral therapy used with hydroxyurea included d4T/ddI (12), ddI (2), d4T (1) and d4T/lamivudine (1). Children received between 24 and 48 weeks of therapy, which was well-tolerated. Hydroxyurea was held temporarily during the first month of therapy in 4 cases because of neutropenia; all patients resumed hydroxyurea at full dosage without recurrence of neutropenia. No patient discontinued therapy permanently because of intolerance or toxicity. For the 13 children who completed 48 weeks of study treatment, the mean plasma HIV RNA concentration decreased from 4.6 log10 copies/ml at baseline to 4.2 log10 copies/ml at study Week 48 (P = 0.035, paired t test). Eight of these 13 children experienced a 0.5-log10 copies/ml or greater drop in HIV RNA concentration in the 48 weeks of study treatment. Appreciable changes in CD4+ lymphocyte percentage were not noted., Conclusions: Hydroxyurea, added to existing therapy with ddI and/or d4T, was well-tolerated and safe in HIV-infected children. Evidence of antiviral activity was observed in some cases.

The infection status of 91 infants born to mothers with human immunodeficiency virus (HIV) infection was determined. Twenty-eight (31%) infants had confirmed HIV infection and 63 (69%) had seroreverted to HIV and lack evidence of infection. During the first 6 months of life HIV culture had a sensitivity and specificity for diagnosis of HIV infection of 80 and 100%, respectively. False negative HIV cultures were observed in only 7 of 35 specimens, 6 from among the 12 infected infants tested at birth. The sensitivity and specificity of polymerase chain reaction (PCR) detection of HIV were 95 and 93% respectively. A single false negative PCR test result was observed among the 19 tests performed on specimens from HIV-infected infants. False positive PCR test results were observed occasionally throughout the first 6 months of life. Detection of HIV-specific IgA antibody lacked diagnostic sensitivity; positive test results were observed in only 53% of specimens obtained from infected infants. Culture and PCR detection offer excellent sensitivity and specificity for diagnosis of HIV infection during the first 6 months of life; however, false-negative HIV cultures sometimes are observed, particularly during the newborn period, and either false negative or false positive PCR test results may be noted occasionally. For purposes of clinical decision-making, any positive test result should be confirmed with a second HIV culture or PCR test performed on a separate blood specimen.

The medical records of 142 infants referred for evaluation solely because they were born to human immunodeficiency virus (HIV)-infected mothers (i.e. not because of signs or symptoms suggesting HIV infection), were reviewed. The infection status of 85 of these infants has been determined; 17 (20%) have confirmed HIV infection and 68 have seroreverted to HIV and lack evidence of infection. During the first 6 months of life HIV culture had better sensitivity, specificity, positive predictive value and negative predictive value for diagnosis of HIV infection than did physical examination, serum immunoglobulin determination or HIV p24 antigen determination. Of the 16 HIV-infected infants who were available for evaluation during the first 6 months of life, all had at least one culture from blood positive for HIV. Two of 4 and 10 of 11 infants were culture-positive at birth and during the first 3 months of life, respectively. A positive HIV culture results was the earliest finding of infection in 15 infants; 10 of these infants concomitantly were found to have hyperimmunoglobulinemia (8 cases) and/or an abnormal physical examination (4 cases). One HIV-infected infant developed hyperimmunoglobulinemia G and A at age 3 months without other evidence of HIV infection until age 5 months when a positive HIV culture was noted. All HIV-infected infants had abnormal findings by physical examination, a positive HIV culture, and/or hyperimmunoglobulinemia by 3 months of age. Infants with normal physical examination and laboratory test results at 3 and/or 6 months of age invariably were HIV-uninfected.

There is a paucity of published information available on extrapulmonary cryptococcosis (EC) in children infected with human immunodeficiency virus, the etiologic agent of the acquired immunodeficiency syndrome. We surveyed investigators in pediatric acquired immunodeficiency syndrome around the country regarding their experience with EC. Investigators from 33 (87%) of 38 institutions responded and information on 13 patients from 11 institutions was analyzed. EC was the acquired immunodeficiency syndrome indicator disease in 9 (69%) of 13 patients. Median age was 8 years with a range of 2 to 17 years. Human immunodeficiency virus risk factors were transfusion (5 patients), hemophilia (4 patients) and perinatal exposure (4 patients). Meningitis, seen in 62% of patients, was the most common clinical manifestation. Although 2 patients with fulminant disease died before therapy was started, 10 (91%) of 11 had a clinical response to amphotericin B with or without flucytosine. Our study indicates a spectrum of EC in pediatric human immunodeficiency virus infection ranging from fulminant, fatal fungemia to chronic meningitis and fever of unknown origin. Cryptococcosis was generally not the cause of death in patients who initially responded to amphotericin B therapy. Optimal antifungal therapy, including the role of fluconazole, warrants further study.

The charts of 104 white and 52 black children with bacteremia caused by Streptococcus pneumoniae or Haemophilus influenzae type b were reviewed to determine each patient's white blood cell (WBC) and absolute polymorphonuclear cell (PMN) counts at the time of presentation to the emergency room. Mean WBC and PMN counts were virtually identical for the racial groups, 18,300 vs. 18,700/microliter and 12,900 vs. 13,000/microliter, respectively. Examination of subgroups of white and black children with or without meningitis or other focal infection also revealed no significant differences between races, although significantly lower mean WBC and PMN counts were found in children with, compared to those without, meningitis regardless of race. As an aid to the identification of children at high risk for S. pneumoniae or H. influenzae type b bacteremia, it appears that WBC and PMN counts may be interpreted without regard to race.

The hospital records of 85 children with bacterial meningitis were reviewed and a subset of 25 children who underwent computed tomography of the head were identified. The major stated indications for computed tomography were fever (8 patients), seizures (4 patients), signs of increased intracranial pressure (4 patients), focal neurologic dysfunction (3 patients) and recurrent meningitis (2 patients). Abnormal findings were demonstrated by computed tomography in 20 of 25 patients but in 8 patients consisted solely of nonspecific dilatation of spaces containing cerebrospinal fluid or of basilar enhancement. The yield of information that was useful either diagnostically or therapeutically was low; positive findings of obvious clinical relevance were present in only 2 cases. Computed tomography provides an accurate means of diagnosing intracranial complications of bacterial meningitis. It must be used conservatively, however, to limit expense and radiation exposure and enhance the yield of potentially relevant information. Computed tomography is indicated for children with persistent neurologic dysfunction, persistently positive cerebrospinal fluid cultures or recurrent meningitis, whereas it is of little value for children with prolonged fever alone.

Urinary tract infections are common among pediatric patients, occurring in approximately 2% of children within the first 5 to 10 years of life. Most urinary tract infections are uncomplicated and respond readily to treatment. However, complications may make treatment difficult and result in serious adverse sequelae. Several characteristics of aztreonam make it an attractive alternative to aminoglycosides and certain other antibiotics for the treatment of complicated urinary tract infections in children. It has been shown, for example, that the drug is highly active against most of the pathogenic organisms responsible for urinary tract infections in the pediatric population, as well as Pseudomonas aeruginosa and many less common, aminoglycoside- and cephalosporin-resistant Gram-negative bacteria. Aztreonam is widely distributed throughout the body and achieves potentially therapeutic concentrations in the kidneys and in urine for up to 24 hours after dosing. The efficacy and safety of this agent compare favorably with standard antibiotic agents. Aztreonam is associated with high rates of microbiologic and clinical cures, and the few side effects reported have been mild and transient.

Charts of 182 outpatient children with bacteremia caused by Streptococcus pneumoniae, Haemophilus influenza type b or Neisseria meningitidis were reviewed. Twenty-four patients (13%) were afebrile (temperature less than 37.8 degrees C) at presentation. Five afebrile patients had no history of fever. Four of the five had localizing signs of infection and one appeared toxic. Afebrile patients were not strikingly different from febrile bacteremic patients by any assessments. Bacteremia in children cannot be excluded on the basis of absence of fever by history and examination. Blood cultures should be performed on afebrile children who either have localizing signs of serious bacterial infection or appear toxic.