Gary D. Overturf

Technical Report: Prevention of Pneumococcal Infections, Including the Use of Pneumococcal Conjugate and Polysaccharide Vaccines and Antibiotic Prophylaxis

Pneumococcal infections are the most common invasive bacterial infections in children in the United States. The incidence of invasive pneumococcal infections peaks in children younger than 2 years, reaching rates of 228/100 000 in children 6 to 12 months old. Children with functional or anatomic asplenia (including sickle cell disease [SCD]) and children with human immunodeficiency virus infection have pneumococcal infection rates 20- to 100-fold higher than those of healthy children during the first 5 years of life. Others at high risk of pneumococcal infections include children with congenital immunodeficiency; chronic cardiopulmonary disease; children receiving immunosuppressive chemotherapy; children with immunosuppressive neoplastic diseases; children with chronic renal insufficiency, including nephrotic syndrome; children with diabetes; and children with cerebrospinal fluid leaks. Children of Native American (American Indian and Alaska Native) or African American descent also have higher rates of invasive pneumococcal disease. Outbreaks of pneumococcal infection have occurred with increased frequency in children attending out-of-home care. Among these children, nasopharyngeal colonization rates of 60% have been observed, along with pneumococci resistant to multiple antibiotics. The administration of antibiotics to children involved in outbreaks of pneumococcal disease has had an inconsistent effect on nasopharyngeal carriage. In contrast, continuous penicillin prophylaxis in children younger than 5 years with SCD has been successful in reducing rates of pneumococcal disease by 84%. Pneumococcal polysaccharide vaccines have been recommended since 1985 for children older than 2 years who are at high risk of invasive disease, but these vaccines were not recommended for younger children and infants because of poor antibody response before 2 years of age. In contrast, pneumococcal conjugate vaccines (Prevnar) induce proposed protective antibody responses (>.15 μg/mL) in >90% of infants after 3 doses given at 2, 4, and 6 months of age. After priming doses, significant booster responses (ie, immunologic memory) are apparent when additional doses are given at 12 to 15 months of age. In efficacy trials, infant immunization with Prevnar decreased invasive infections by >93% and consolidative pneumonia by 73%, and it was associated with a 7% decrease in otitis media and a 20% decrease in tympanostomy tube placement. Adverse events after the administration of Prevnar have been limited to areas of local swelling or erythema of 1 to 2 cm and some increase in the incidence of postimmunization fever when it is given with other childhood vaccines. Based on data in phase 3 efficacy and safety trials, the US Food and Drug Administration has provided an indication for the use of Prevnar in children younger than 24 months.

Granulocyte colony-stimulating factor as a marker for bacterial infection in neonates

OBJECTIVE To evaluate granulocyte colony-stimulating factor (G-CSF) as an early marker of bacterial or fungal infection in neonates. STUDY DESIGN We measured G-CSF levels in infants of varying gestational and postnatal ages. We separated the infants into three groups: group 1, positive bacterial or fungal blood culture result; group 2, negative blood culture result but evidence of clinical sepsis; and group 3, negative blood culture result and no or weak evidence of sepsis. Comparison of mean G-CSF levels by group was accomplished by an analysis of variance. RESULTS One hundred seventy-six evaluations for sepsis were done for 156 infants with gestational ages ranging from 24 to 43 weeks; 50% of these infants were less than 35 weeks of gestational age. The mean G-CSF levels of groups 1 and 2 were significantly higher than those of group 3. The mean G-CSF level of each group was 2278 pg/ml (group 1), 1873 pg/ml (group 2), and 280 pg/ml (group 3) (p < 0.001). On the basis of a cutoff level of 200 pg/ml, the sensitivity of the test was 95%, specificity 73%, positive predictive value 40%, and negative predictive value 99%. CONCLUSION G-CSF levels represent a sensitive marker of infection in neonates of all gestational ages.

Staphylococcus intermedius: Clinical presentation of a new human dog bite pathogen

Staphylococcus intermedius is a Gram-positive, coagulase-positive coccus that can be distinguished from Staphylococcus aureus by routine microbiological testing. Whereas S intermedius is recognized as flora and pathogen of dogs, it has never been isolated from human infections. We hypothesized that S intermedius may cause human dog bite wound infections and that it has been previously misidentified as S aureus. Fourteen isolates from clinically infected dog bite wounds that were originally identified as S aureus were subjected to further testing; three (22%) were found to be S intermedius. The clinical and microbiological characteristics of these three S intermedius cases are described. All three patients were nonimmunocompromised persons seen within 24 hours for bites on the upper extremity. All patients developed cellulitis within one to three days. All S intermedius isolates were distinguished from S aureus by the lack of acetoin production and by the presence of beta-galactosidase activity. S intermedius was susceptible to a wide range of antibiotics; one isolate was resistant to penicillin. Two patients were treated with penicillin, one with amoxicillin-clavulanate, and all were clinically cured. These are the first three reported human infections involving S intermedius. Further study is necessary to define its clinical importance as a potential human pathogen.

Reactions to booster pneumococcal vaccination in patients with sickle cell disease

Repeat (booster) pneumococcal vaccination was administered to 32 patients with sickle cell disease in a double blind, placebo-controlled crossover study as early as 2.3 years after initial immunization. A significantly greater proportion of patients reported local pain, swelling or redness after booster, as compared to that after placebo (P < 0.001), and pneumococcal antibody titer before vaccination was the predominant predictive variable for the development of fever, local pain and swelling after booster. A comparison of reaction rates following primary or booster immunization showed no significant differences in the frequency of reported symptoms except for muscle pain which occurred less frequently after booster (P < 0.005). The concern for adverse reactions after repeat pneumococcal vaccination should not be an obstacle to the pursuit of further studies on the efficacy of pneumococcal vaccine and booster responses.

Treatment of bacterial meningitis with ceftazidime.

Ceftazidime was prospectively evaluated in the treatment of bacterial meningitis in 19 pediatric patients. Haemophilus influenzae type b (HIB) was the etiologic agent in 17 patients, and Streptococcus pneumonia and Neisseria meningitidis were the etiologic agents in one patient each. Ceftazidime was administered intravenously in a dosage of 150 mg/kg/day divided into eight hourly doses for a mean of 15 days (range, 14 to 22 days) for H. influenzae type b meningitis. The clinical and microbiologic response was appropriate in all cases. The mean ceftazidime CSF concentration was 6.7 micrograms/ml at approximately 2 hours following iv infusions. This concentration was 16- to greater than 100-fold the minimal bactericidal concentration determined for the isolated pathogens. These preliminary observations support ceftazidime as a candidate cephalosporin for the treatment of bacterial meningitis caused by H. influenzae. Additional study is required to further define its role in meningitis caused by S. pneumoniae and N. meningitidis.

Ampicillin-Chloramphenicol-Resistant Haemophilus influenzae : Plasmid-Mediated Resistance in Bacterial Meningitis

ABSTRACT. A 4-month-old infant with congenital heart disease and sepsis and arthritis, and subsequently meningitis, caused by an antibiotic-resistant strain of Haemophilus influenzae type b, failed to respond to sequential therapy with ampicillin and trimethoprim/sulfamethoxazole. Following treatment with ceftizoxime, the infant was well for 42 days, until he returned to the hospital and died. A total of 10 Haemophilus influenzae type b isolates, all outer membrane protein subtype 5L, was isolated from the pretreatment blood and synovium, cerebrospinal fluid and subdural fluids, and the petrous pyramids at autopsy. Pretreatment isolates had no detectable plasmid UNA, chloramphenicol acetyltransferase or β-lactamase; the minimal inhibitory concentration for ampicillin (AM) and chloramphenicol (CM) was 0.2 and 0.8 μg/ml, respectively. However, all cerebrospinal fluid isolates had a 42-44 mD plasmid and produced chloramphenicol acetyltransferase and β-lactamase; the minimal inhibitory concentration of these isolates to AM and CM were 12.5 and 25 μg/ml, respectively, and were also resistant to tetracycline and sulfonamide. Resistance to AM and CM was cotransferred by filter-mating conjugation at a frequency of one to two transconjugants per 10s to an Rd haemophilus recipient. Posttreatment isolates from the petrous pyramids also were resistant to AM and CM and produced chloramphenicol acetyltransferase and β-lactamase activity, but had no plasmid DNA. These findings and data from genetic studies suggested that plasmid-bearing antibiotic-resistant Haemophilus influenzae type b was selected from a heterogenous population, and that the AM/CM resistance transposons were incorporated into the bacterial chromosome.

EFFECT OF PROPHYLACTIC ACEISMINOPHEN (AC) ON MODIFYING LOCAL AND SYSTEMIC REACTIONS TO DTP VACCINATION

To determine the effect of prophylactic AC on decreasing reactions after DTP vaccination, 261 children were assigned to receive prertBasured doses of a study medicine containing either AC or placebo (PL), in a double-blind randomized protocol. AC or PL was given before (0-30 min.), and 3, 7, 12 and 18 hrs after vaccination. Fever, local and systemic reactions were monitored at 3, 7, 12 and 24 hrs. Switching to open AC (OP) was allowed if the child had a temperature above 38.9°C or was in moderate pain. Completeness of study medicine use was (AC/PL): all 5 doses=78%/61%; ≥4 doses 87%/75%; ≥3 doses=96%/83%. Significant differences (p<0.05) between AC/PL were: T >38°C at 3 hrs=2%/11%; T >38°C at 6 hrs= 10%/32%; T ≥38°C at 12 Ers=19%/32%; fussiness 49%/71%, and severe pain at the vaccination site 6%/17%. Fewer parents in the AC group switched to OP due to fever or pain:14%/25%. Switching to OP occurred earlier in the PL group (mean 8.5 hrs) than in the AC group (mean 14.8 hrs). There were no significant differences between the two groups for fever ≥38.5°C, redness, swelling, induration, overall pain, fever ≥38°C at 24 hrs, drowsiness, anorexia, emesis, or crying ≥ ½ hr. Prophylactic AC as given in this study reduces the occurrence of fever, severe pain, and fussiness, but does not appear to modify other local and systemic reactions following DTP immunization.

853 PNEUMOCOCCAL SEPTICEMIA IN CHILDREN WITH SICKLE CELL ANEMIA. CHANGING TREND OF SURVIVAL

Streptococcus pneumoniae infection has been the predominant cause of death among children with sickle cell anemia (SS). We report our observed change in the pattern of progression of septicemia to meningitis and death in non-immunized SS children who were not on prophylactic penicillin in the face of a persistently high incidence of pneumococcal disease. Of 233 SS children less than age 6 observed for 781 person years, the overall incidence rate of pneumococcal septicemia was 5.9 episodes per 100 person years. Prior to July 1972, of 23 children who had pneumococcal septicemia, 8 (35%) died and 15 (65%) developed meningitis, whereas since July 1972, 11 children have had pneumococcal septicemia, but no children died and only 2 (18%) developed meningitis (P<0.05). This decrease in major morbidity is attributed to the establishment of a clinical program which provides close medical supervision of the SS child with fever and the rapid institution of parenteral antibiotic therapy.

861 PNEUMOCOCCAL IMMUNIZATION OF PATIENTS WITH SICKLE CELL DISEASE (SCD): REACTIONS AND ANTIBODY (Ab) RESPONSE

Patients with SCD (n=174) immunized with PV had a high rate (70%) of mild reactions, primarily at the site of injection and directly associated (p <0.01) with the level of preimmunization pneumococcal IHA Ab titer. Ab response to different antigens followed 3 patterns: poor or good response regardless of age at immunization and improving response with advancing age at immunization; increase in Ab was strongly correlated (p <0.0005) with increasing level of preimmunization Ab.In 24 months of surveillance 3 episodes of type 23 pneumococcal sepsis were documented in study patients: 2 children under age 30 months (incidence, 4.40/100 patient years in children age 1-4 years) and a child age 5.6 years (0.66/100 patient years in children ≥5 years). The incidence of pneumococcal sepsis among nonimmunized children age 1-4 years followed at Los Angeles County-University of Southern California SCD Center was 6.20-9.03/100 patient years.Therefore, anamnestic response seems to contribute strongly to the enhanced Ab response observed in older children. Only modest vaccine protection may be expected among children with SCD who receive a single dose of PV.