Gloria P. Heresi

The pharmacokinetics and safety of micafungin, a novel echinocandin, in premature infants

Background: Candidal fungal infection rates in neonates are increasing and are a significant cause of mortality, especially in low birth weight infants. Micafungin is an echinocandin that works by inhibiting 1,3-β-D-glucan synthase, an enzyme responsible for fungal cell wall synthesis. The objective of this study was to determine the safety and pharmacokinetics of micafungin in premature infants. Methods: This was a phase I, single-dose, multicenter, open-label, sequential-dose trial of intravenous micafungin investigating 3 doses (0.75 mg/kg, 1.5 mg/kg and 3.0 mg/kg) in 18 premature infants weighing >1000 g (n = 6 in each dosage group). A further 5 infants (500–1000 g) were enrolled in the 0.75 mg/kg dosage group only. Results: The mean ± standard deviation gestational age in the >1000 g dosage group was 26.4 ± 2.4 weeks and, on entry, patients had one or more of a variety of underlying conditions, including sepsis, pneumonia and other infections caused by Candida or other species. Micafungin pharmacokinetics in preterm infants appears linear. However, premature infants >1000 g on average displayed a shorter half-life (8 hours) and a more rapid rate of clearance (approximately 39 mL/h per kg) compared with published data in older children and adults. All doses of micafungin were well tolerated and no serious drug-related adverse events were observed. Conclusions: Single doses of micafungin, ranging up to 3.0 mg/kg, appear well tolerated in premature infants weighing >1000 g. The drugs elimination half-life and total plasma clearance in preterm infants appear dissimilar to published values for these parameters in older children and adults. The reason(s) for this apparent difference remain to be investigated.

The pharmacokinetics and pharmacodynamics of micafungin in experimental hematogenous Candida meningoencephalitis: Implications for echinocandin therapy in neonates

BACKGROUND Hematogenous Candida meningoencephalitis (HCME) is a relatively frequent manifestation of disseminated candidiasis in neonates and is associated with significant mortality and neurodevelopmental abnormalities. The outcome after antifungal therapy is often suboptimal, with few therapeutic options. Limited clinical data suggest that echinocandins may have role to play in the treatment of HCME. METHODS We studied the pharmacokinetics and pharmacodynamics of micafungin in a rabbit model of neonatal HCME and bridged the results to neonates by use of population pharmacokinetics and Monte Carlo simulation. RESULTS Micafungin exhibited linear plasma pharmacokinetics in the range of 0.25-16 mg/kg. Micafungin penetrated most compartments of the central nervous system (CNS), but only with doses >2 mg/kg. Micafungin was not reliably found in cerebrospinal fluid. With few exceptions, drug penetration into the various CNS subcompartments was not statistically different between infected and noninfected rabbits. A dose-microbiological response relationship was apparent in the brain, and near-maximal effect was apparent with doses of 8 mg/kg. Monte Carlo simulations revealed that near-maximal antifungal effect was attained at human neonatal doses of 12-15 mg/kg. CONCLUSIONS These results provide a foundation for clinical trials of micafungin in neonates with HCME and a model for antimicrobial bridging studies from bench to bedside in pediatric patients.

Community-associated methicillin-resistant Staphylococcus aureus in pediatric patients.

Community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) infections increased from 2000 to 2003 in hospitalized pediatric patients in Houston. CA-MRSA was associated with greater illness than was infection with methicillin-susceptible strains. Children with CA-MRSA were younger and mostly African American. Of MRSA isolates, 4.5% had the inducible macrolide-lincosamide-streptogramin B phenotype.

Campylobacter jejuni Enteritis

We report the development of Campylobacter jejuni enteritis in a patient with preexisting humoral and cellular immune recognition of C. jejuni antigens. This is one of few studies in which the immunologic status of a person with regard to C. jejuni before and after C. jejuni infection is directly compared, and it is the only study of which we are aware that includes measurements of cellular immunity. The findings may be important to Campylobacter vaccine development efforts.

Effect of supplementation with an iron-fortified milk on incidence of diarrhea and respiratory infection in urban-resident infants.

To address the hypothesis that increased infectious morbidity is associated with iron supplementation, 783 randomly selected infants were provided with a powdered full fat cows milk (non-fortified group) and 872 with a powdered acidified full fat cows milk fortified with 15 mg of iron as ferrous sulfate (fortified group). All infants were followed from birth to 15 months of age with a monthly home visit by a nurse who recorded morbidity occurring during the previous 30 days. At 9 months of age, 15% of infants in each cohort were receiving breast milk only; data for these infants were segregated to make the third group. Episodes (mean +/- SD) of diarrhea/infant/year were 1.06 +/- 1.29, 1.14 +/- 1.37, and 0.82 +/- 1.04 for the fortified, non-fortified and breast-fed groups, respectively; the fortified and non-fortified bottle-fed groups had a very similar incidence of respiratory illness; 2.66 +/- 2.07 and 2.74 +/- 2.24 episodes/infant/year, respectively. The incidence of respiratory illness for both bottle-fed groups was significantly higher than that for the breast-fed group (2.22 +/- 1.84 respiratory episodes/infant/year). We conclude that for the infants the tested form of iron fortified milk, which is sufficient to lower iron deficiency anemia, does not result in an increased incidence of diarrhea or respiratory illness.

Recurrent group B streptococcal disease in infants: Who should receive rifampin?

A preterm breast-fed infant had three episodes of type Ia/c group B streptococcus septicemia. After the second episode rifampin was given to the infant, but further Ia/c exposure to maternal breast milk ensued. We propose rifampin treatment for both the mother and infant in cases of recurrent group B streptococcus disease.

Phagocytosis and immunoglobulin levels in hypocupremic infants

Abstract Nineteen hypocupremic marasmic infants 5–14 months of age with a normal wt/1gth ratio, were immunologically evaluated during their rehabilitation. The infants were studied 2–3 months after admission to a Closed Nutritional Recovery Center and subsequently after copper supplementation. Two groups were defined: a severely copper deficient group (A), with abnormal copper and ceruloplasmin levels; and a marginal copper deficient group (B), with abnormal plasma copper level and normal serum ceruloplasmin. Immunoglobulin levels were measured by radial immunodiffusion technique and phagocytosis to S. aureus by using autologous and normal homogogous plasma. After copper supplementation plasma copper increased to normal values in both groups of infants. Ceruloplasmin exceeded normal ranges in group A whereas no changes were detected in group B. Serum immunoglobulins were normal and secretory IgA remained low in most of the infants. Phagocytic indices increased in most infants with both types of plasma after copper supplementation in groups A and B (p

Severe necrotizing pneumonia in children, Houston, Texas, USA.

To the Editor: Routine vaccination of children with the 7-valent pneumococcal conjugate vaccine (PCV-7; Wyeth Pharmaceuticals, Collegeville, PA, USA), initiated in the United States in 2000, was followed within 2 years by an extensive and rapid decline in invasive pneumococcal disease (IPD) (1). During the past few years, increasing frequency of invasive disease including necrotizing pneumonia caused by serotypes not included in the vaccine has been reported (2). We show an expanded pattern of the changing spectrum of the disease associated with nonvaccine serotypes through this report of 4 cases of necrotizing pneumonia in children, caused by Streptococcus pneumoniae serotype 19A. Over a 6-month period ending in March 2008, 4 children (median age 3.6 years, 1 with asthma) (Table) were brought to our hospital with signs of respiratory distress and a 4- to 7-day history of fever and cough. All had decreased breath sounds or crackles, and radiologic studies showed evidence of complicated pneumonia, which led to hospital admission (3 to an intensive care unit [ICU]). S. pneumoniae 19A was isolated from normally sterile sites with each child. All received intravenous antimicrobial drugs followed by an oral antimicrobial drug regimen and were discharged in good health. By reviewing immunization records, we confirmed that all had completed the PCV-7 series before becoming ill. Table Characteristics of patients in study of severe necrotizing pneumonia in children, Houston, Texas, USA, 2007–2008* During the same period, complicated pneumonia was identified in 7 other inpatients by using the International Classification of Diseases, 9th revision, codes for necrotizing pneumonia and empyema and Current Procedural Terminology codes for thoracoscopic surgery (median age 4.3 years); 2 had asthma, 1 had congenital diaphragmatic hernia with resultant left lung hypoplasia. No causative organism was identified for any of these cases. As illustrated by our 4 cases, serotype 19A is emerging as an increasing cause of severe disease such as complicated pneumonia. Although the incidence of IPD in general has decreased since the introduction of PCV-7, the emergence of nonvaccine serotypes as a cause of severe disease is becoming more prevalent. Among 8 geographic areas in the United States, the incidence of IPD caused by nonvaccine serotypes in children <5 years of age increased from 16.3 cases/100,000 population to 19.9 cases/100,000 population, respectively, from prevaccine years 1998–1999 to in 2004 (3). Because organisms were not isolated from the 7 other patients with necrotizing pneumonia during the same period, we are unable to comment on whether S. pneumoniae 19A was the predominant cause of necrotizing pneumonia in our study. However, in comparing our patients with these 7 patients, those with S. pneumoniae 19A appear to have had a more complicated course of illness, longer hospital stays (mean 19 days vs. 13 days), and a longer course of intravenous antimicrobial drugs (mean 19.2 days vs. 17 days). Although these 7 patients required more video-assisted thoracoscopic surgery than did our 4 patients (100% vs. 75%), those with S. pneumoniae 19A necrotizing pneumonia had a more severe clinical course of illness resulting in more ICU admissions (75% vs. 29%) and intubations (75% vs. 14%). All 4 of our patients had completed the PCV-7 series before becoming ill. The emergence of nonvaccine serotypes as a cause of severe disease may be caused by serotype replacement and increased nasopharyngeal carriage of nonvaccine serotypes after receiving PCV-7 (4). Our report supports the theory of serotype replacement. The increasing incidence of invasive disease caused by nonvaccine serotypes has prompted development of an expanded pneumococcal vaccine to include serotypes 1, 3, 5, 6A, 7F, and 19A in addition to those covered by PCV-7 (5). The need for this expanded vaccine is becoming more evident as the number of children with severe pneumococcal disease increases due to current nonvaccine serotypes.

Effect of an iron fortified milk on morbidity in infancy. A field trial

Abstract The effect of an iron fortified milk on gastrointestinal and respiratory illness was evaluated in a prospective longitudinal field trial in which infants were provided beginning at 3 and continuing through 15 months of age with, either iron fortified 15 mg Fe/l (n=53) or non fortified (n=47) milk. Gastrointestinal and respiratory symptoms and signs were recorded daily. The mean incidence of diarrhea was 1.1 and 1.2 episodes per year per child in the fortified and non fortified groups, respectively. The figures per child/year for respiratory infections were 3.9 and 3.9 respectively. The results demonstrate that iron fortification at doses sufficient to significantly eradicate iron deficiency anemia is not associated with an increased incidence of gastrointestinal and respiratory illness.

Impaired lymphoproliferative response to alloantigens and phytohaemagglutinin in marasmic infants.

Abstract The lymphoproliferative response using a whole blood microtechnique was studied in marasmic infants. The blastic transformation to alloantigens was measured in one way mixed leukocyte cultures (MLC) and phytohaemagglutinin (PHA) by 3 H-thymidine incorporation. The results were expressed as cpm in stimulated cultures and stimulation indices. The mean cpm of leukocyte cultures from marasmic and control infants stimulated with irradiated leukocytes from 3 unrelated donors were 2813, 3083, 1816 and 6243, 8216, 6767 respectively (p