Carla Odio

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.

Caspofungin therapy of neonates with invasive candidiasis.

Background: Invasive candidiasis is an increasing problem in neonatal intensive care units worldwide and is an important cause of morbidity, mortality and prolongation of hospital stay. Despite administration of amphotericin B, invasive candidiasis in neonates is sometimes complicated by persistent fungemia and refractory invasive candidiasis. The problem has been augmented by the increasing prevalence of non-albicans species that often are resistant to fluconazole and to amphotericin B. Population and Methods: The population consisted of 1 term and 9 premature neonates with invasive candidiasis caused by Candida albicans (n = 4), Candida parapsilosis (n = 3), Candida tropicalis (n = 2) and Candida glabrata (n = 1). Despite initial therapy with deoxycholate amphotericin B, blood cultures remained positive in all patients for 13–49 days. Invasive candidiasis progressed to meningitis and enlarging renal Candida bezoars in the kidney of one patient and an enlarging atrial vegetation in another. Another patient developed severe hypokalemia refractory to potassium supplementation. Two of the C. albicans and all of the non-albicans Candida isolates were resistant to fluconazole; the C. glabrata isolate was resistant to amphotericin B. Amphotericin B was discontinued and caspofungin initiated in all patients in a dosage of 1 mg/kg/d for 2 days followed by 2 mg/kg/d. Results: All positive blood cultures cleared between 3 and 7 days after initiation of caspofungin, the atrial vegetation resolved and the renal Candida bezoars disappeared. Renal and hepatic function tests did not show any values above normal throughout caspofungin therapy. There were no attributable clinical adverse events during the administration of caspofungin in any of the patients. Conclusions: Caspofungin was effective, safe and well-tolerated as an alternative therapy for persistent and progressive candidiasis in those neonates who were unresponsive to or intolerant of deoxycholate amphotericin B.

Double blind, randomized, placebo-controlled study of dexamethasone therapy for hematogenous septic arthritis in children

Background. Septic arthritis is associated with residual dysfunction in 10 to 25% of affected children. Concentrations of cytokines detected in synovial fluid of children with bacterial arthritis correlate with the severity of inflammation. Treatment with dexamethasone decreased cartilage degradation in experimental Haemophilus influenzae b and Staphylococcus aureus arthritis. Endpoints. To decrease the number of patients with residual dysfunction of the affected joint at the end of therapy and at 6 and 12 months and to speed clinical recovery by the administration of dexamethasone. Methods. In a double blind manner we randomly selected 123 children with suspected hematogenous bacterial arthritis to receive dexamethasone or saline for 4 days. Antibiotic therapy was tailored according to age and the recovered pathogen. Results. Of the 123 children enrolled, 61 were assigned to the dexamethasone group and 62 to the placebo group. Only 50 and 50 patients in each group were evaluable. The 2 groups of patients were comparable with respect to age, sex, duration of symptoms, pathogen, affected joint and therapeutic and diagnostic procedures. Staphylococcus aureus accounted for 67% of the isolates, Haemophilus influenzae type b for 13% and Streptococcus pneumoniae for 9%. Dexamethasone therapy reduced residual dysfunction at the end of therapy, P = 0.000068; at 6 months, P = 0.00007; and at 12 months, P = 0.00053 of follow-up and shortened the duration of symptoms (P = 0.001) during the acute phase. The 26% incidence of residual dysfunction in the control patients was similar to the 25% found in other series. Conclusions. A short course of dexamethasone reduced residual joint dysfunction and shortened significantly the duration of symptoms in children with documented hematogenous septic arthritis. These results suggest that a 4-day course of low dose dexamethasone given early benefits children with hematogenous septic arthritis.

Prospective, randomized, investigator-blinded study of the efficacy and safety of meropenem vs. cefotaxime therapy in bacterial meningitis in children

OBJECTIVES To compare the efficacy and safety of meropenem with cefotaxime for the treatment of infants and children with bacterial meningitis. METHODS Infants and children with strongly suspected or documented bacterial meningitis were randomly assigned in a prospective multicenter study to receive either meropenem or cefotaxime. Patients were assessed at the end of therapy and at 5 to 7 weeks and 5 to 7 months after the end of treatment for the presence of neurologic and sensory neural sequelae. RESULTS A total of 258 children were randomized to either treatment group. A further 8 patients with suspected pneumococcal meningitis were treated with meropenem without randomization. Of the randomized patients 154 were fully evaluable, 79 in the meropenem group and 75 in the cefotaxime group. At the end of treatment there were no significant differences in clinical outcome between the two treatment groups. Clinical cure with or without sequelae was achieved in 97 and 96% of the meropenem- and cefotaxime-treated patients, respectively. At the end of treatment and at 5 to 7 weeks, 46 and 54% of meropenem patients were cured with no sequelae, respectively. Corresponding results for cefotaxime patients were 56 and 58%. All pathogens were eradicated. In total 37 patients had seizures during treatment, 15 (12%) in the meropenem and 22 (17%) in the cefotaxime group. None of the seizures was considered to be drug-related. CONCLUSIONS This trial shows that meropenem is suitable therapy for bacterial meningitis in infants and children and that it offers an efficacy and safety profile similar to that of cefotaxime.

Brain abscess in infants and children

Y. Er~ahin (~) 9 S. Mutluer 9 E, Giizelba~ Division of Pediatric Neurosurgery, Department of Neurosurgery, Ege University Medical School, Bornova, TR-35100 Izmir, Turkey Abstraet Forty-four consecutive patients with brain abscesses, aged between 1 month and 16 years, were reviewed. The cause of abscess was meningitis in 36% of the cases, otitis in 27%, head injury in 16%, congenital heart disease in 9%, other in 5%, and undetected in 5%. Thirty patients had a single abscess and 12 had multiple abscesses. Multiloculated abscess was present in 2. Total excision was accomplished in 22 patients. Three patients underwent needle aspiration. Drainage of the abscess was performed in 13. Secondary excision was needed in 5 patients. One patient was treated nonsurgically. Streptococci, staphylococci and Proteus mirabilis were the microorganisms recovered in cultures. Overall mortality was 20% (9 patients). Mortality was significantly higher in patients under 2 years of age than in those older. Of 15 patients who were comatose at the time of admission, 6 died. Etiology, diagnostic method, and treatment modalities were not found to be significant factors in terms of predicting mortality.

Single dose antibiotic therapy is not as effective as conventional regimens for management of acute urinary tract infections in children

One hundred thirty-two children with acute urinary tract infection were randomly assigned to receive trimethoprim-sulfamethoxazole in one dose, two doses daily for 3 days or two doses daily for 7 days. The patient characteristics, etiologic agents and frequency of roentgenologic abnormalities were similar for the three treatment groups. There was no significant difference in bacteriologic cure rates for the single dose regimen (93%) and multidose regimens (96%). The difference in rates of recurrent urinary tract infection between the single dose (20.5%) and 3-day (5.6%) and 7-day (8%) regimens was statistically significant (P = 0.033). A single dose of trimethoprim-sulfamethoxazole is inadequate treatment for infants and children with acute urinary tract infection.

Disseminated histoplasmosis in infants

BACKGROUND Disseminated histoplasmosis usually occurs in immunocompromised patients who reside in Histoplasma capsulatum-endemic regions. It has also been described in immunocompetent infants after exposure to a large inoculum of the pathogen resulting in case fatality rates of 40 to 50%. METHODS From 1983 through 1996 all infants with documented disseminated histoplasmosis were treated with amphotericin B followed by daily ketoconazole for 3 months. Immunologic workups were performed at the time of diagnosis and at 4 to 6 weeks of therapy. Surviving patients were followed for at least 1 year. Time to resolution of signs and symptoms was recorded, as were complications. RESULTS We managed 40 patients with disseminated histoplasmosis. The age in months at diagnosis was 15.3+/-10.2 (mean +/- SD), and 24 were male. All patients were from endemic regions and they presented with fever, spleen and/or liver enlargement and hematologic abnormalities. Diagnosis was made by histology and culture of bone marrow, spleen, lymph node, bronchoalveolar or liver samples. Twenty patients presented with T cell deficiency that resolved at 4 to 6 weeks of therapy in all of the retested patients, and 10 of 12 tested patients had hyperglobulinemia that resolved. Thirty-five (88%) patients were cured by treatment; 4 died and 1 relapsed. CONCLUSIONS Disseminated histoplasmosis should be considered in infants from endemic areas who present with fever, hepatosplenomegaly and hematologic abnormalities. These patients develop transient hyperglobulinemia and T cell deficiency that resolve with treatment. Treatment with amphotericin B followed by an oral azole for 3 months is effective in most patients.

Evaluation of aztreonam and ampicillin vs. amikacin and ampicillin for treatment of neonatal bacterial infections

In a prospective randomized, open study we evaluated aztreonam (AZ) for treatment of neonatal bacterial infections. There were 147 patients enrolled in the study; 75 received AZ and ampicillin (AMP) and 72 amikacin (AM) and AMP (conventional therapy). Twenty-eight AZ/AMP-treated patients and 32 conventionally treated patients had bacteriologically documented infections caused by gram-negative enteric bacilli or Pseudomonas species. Treatment groups were comparable in age, clinical status, and type and severity of underlying disease at the time of enrollment. Bronchopneumonia and infections caused by Pseudomonas species oc-

Comparative efficacy of ceftazidime vs. carbenicillin and amikacin for treatment of neonatal septicemia

The efficacy and safety of ceftazidime were compared with those of carbenicillin and amikacin in 60 neonates with proved invasive bacterial infections. The two treatment groups of patients were comparable with regard to sex, gestational and chronologic ages, associated risk factors, clinical condition on enrollment, focus of infection and bacteriology. Escherichia coli was isolated from blood cultures of 31%, Pseudomonas aeruginosa from cultures of 25%, Klebsiella sp. from cultures of 13% and other Gram-negative enteric bacilli from cultures of 17% of the patients. Staphylococcus aureus was isolated from 20% (12 of 60), and coagulase-negative staphylococci from 8% (5 of 60) of the patients. All Gram-negative coliform bacilli were susceptible to ceftazidime whereas 10, 56 and 77% were resistant to amikacin, carbenicillin and ampicillin, respectively. Serum bactericidal activity against the offending pathogen was as much as 5-fold greater in ceftazidime-treated compared with conventionally treated patients. Seven patients with infections caused by organisms resistant to the study drugs were excluded from analysis. Case-fatality rates were 6.4% (2 of 31) and 21% (6 of 28) in the ceftazidime- and amikacin/carbenicillin-treated patients, respectively. Total failure rates, including deaths, were significantly higher in patients treated with amikacin/carbenicillin (8 of 28, 28.5%) compared with that of ceftazidime-treated patients (2 of 31, 6.4%). Thirteen percent (5 of 31) and 3% (1 of 28) of the ceftazidime- and amikacin/carbenicillin-treated patients, respectively, developed invasive Candida albicans superinfection while receiving treatment. In this study results of treatment with ceftazidime were superior to results of treatment with amikacin/carbenicillin for invasive bacterial infections of newborn infants.(ABSTRACT TRUNCATED AT 250 WORDS)

A double-blind study of the efficacy and safety of multiple daily doses of amikacin versus one daily dose for children with perforated appendicitis in Costa Rica

BACKGROUND There is evidence that aminoglycosides given in a single daily dose (once daily dose, ODD) are as effective and safe as multiple daily doses (MDD). However, the published pharmacokinetic and pharmacodynamic data are overly representative of pediatric populations in Europe and the USA, and not representative of low or middle-income countries such as Costa Rica, in which the patient population might differ from those in higher income settings. METHODS A double-blind, randomized clinical trial of the efficacy and safety of ODD vs. MDD amikacin therapy was conducted for children aged 2-12 years with an intraoperative diagnosis of perforated appendicitis. One hundred patients were randomized following a one-to-one randomization to receive either amikacin 7.5 mg/kg every 8 h (MDD) or 22.5 mg/kg as a single dose (ODD). Patients in both groups were given clindamycin 10 mg/kg every 6 h. Efficacy was evaluated by the occurrence of intra-abdominal abscesses, documented by abdominal ultrasound, and therapeutic failure. Safety was determined by the presence of renal or cochlear toxicity. RESULTS Fifty patients were enrolled in each group. There were no statistically significant differences in the incidence of intra-abdominal abscesses or therapeutic failures, or in the occurrence of cochlear or renal toxicity, between the MDD and ODD treatment groups. CONCLUSIONS In this patient population of Costa Rican children with perforated appendicitis, we found that amikacin ODD is as safe and effective as the MDD regimen. This could have implications for national health systems such as that in Costa Rica, as ODD is presumably a more economic option and may reduce the cost of antibiotic treatment in patients with perforated appendicitis. This would need to be confirmed through an economic analysis, which is outside the purview of this paper.