Maria Paris

The Beneficial Effects of Early Dexamethasone Administration in Infants and Children with Bacterial Meningitis

BACKGROUND In experimental models of meningitis and in children with meningitis, dexamethasone has been shown to reduce meningeal inflammation and to improve the outcome of disease. METHODS We conducted a placebo-controlled, double-blind trial of dexamethasone therapy in 101 infants and children admitted to the National Childrens Hospital, San José, Costa Rica, who had culture-proved bacterial meningitis or clinical signs of meningitis and findings characteristic of bacterial infection on examination of the cerebrospinal fluid. The patients were randomly assigned to receive either dexamethasone and cefotaxime (n = 52) or cefotaxime plus placebo (n = 49). Dexamethasone (0.15 mg per kilogram of body weight) was given 15 to 20 minutes before the first dose of cefotaxime and was continued every 6 hours thereafter for four days. RESULTS The demographic, clinical, and laboratory profiles were similar for the patients in the two treatment groups. By 12 hours after the beginning of therapy, the mean opening cerebrospinal pressure and the estimated cerebral perfusion pressure had improved significantly in the dexamethasone-treated children but worsened in the children treated only with cefotaxime (controls). At 12 hours meningeal inflammation and the concentrations of two cytokines (tumor necrosis factor alpha and platelet-activating factor) in the cerebrospinal fluid had decreased in the dexamethasone-treated children, whereas in the controls the inflammatory response in the cerebrospinal fluid had increased. At 24 hours the clinical condition and mean prognostic score were significantly better among those treated with dexamethasone than among the controls. At follow-up examination after a mean of 15 months, 7 of the surviving 51 dexamethasone-treated children (14 percent) and 18 of 48 surviving controls (38 percent) had one or more neurologic or audiologic sequelae (P = 0.007); the relative risk of sequelae for a child receiving placebo as compared with a child receiving dexamethasone was 3.8 (95 percent confidence interval, 1.3 to 11.5). CONCLUSIONS The results of this study, in which dexamethasone administration began before the initiation of cefotaxime therapy, provide additional evidence of a beneficial effect of dexamethasone therapy in infants and children with bacterial meningitis.

Evaluation of antimicrobial regimens for treatment of experimental penicillin- and cephalosporin-resistant pneumococcal meningitis.

The most appropriate therapy for meningitis caused by Streptococcus pneumoniae strains resistant to the extended-spectrum cephalosporins is unknown. We evaluated ceftriaxone, vancomycin, and rifampin alone and in different combinations and meropenem, cefpirome, and clinafloxacin alone in the rabbit meningitis model. Meningitis was induced in rabbits by intracisternal inoculation of one of two pneumococcal strains isolated from infants with meningitis (ceftriaxone MICs, 4 and 1 microgram/ml, respectively). Two doses, 5 h apart, of each antibiotic were given intravenously (except that ceftriaxone was given as one dose). Cerebrospinal fluid bacterial concentrations were measured at 0, 5, 10, and 24 h after therapy was started. Clinafloxacin was the most active single agent against both strains. Against the more resistant strain, ceftriaxone or meropenem alone was ineffective. The combination of vancomycin and ceftriaxone was synergistic, suggesting that this combination might be effective for initial empiric therapy of pneumococcal meningitis until results of susceptibility studies are available.

Effect of dexamethasone on therapy of experimental penicillin- and cephalosporin-resistant pneumococcal meningitis.

Treatment of pneumococcal meningitis has become problematic because of the emergence of penicillin- and cephalosporin-resistant strains and because of the concern that dexamethasone therapy might reduce penetration of antibiotics into the cerebrospinal fluid (CSF). We addressed these issues with our rabbit meningitis model by studying two pneumococcal isolates that were resistant to penicillin and ceftriaxone and susceptible to vancomycin and rifampin. Ceftriaxone, vancomycin, and rifampin were given alone or in combination, with or without coadministration of dexamethasone. Treatment was started 12 to 14 h after intracisternal inoculation of approximately 10(4) CFU of one of the organisms. Rifampin concentrations in serum and CSF were similar, regardless of whether dexamethasone was given, whereas those of ceftriaxone were somewhat lower at each time point in animals given dexamethasone. The penetration of vancomycin into CSF was consistently and substantially reduced with dexamethasone treatment, which resulted in a delay in CSF sterilization not observed in non-dexamethasone-treated animals. When rifampin was used with ceftriaxone for treatment of meningitis caused by the more resistant strain, bacteriologic cure occurred promptly, with or without dexamethasone therapy. In areas with high rates of occurrence of resistant pneumococcal strains, we believe initial empiric therapy of bacterial meningitis should include two antibiotics: ceftriaxone and either rifampin or vancomycin. When dexamethasone is used, the combination of ceftriaxone and rifampin is preferred for therapy.

Dilemmas in diagnosis and management of cephalosporin-resistant Streptococcus pneumoniae meningitis

We recently managed an infant with meningitis caused by Streptococcus pneumoniae in whom ceftriaxone failed to sterilize the cerebrospinal fluid after 6 days of therapy. This strain, which had a penicillin minimal inhibitory concentration (MIC) of 2 micrograms/ml, appeared susceptible to ceftriaxone (MIC < 0.5 micrograms/ml) when evaluated by a commercial MIC panel (Microtech Medical Systems, Inc., Aurora, CO) but was found to have a ceftriaxone MIC of 4 micrograms/ml when evaluated by conventional microtiter broth dilution technique. Furthermore ceftriaxone therapy of meningitis induced with this strain in a rabbit model was ineffective. Thirteen of 112 pneumococcal strains (11.6%) isolated recently at Childrens Medical Center of Dallas were penicillin-resistant, and 3 of these were highly penicillin-resistant (MIC > or = 2 micrograms/ml). The incidence of pneumococcal strains with cefotaxime MICs > or = 1.0 micrograms/ml has increased from 0 of 258 from 1981 to 1983 to 5 of 112 (4.5%) from 1991 to 1992. The definition of cephalosporin resistance for pneumococci requires modification and further studies of the antibiotic management of meningitis caused by such strains are needed because resistance to cephalosporins is increasing and the extended spectrum cephalosporins may be ineffective as sole therapy.

The Effect of Interleukin-10 on Meningeal Inflammation in Experimental Bacterial Meningitis

Interleukin-10 (IL-10) is a cytokine with antiinflammatory effects. In a rabbit model of meningitis, IL-10 was given intracisternally or intravenously to evaluate the impact on inflammation induced by lipooligosaccharide (LOS), Haemophilus influenzae type b (Hib), or Listeria monocytogenes. Intracisternal IL-10 in concentrations >1 microg significantly reduced tumor necrosis factor-alpha (TNF-alpha) and lactate values in cerebrospinal fluid (CSF). Intravenous IL-10 (1 mg/kg) in two doses after intracisternal LOS significantly reduced CSF TNF-alpha and lactate. When Hib was used, animals were treated with ceftriaxone and dexamethasone with or without IL-10 (1 mg/kg). TNF-alpha was significantly reduced in animals treated with IL-10, dexamethasone, or both compared with levels in rabbits receiving ceftriaxone alone. Comparable results were obtained when L. monocytogenes was inoculated and animals were treated with ampicillin with or without IL-10, dexamethasone, or nothing. In conclusion, IL-10 modulates CSF TNF-alpha concentrations in experimental LOS, Hib, or L. monocytogenes meningitis. The maximal inhibitory effect was seen when IL-10 and dexamethasone were combined.

Evaluation of CP-99,219, a new fluoroquinolone, for treatment of experimental penicillin- and cephalosporin-resistant pneumococcal meningitis.

CP-99,219 is a new fluoroquinolone that has excellent activity against gram-positive organisms including penicillin- and cephalosporin-resistant Streptococcus pneumoniae strains. In our well-established rabbit model of meningitis, we conducted experiments to determine the concentrations of CP-99,219 in cerebrospinal fluid (CSF) after intravenous administration and its ability to eradicate two penicillin-resistant pneumococcal isolates. The peak and trough concentrations of CP-99,219 in the CSF were from 19 to 25% of the concentrations simultaneously obtained in serum and were unaffected by concomitant dexamethasone administration. Compared with untreated (control) animals, three doses of CP-99,219 given 5 h apart significantly reduced the bacterial count in CSF by 5 to 6 log10 CFU at 10 h. Although 47% of the dexamethasone-treated animals and 18% of those not given the steroid had positive cultures at 24 h (14 h after administration of the last antibiotic dose), the mean bacterial counts did not change from those observed at 10 h. Additionally, only results for animals infected with one of the two pneumococcal strains appeared to be affected by concomitant dexamethasone therapy.

Systemic cytokine response in children bitten by snakes in Costa Rica

Background To characterize the host response to venom from snakes of the familyViperidaein Costa Rica, we investigated the release of cytokines: IL-1, IL-6, IL-8, TNF-α, MIP-1β, and RANTES in pediatric patients who were bitten by a snake. Methods Patients were included in this study if they were admitted to the hospital within 24 hours of the snakebite. Blood samples were taken immediately on admission to the hospital, and then at intervals of 3, 12, and 24 hours, and on days 3, 5, and 7 after the accident. Patients received gentamicin plus clindamycin or gentamicin plus penicillin intravenously for a minimum of 3 days or longer if necessary. IL-1, IL-8, TNF-α, MIP-1β, and RANTES were determined by monoclonal antibody-based ELISAs, while IL-6 was determined by bioassay. Results Eighteen patients were included in this study; 15 were bitten byBothrops asperand three byB. lateralis. Eleven patients were male. Median (range) age was 9 (1–12) years. Nine patients had detectable serum concentrations of IL-6 (200 pg/ mL) and IL-8 (51 pg/mL) on admission, increasing to 500 pg/mL and 115 pg/mL for IL-6 and IL-8, respectively, during the first 12–24 hours. Cytokine concentrations returned to normal or undetectable ranges by 72 hours. TNF-α concentrations peaked at 12 hours (mean: 48 pg/mL). Low, but detectable concentrations of MIP-1β were observed in some patients at various time intervals (48 pg/mL), whereas IL-1 was not detectable at any time point. Regulated on Activation Normal T cell Expressed and Secreted (RANTES) concentrations were evaluated in only five patients, being elevated in all of them. Patients with elevated cytokine concentrations required early fasciotomy (<24 hours after the accident) more often than those who had normal or undetectable cytokine concentrations (P < 0.05). There were no statistically significant associations between severity of envenomation, or outcome, and elevated serum cytokine concentrations (P > 0.05). Conclusions Bothropssp snake venoms induce clinical and pathophysiologic alterations similar to acute trauma, with release of proinflammatory cytokines. A better understanding of the role of the inflammatory response could lead to the development of new therapeutic strategies to improve the outcome in snakebitten patients.

A multicenter, open label, double tympanocentesis study of high dose cefdinir in children with acute otitis media at high risk of persistent or recurrent infection.

Background: Given the relatively high prevalence of recurrent and persistent acute otitis media (AOM) and the prominent etiologic role of Streptococcus pneumoniae, especially penicillin-nonsusceptible strains in children with these conditions, new alternative treatments are desirable. Methods: Children 6 months–4 years of age with AOM considered to be at risk for recurrent or persistent infection received large dosage cefdinir 25 mg/kg oral suspension once daily for 10 days. Children were evaluated pretreatment (day 1), on therapy (days 4–6), end of therapy (days 12–14) and at follow-up (days 25–28). All children had tympanocentesis at enrollment. In culture-positive children, tympanocentesis was repeated after 3–5 days (days 4–6) unless evidence of absence of middle ear effusion was documented. Results: Of 447 children enrolled, 230 were clinically and bacteriologically evaluable (74% 2 years old or younger; 57% treated for AOM in previous 3 months). Bacteriologic eradication, based on repeat tympanocentesis on days 4–6, was achieved in 74% (170 of 230) of children; 76% (201 of 266) of AOM pathogens were eradicated. Eradication of penicillin-susceptible, -intermediate and -resistant S. pneumoniae was 91% (50 of 55), 67% (18 of 27) and 43% (10 of 23), respectively (P < 0.001); eradication of H. influenzae was 72% (90 of 125). Overall clinical response at days 12–14 was 83% (76 and 82% for children with S. pneumoniae and Haemophilus influenzae, respectively). Sustained clinical response at days 25–28 was 85%. Clinical response was 83% for culture-positive children versus 96% for culture-negative children at baseline tympanocentesis (P < 0.001). Conclusions: In this study of AOM among children at risk for persistent or recurrent infection, large dose cefdinir resulted in an overall successful clinical response at end of treatment of 83%. This regimen was efficacious against penicillin-susceptible S. pneumoniae, but effectiveness was markedly decreased against nonsusceptible strains and was moderate for H. influenzae strains.

Comparison of five-day cefdinir treatment with ten-day low dose amoxicillin/clavulanate treatment for acute otitis media.

Background: Short course β-lactam antibiotic therapy for acute otitis media (AOM) should improve patient adherence, but it has not been evaluated since the heptavalent pneumococcal conjugate vaccine became routinely used in the United States. Methods: In a prospective, investigator-blinded, multicenter study, 425 patients, age 6 months–6 years, with a clinical diagnosis of nonrefractory AOM were randomized to receive either 5 days of cefdinir therapy (14 mg/kg divided twice daily) or 10 days of amoxicillin/clavulanate therapy (45/6.4 mg/kg divided twice daily). Clinical response was assessed at end of therapy (2–4 days postantibiotic, respectively) and week 4 (study days 25–28). Results: With no difference in demographics between treatment groups, overall the mean age (±SD) was 2.8 ± 1.8 years, 65% had received conjugated pneumococcal vaccination and 48% had bilateral AOM. The satisfactory clinical response rate at end of therapy was comparable for cefdinir versus amoxicillin/clavulanate (88%, 170 of 194 versus 85%, 164 of 192; 95% CI −4.9, 9.3). Although this must be interpreted with caution, cefdinir showed an apparent trend for higher efficacy than amoxicillin/clavulanate (92%, 72 of 78 versus 77%, 55 of 71; P = 0.019) in a subsample of patients 6–24 months old who had received conjugated pneumococcal vaccination. The incidence of drug-related adverse events was less for cefdinir than for amoxicillin/clavulanate (24%, 50 of 211 versus 38%, 82 of 214; P = 0.0018) Conclusion: For children with nonrefractory AOM, based only on clinical endpoints, 5 days of therapy with cefdinir 14 mg/kg divided twice daily was comparable overall with 10 days of therapy with low dose amoxicillin/clavulanate 45/6.4 mg/kg divided twice daily.

Albendazole therapy for Microsporidium diarrhea in immunocompetent Costa Rican children.

Background: Microsporidia comprise a large group of obligate intracellular parasites. Although several species have emerged as opportunistic agents in immunocompromised patients, cases have also been reported in immunocompetent patients. Methods: During 21 months, we conducted a randomized, open label study in 200 children hospitalized with Microsporidium subacute diarrhea. Patients had prolonged, nonbloody, nonmucoid diarrhea, with ≥10 bowel movements/day for >10 days. Patients had negative rotavirus tests, bacterial stool cultures and sugar reductive tests in feces. Stool examinations to rule out Giardia intestinalis and intestinal nematodes were performed. Microsporidium was identified by light microscopy in stool specimens stained with Giemsa and Weber techniques. One hundred patients received oral albendazole (15 mg/kg/day twice a day for 7 days) and 100 patients received only supportive therapy. Results: Both groups were comparable regarding gender, age, clinical evolution and weight. Median (range) age was 24 (6–36) months. All children had abdominal pain, nausea, vomiting and anorexia. The primary endpoint, defined as clinical improvement within 48 h of initial therapy, occurred in 95 and 30% of the albendazole-treated and untreated patients, respectively (P < 0.05). There was a significant decrease in stool frequency, reduction of clinical findings and decrease in Microsporidium parasites in stool specimens of children treated with albendazole compared with the untreated group. Median (range) duration of diarrhea was 5 (3–7) days in albendazole-treated patients versus 10 (8–15) days in untreated patients (P < 0.05). Conclusion: Albendazole therapy was effective in improving the clinical manifestations and decreasing the duration of the illness of children with diarrhea caused by Microsporidium.