Induction of immunity against lethal Haemophilus influenzae type b infection by Escherichia coli core lipopolysaccharide.

Efforts to prevent Haemophilus influenzae type b (HIB) infections in infancy have been hampered by the low immunogenicity of capsular polysaccharide vaccines in children younger than 18 mos. In searching for alternate immunogens, we have studied the protective potential of polysaccharide-poor, lipid-rich endotoxin (LPS) core in experimental HIB infections. Because all gram-negative bacteria have similar LPS core structures, we were able to use as vaccine the J5 mutant of Escherichia coli 0111, the LPS of which consists only of core components, and thus to avoid problems in interpretation arising from vaccine contamination with non-LPS HIB immunogens. Mice were given graded inocula of HIB and developed lethal infection analogous to human HIB disease when virulence was enhanced with mucin and hemoglobin. After active immunization with heat-killed E. coli J5, 40/50 (80%) of infected mice survived, compared with 14/50 (28%) of saline-immunized controls (P less than 0.005). Passive immunization with rabbit antiserum against E. coli J5 prevented lethal HIB infection when administered 24 or 72 h before or 3 h after infection. This protection was abolished by adsorption of antiserum with purified J5 LPS, with survival reduced from 14/24 to 0/24 (P less than 0.005). Furthermore, rabbit antiserum to purified J5 LPS gave just as potent protection against death as antiserum to whole J5 cells. These studies demonstrate that immunity to core LPS confers protection against experimental murine HIB infection and provide the framework for a new approach to prevention of human disease from HIB.

Pharmacokinetics of two dosage regimens of ciprofloxacin during a two-week therapeutic trial in patients with cystic fibrosis.

Twenty-nine adult patients with cystic fibrosis received 750 or 1,000 mg of ciprofloxacin orally every 12 hours for two weeks. Pharmacokinetic data were collected on Days 1, 7, and 14. Pharmacokinetic analyses revealed minor differences between the dosage regimens, and results were similar on the first, seventh, and last day of therapy. Means for peak serum concentration (3.1 to 5.0 micrograms/ml), elimination half-life (4.8 to 5.3 hours), area under the time-concentration curve, and serum clearance (36.8 to 44.5 liter/hour) were similar to previously reported results for patients without cystic fibrosis. Sputum concentrations approximated serum values.

Randomized study of two dosage regimens of ciprofloxacin for treating chronic bronchopulmonary infection in patients with cystic fibrosis.

Twenty-nine adult patients with cystic fibrosis who had chronic bronchopulmonary infection were randomly assigned to receive 750 or 1,000 mg of oral ciprofloxacin every 12 hours for two weeks. Assessments for efficacy and safety were made on treatment Days 7 and 14 and one week following completion of therapy, and pharmacokinetic data were collected on Days 1, 7, and 14. Fifteen of 28 evaluable patients showed clinical improvement, and none had clinical deterioration. The higher dosage of ciprofloxacin did not enhance the clinical response. Statistically significant, stepwise changes in clinical scores, pulmonary function, and sputum concentrations of Pseudomonas aeruginosa and Staphylococcus aureus were noted, but regression toward initial values occurred by one week after treatment. Although all P. aeruginosa isolates were initially inhibited by 2 mg/liter of ciprofloxacin or less, 45 and 35 percent of isolates were resistant after 14 days of therapy and one week later, respectively. Outpatient oral ciprofloxacin therapy was commonly associated with clinical improvement in adult patients with cystic fibrosis who have chronic bronchopulmonary infection, regardless of the emergence of resistant P. aeruginosa, and adverse reactions were infrequent. Further studies must delineate the long-term consequences of the frequent emergence of bacterial resistance.

Pediatric nocardiosis.

Characteristics of Nocardia infection, which occurred in ten Oklahoma children between 1975 and 1980, are described. Fatal N asteroides infection occurred in three immunocompromised patients. Pneumonia was the presenting feature in each; one patient had disseminated disease. The first reported case of shunt-associated N asteroides ventriculitis occurred in a 2-month-old girl, who was successfully treated with oral trimethoprim-sulfamethoxazole. N brasiliensis was isolated from six immunologically competent children, five of whom had localized, uncomplicated, cutaneous infections. The sixth child developed osteomyelitis following a compound skull fracture. Based on this experience and a review of the literature, N asteroides infections are associated with immunocompromised hosts, and usually are seen as pneumonia with occasional dissemination to other sites. In contrast, N brasiliensis infections are more common than previously thought and usually occur in otherwise normal children as acute posttraumatic pyoderma.

Potential of moxalactam and other new antimicrobial agents for bilirubin-albumin displacement in neonates.

The effects of several novel antibiotics on in vitro binding of bilirubin to human serum albumin were investigated. At physiologic bilirubin-albumin ratios and pH values, aztreonam, imipenem, azlocillin, enoxacin and ciprofloxacin did not compete with bilirubin at drug concentrations less than 900 micrograms/mL. Cefoperazone caused an apparent increase in unbound bilirubin only at concentrations greater than 35 microM (330 micrograms/mL). Moxalactam, however, caused a linear increase in unbound bilirubin, greater than that seen with sulfisoxazole, over the entire range of antibiotic concentrations. These results may have implications for the use of these newer antimicrobial agents in neonatal infections.

The timing of tuberculin tests in relation to immunization with live viral vaccines.

The validity of the recommendation that routine screening for tuberculosis precede the administration of live viral vaccines was tested in a field study. One hundred and ten children already known to be tuberculin-positive, mostly on the basis of prior vaccination with BCG, were immunized with live viral vaccine and retested with tuberculin at the same time. Reversion to a negative tine test occurred in 3% of children given measles, mumps, or rubella vaccine, and 3.6% of controls who received no vaccine but had the tuberculin test repeated at the same interval. Very few Mantoux reactions (two of 68) reverted to negative in children given one of the three vaccines, singly or in combination; some became smaller, but there was no significant difference in the changes in the size of the Mantoux reaction between the vaccinated group and the control group, with the exception of an unexplained increase in the size of the reaction in many of those who received rubella vaccine. Screening for tuberculosis by tine or Mantoux test is not invalidated by simultaneous administration of vaccines against measles, mumps, or rubella, given singly or in combination, as part of preventive care programs.

Oral antibiotic therapy of skeletal infections in children.

Oral and intravenous (IV) antibiotic regimens were compared in 15 children with etiologically defined osteomyelitis and/or septic arthritis. On admission all children were started on standard IV therapy; seven were changed to oral antibiotics within 72 hours and the remaining eight continued on IV therapy for four weeks. Oral antibiotic doses were adjusted to achieve a peak serum bactericidal titer of greater than or equal to 1:8 against the patient's own pathogen. All patients were treated in hospital for four weeks; therapy continued for a minimum of six weeks or until the erythrocyte sedimentation rate (ESR) fell below 20 mm/hr. The clinical course and outcome were similar in both groups. There were no treatment failures nor any relapses during a 12-month follow-up period. This prospective study supports, with controlled data, the concept that acute skeletal infections can be safely and successfully treated with carefully monitored oral therapy.

Aerosolized ribavirin treatment of respiratory syncytial virus infection in infants hospitalized during an epidemic.

Thirty-three infants with predisposing conditions and/or severely symptomatic with respiratory syncytial virus (RSV) infection were treated with aerosolized ribavirin during a 12-week period at Oklahoma Children's Memorial Hospital. These patients were compared with 97 untreated patients with RSV infection hospitalized during the same epidemic. Despite preconditions which selected for a more seriously ill treatment group, patients who received ribavirin showed prompter resolution of the illness than did untreated controls. Greatest clinical improvement in treated patients occurred between the first and second days of ribavirin therapy; mean ribavirin treatment duration was 4.5 days. Ten of 22 ribavirin-treated patients continued to excrete RSV after conclusion of antiviral therapy. No adverse hematologic, renal or metabolic effects occurred with ribavirin therapy. Our experience with ribavirin therapy during a major epidemic confirms and extends the results of previous controlled evaluations demonstrating this treatment safe and effective in high risk and seriously ill infants with RSV bronchiolitis and bronchopneumonia.

Ribavirin effect on pulmonary function in young infants with respiratory syncytial virus bronchiolitis.

To assess the effect of ribavirin on pulmonary function in infants with respiratory syncytial virus bronchiolitis, we performed a randomized (nonmatched), double blinded, placebo-controlled study of 19 infants with RSV bronchiolitis. Infants with underlying respiratory, cardiac or immunologic disease were excluded. Patients were given ribavirin (10) or placebo (9) via an aerosol generator for 18 hours/day for 3 days. Pulmonary function (dynamic compliance, total lung resistance) was calculated using a pneumotachographic method on Days 1, 2 and 7. Differences between groups on clinical criteria were not found. Approximately one-half of each group showed increased compliance and decreased lung resistance after 24 to 48 hours of therapy. By Day 7 compliance had increased 30% in the placebo group and 210% in the ribavirin-treated infants (P = 0.05). Significant differences in the rate of change of lung resistance were not seen by Day 7. We conclude that previously noted improvements in the early course of respiratory syncytial virus bronchiolitis treated with ribavirin do not appear to be a result of measurable changes in pulmonary function. However, paradoxical increases in airway resistance were not found in patients treated with ribavirin.

Invasive Haemophilus influenzae type B infections: a continuing challenge.

Invasive Haemophilus influenzae type b infections are a major cause of severe infections in children between 2 months and 5 years of age. Meningitis, arthritis, pneumonia, cellulitis, osteomyelitis, and epiglottitis affect approximately 25,000 patients annually and are a major cause of mortality and morbidity in children. H. influenzae type b clinical syndromes, diagnostic methods, epidemiology, immunity, and treatment are discussed in this review. Although potent antibiotics have long been available for treatment, mortality and morbidity rates have not declined substantially in the last 15 years. Prevention of disease is therefore a continuous medical challenge. Secondary cases can be prevented by identification of the high-risk groups and the application of appropriate techniques, including antimicrobial prophylaxis. Primary prevention is the major goal of current research. H. influenzae type b vaccines currently are available for protection of infants 18 months of age and older. Prevention of primary and secondary disease and future developments, including new vaccine strategies, are stressed.

Measles.

Measles has become epidemic over most of the world, with an important increase in the number of cases and associated morbidity and mortality in the United States since 1986. The two major factors responsible for this rise in the number of cases are, first, the increase in unvaccinated preschool-age children and, second, vaccine nonresponders (approximately 5%). The highest attack rate occurred in teenagers (15 to 19 years old) and in nine states (82% of cases). This situation has prompted revised immunization recommendations for those counties reporting more than five cases of measles among preschool-age children during each of the previous 5 years. In these counties, a first dose with monovalent measles vaccine is recommended at 9 months of age, followed by a second dose with measles, mumps, and rubella vaccine at 15 months of age, and revaccination of all children at the time of school entry. Recent publications regarding the use of vitamin A and certain antiviral agents are encouraging and are discussed in the manuscript. All cases of measles should be reported and investigated promptly. A good outbreak-control program will depend on the rapid recognition of the disease, a team approach, and prompt vaccination or IgG administration to susceptible persons.

Serum standards for the bioassay of aminoglycosides in cerebrospinal fluid.

Four diluents were compared as reference standards for the assay of gentamicin in cerebrospinal fluid (CSF): human CSF, human serum, distilled water, and 150 mmol NaCl/4.5 mmol CaCl2. Standards prepared in pooled human serum were the best alternative to CSF for the assay of gentamicin and were also useful for the assay of tobramycin, netilmicin, amikacin, and sisomicin. The pH (6.0-9.8) of CSF did not alter the results of the assay.

In vitro antibacterial activity of amikacin, a new aminoglycoside, against clinical bacterial isolates from children.

Four hundred and fifty-eight clinical bacterial isolates from a children's hospital were examined for antibiotic susceptibility to amikacin (BB-KS) in comparison with a number of other antibiotics by the disk diffusion and agar dilution methods. The wide spectrum of activity of amikacin against Gram-negative bacteria was confirmed; it included E. coli, Proteus species, Enterobacter species, and Pseudomonas aeruginosa. Staphylococci were highly sensitive, but other Gram-positive bacteria tested were resistant. A disk zone diameter of 10 mm effectively separated resistant form sensitive bacteria in a standard disk diffusion test.

Evaluation of amoxicillin therapy in ill children.

Ampicillin and amoxicillin were evaluated in 37 ill children. Detailed pharmacokinetic studies in 27 of these children demonstrated an advantage in oral absorption of amoxicillin over ampicillin at dosages of both 12.5 and 25 mg/kg per dose. Individual variation was great for both drugs. No sequence effect was noted for patients receiving ampicillin before either ampicillin or amoxicillin. Amoxicillin was tolerated well by the majority of patients, and the drug was not discontinued because of side effects in any patient. No toxicities were noted for amoxicillin in any of the 20 patients studied for abnormalities in hematologic hepatic, and renal functions. Pharmacokinetics, clinical efficacy, tolerance, and toxicity studies support the clinical usage of amoxicillin in pediatric infectious diseases. However, comparative, controlled clinicalinvestigations are needed to better define the clinical advantages of this drug over ampicillin.

Comparative analysis of Haemophilus influenzae type b and Escherichia coli J5 lipopolysaccharides.

Haemophilus influenzae type b (HIB) and Escherichia coli J5 (J5) lipopolysaccharides (LPS) were examined to explore the basis of previously observed cross-protection. HIB-LPS and J5-LPS contained ketodeoxyoctonate, glucose, glucoheptose and glucosamine as common carbohydrate moieties, and laurate, myristate, beta-hydroxymyristate and palmitate as common fatty acids, although in different ratios. J5-LPS was five times more lethal than HIB-LPS for chick embryos. Weak serological cross-reactivity was observed by haemagglutination and two-dimensional immunoelectrophoresis. No significant cross-reactivity was demonstrated by enzyme-linked immunosorbent or toxicity-neutralisation assays. The cross-reactivity observed between HIB-LPS and J5-LPS was probably due to common components in the core glycolipid.

Bacterial meningitis--an update.

This report emphasizes new clinical information about bacterial meningitis in infants and children. Important elements of diagnosis include examination for the presence of shock and increased intracranial pressure. In such cases, initial treatment should focus on appropriate fluid therapy, administration of oxygen, reduction of intracranial pressure and use of corticosteroids. Currently, antibiotics of choice include ampicillin plus either cefotaxime or ceftriaxone in young infants, and one of these cephalosporins in older patients (beyond 3 months of age). Shorter durations of therapy (5 to 7 days for meningococcus, 7 days for haemophilus and 7-10 days for pneumococcus) are now commonly employed. In many centers, dexamethasone is started before the first dose of antibiotic and continued for 4 days to reduce neurologic and audiologic sequelae. Future trends will include studies of endotoxin neutralizers and non-steroidal anti-inflammatory drugs to reduce further tissue injury in meningitis. Prevention of meningitis is the ultimate goal. Since Haemophilus influenzae vaccination can now begin at 2 months, this approach may bring important results soon.

Haemophilus influenzae infections. The impact of resistance on the use of aminopenicillins and other antimicrobials in outpatient therapy.

The clinical manifestations of Haemophilus influenzae infections and the growing problem of ampicillin-resistant strains are reviewed. Despite the fact that approximately 25 percent of H. influenzae are resistant to penicillin and ampicillin, oral aminopenicillins (ampicillin, amoxicillin, bacampicillin, and cyclacillin) are commonly used for the outpatient management of these infections. The characteristics of these drugs and the rationale for their use are discussed and compared with alternative approaches to therapy. This subject requires periodic review in consideration of the increasing prevalence of ampicillin and multiple antibiotic resistance among H. influenzae isolates.

Pertussis complicated by the syndrome of inappropriate antidiuretic hormone secretion. Pathophysiology and management.

Two cases of pertussis complicated by the syndrome of inappropriate antidiuretic hormone secretion (SIADH) are reported. Both patients experienced seizures associated with hyponatremia. Patients with severe pertussis are at risk for SIADH and should be monitored closely for its development.

Clinical profile of pediatric patients hospitalized with respiratory syncytial virus infection.

To update the clinical profile of pediatric patients hospitalized with RSV infection, we retrospectively reviewed the records of 246 children (male:female ratio 1.44:1) admitted during one season to a tertiary-care hospital. The most common admitting diagnoses were bronchiolitis (37.4%), pneumonia (32.5%), and possible septicemia (13%). Median age was 3 months; median length of stay, three days. Twice as many minorities were admitted with RSV infection as all other admissions during the same year. Family history of asthma, while common (35%), did not affect length of stay or complications. Of the 38 (15%) patients requiring intensive care, 29 (76%) underwent ventilation. Patients with underlying cardiopulmonary disease had more complications, were more likely to require intensive care (about 50%), and had significantly longer hospital stays than others. All three patients (1.2%) who died had congenital heart disease. Common risk factors included young age, chronic cardiopulmonary disease, male sex, and possibly family history of asthma. Although the most typical clinical diagnoses remain bronchiolitis and pneumonia, a systemic illness resembling the sepsis syndrome has emerged at our institution as a significant clinical presentation.

Serial 67Ga-citrate imaging during treatment of acute osteomyelitis in childhood.

To test the hypothesis that abnormalities on 67Ga-citrate scans parallel the clinical course of acute osteomyelitis and revert to normal with successful antibiotic therapy, serial scans were performed in ten children. Scans improved markedly within the first two to four weeks of treatment, but abnormalities persisted at six or more weeks in over 50% of the cases, despite complete clinical resolutions of disease.