Newer antifungal agents.

PURPOSE OF REVIEW: In recent years there has been an evolution of a better understanding of the pharmacology and clinical indications of existing antifungal agents and also the development of new broad-spectrum triazoles and a newer class of antifungal agents, the echinocandins. The availability of these agents has broadened the therapeutic options of invasive fungal disease among children and consequently antifungal therapy has become increasingly complex. RECENT FINDINGS: Adoption of adult guidelines' recommendations has been used to guide pediatric treatment as specific pediatric data were often lacking. This approach has not always selected the most appropriate therapy for newborns or young infants, as the under-dosage of voriconazole based on adult data revealed. Therefore, a detailed understanding of the available antifungal agents in children is crucial for the successful treatment of these serious infections. SUMMARY: In this review we summarize the main findings regarding antifungal treatment among children that have been recently published, focusing on the pharmacology and pediatric use of newer antifungal agents.

[Plasma antiretroviral levels in children with human immunodeficiency virus infection. Influence of sex and age]. / Niveles plasmáticos de antirretrovirales en niños con infección por el virus de la inmunodeficiencia humana. Influencia del género y de la edad.

INTRODUCTION: Pharmacologic studies have shown a relationship between plasma antiretroviral levels and toxicity/viral activity. Nevertheless, pharmacokinetic and pharmacodynamic data are inconsistent and limited in HIV-infected children. An analysis was performed of plasma antiretroviral concentrations in clinical practice and their influence on therapy efficacy in HIV-infected children. METHODS: Observational, prospective, multicenter study, including HIV-infected children followed up at 5 reference hospitals between March 2006 and June 2008. Pre-dose plasma antiretroviral levels were determined and the relationships with various clinical and analytical variables were investigated. RESULTS: A total of 129 patients were included, and 41.3% had antiretroviral plasma levels outside the established range. No differences were found between sexes. Children younger than 1 year had a higher rate of suboptimal levels and higher viral load than the remaining children. CONCLUSION: Antiretroviral plasma concentrations are more frequently suboptimal in children younger than 1 year. This finding is related with greater viral failure and implies a considerable challenge in this population, which requires very long-term treatment.

Malaria in infants below six months of age: retrospective surveillance of hospital admission records in Blantyre, Malawi.

BACKGROUND: Information on the burden of malaria in early infancy is scarce. Young infants are relatively protected against clinical malaria during the first six months of life due to the presence of maternal antibodies and foetal haemoglobin, and have received relatively little attention with respect to research and treatment guidelines. The World Health Organization provides treatment guidelines for children from six months onwards, without specific treatment guidelines for the younger infants. A number of recent reports however suggest that the burden in this young age group may be underestimated. METHODS: A retrospective review of paediatric hospital records at the Queen Elizabeth Central Hospital in Blantyre from 1998 to 2008 from three data sources was carried out. The number of admitted infants < 6 months and < or = 15 years was obtained from the registry books of the Paediatric-Nursery-Department and the Malaria Research Laboratory. For the period 2001-2004, more detailed malaria related admission information was available as part of an ongoing study on severe malaria, allowing a calculation of the proportion of infants < 6 months of age among admissions in children < 5 years. RESULTS: Retrospective analysis of hospital records showed that over the course of these years, the average annual proportion of paediatric admissions in children < or = 15 years with confirmed malaria aged < 6 months was 4.8% and ranged between 2.8%-6.7%. This proportion was stable throughout the seasons. Between 2001-2004, 9.9% of admissions with confirmed malaria in children < 5 years occurred in infants < 6 months, with numbers increasing steadily during the first six months of life. CONCLUSIONS: These findings are consistent with recent reports suggesting that the burden of malaria during the six first months of life may be substantial, and highlight that more research is needed on dose-optimization, safety and efficacy of anti-malarials that are currently used off-label in this vulnerable patient group.

Long-term response to highly active antiretroviral therapy with lopinavir/ritonavir in pre-treated vertically HIV-infected children.

BACKGROUND: Immune recovery after prolonged highly active antiretroviral therapy (HAART) with lopinavir/ritonavir has been reported in adults but not in children. Our study aimed at evaluating the long-term use of lopinavir/ritonavir among children in a clinical setting. METHODS: We carried out a retrospective study on 69 protease inhibitor (PI)-experienced vertically HIV-infected children on HAART containing lopinavir/ritonavir. We analysed the changes in percentage CD4+ cell count (%CD4+) and viral load (VL) and identified prognostic factors to achieve CD4+ >25% and undetectable VL (uVL) ( 100,000 copies/mL. We found that %CD4+ at baseline had a strong positive association with achieving CD4+ >25% at 6, 12, 18, 24, 36 and 48 months of follow-up. We also found that length of PI use had a negative association with reaching CD4+ >25% at 24 and 48 months and achieving uVL at 12 and 24 months. VL at baseline had a negative association with achieving uVL at 18 and 24 months. CONCLUSIONS: Our study demonstrates ongoing immune recovery among children on HAART with lopinavir/ritonavir after 4 years of follow-up. Lopinavir/ritonavir, when given as part of a salvage regimen, is safe and well tolerated in HIV-infected children.

Predictive factors of virological success to salvage regimens containing protease inhibitors in HIV-1 infected children.

BACKGROUND: The impact of HIV drug resistance mutations in salvage therapy has been widely investigated in adults. By contrast, data available of predictive value of resistance mutations in pediatric population is scarce. METHODS: A multicenter, retrospective, observational study was conducted in children who received rescue salvage antiretroviral therapy after virologic failure. CD4 counts and viral load were determined at baseline and 6 months after rescue intervention. Genotypic HIV-1 resistance test and virtual phenotype were assessed at baseline. RESULTS: A total of 33 children met the inclusion criteria and were included in the analysis. The median viral load (VL) and median percentage of CD4+ at baseline was 4.0 HIV-RNA log copies/ml and 23.0% respectively. The median duration that children were taking the new rescue regimen was 24.3 weeks (23.8-30.6). Overall, 47% of the 33 children achieved virological response at 24 weeks. When we compared the group of children who achieved virological response with those who did not, we found out that mean number of PI related mutations among the group of responders was 3.8 vs. 5.4 (p = 0.115). Moreover, the mean number of susceptible drugs according to virtual phenotype clinical cut-off for maximal virologic response was 1.7 vs. 0.8 and mean number of susceptible drugs according to virtual phenotype cut-off for minimal virlologic response was 2.7 vs. 1.3 (p < 0.01 in all cases). Eighteen children were rescued with a regimen containing a boosted-PI and virological response was significantly higher in those subjects compared with the others (61.1% vs. 28.6%, p < 0.01). CONCLUSION: Salvage treatment containing ritonavir boosted-PIs in children with virological failure was very efficient. The use of new tools as virtual phenotype could help to improve virologic success in pediatric population.

Effects of highly active antiretroviral therapy with nelfinavir in vertically HIV-1 infected children: 3 years of follow-up. Long-term response to nelfinavir in children.

BACKGROUND: Antiretroviral treatment (ART) in children has special features and consequently, results obtained from clinical trials with antiretroviral drugs in adults may not be representative of children. Nelfinavir (NFV) is an HIV-1 Protease Inhibitor (PI) which has become as one of the first choices of PI for ART in children. We studied during a 3-year follow-up period the effects of highly active antiretroviral therapy with nelfinavir in vertically HIV-1 infected children. METHODS: Forty-two vertically HIV-infected children on HAART with NFV were involved in a multicentre prospective study. The children were monitored at least every 3 months with physical examinations, and blood sample collection to measure viral load (VL) and CD4+ cell count. We performed a logistic regression analysis to determinate the odds ratio of baseline characteristics on therapeutic failure. RESULTS: Very important increase in CD4+ was observed and VL decreased quickly and it remained low during the follow-up study. Children with CD4+ <25% at baseline achieved CD4+ >25% at 9 months of follow-up. HIV-infected children who achieved undetectable viral load (uVL) were less than 40% in each visit during follow-up. Nevertheless, HIV-infected children with VL >5000 copies/ml were less than 50% during the follow-up study. Only baseline VL was an important factor to predict VL control during follow-up. Virological failure at defined end-point was confirmed in 30/42 patients. Along the whole of follow-up, 16/42 children stopped HAART with NFV. Baseline characteristics were not associated with therapeutic change. CONCLUSION: NFV is a safe drug with a good profile and able to achieve an adequate response in children.

Bloodstream Infections in Hospitalized Children: Epidemiology and Antimicrobial Susceptibilities.

BACKGROUND: Bloodstream infection is a major cause of morbidity and mortality. Much of our understanding of the epidemiology and resistance patterns of bloodstream infections comes from studies of hospitalized adults. METHODS: We evaluated the epidemiology and antimicrobial resistance of bloodstream infections occurring during an 11-year period in a large, tertiary care children's hospital in the US. All positive blood cultures were identified retrospectively from clinical microbiology laboratory records. We excluded repeat positive cultures with the same organism from the same patient within 30 days and polymicrobial infections. RESULTS: We identified 8196 unique episodes of monomicrobial bacteremia in 5508 patients. Overall, 46% were community onset, 72% were Gram-positive bacteria, 22% Gram-negative bacteria and 5% Candida spp. Coagulase negative Staphylococcus was the most common isolated organism. ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacter spp.) accounted for 20% of episodes. No S. aureus isolate was resistant to vancomycin or linezolid, and no increase in vancomycin minimum inhibitory concentration among methicillin-resistant S. aureus was observed during the study period. Clinically significant increases in vancomycin-resistant Enterococcus, ceftazidime-resistant P. aeruginosa or carbapenem-resistant Enterobacteriaceae were not observed during the study period; however, rates of methicillin-resistant S. aureus increased over time (P < 0.01). CONCLUSIONS: Gram-positive and ESKAPE organisms are leading causes of bacteremia in hospitalized children. Although antimicrobial resistance patterns were favorable compared with prior reports of hospitalized adults, multicenter studies with continuous surveillance are needed to identify trends in the emergence of antimicrobial resistance in this setting.

Frontline Clinician Knowledge of Antimicrobial Prescribing in an Academic Tertiary Children's Hospital: A Point Prevalence Study.

Frontline clinicians caring for hospitalized children typically knew the indication for antimicrobial therapy but less often knew the current day or planned duration of therapy or of plans for intravenous to oral conversion. Night shift clinicians were less likely to know day of therapy and duration of therapy than day shift clinicians caring for the same patients.

Daptomycin Use in United States Children's Hospitals.

We described 1035 pediatric hospitalizations with daptomycin use in 794 patients since 2004. Daptomycin use was uncommon but increased over time. A minority of hospitals accounted for the majority of use. This variability of daptomycin use highlights the need for future studies to assess the efficacy and safety of daptomycin in children.

Communicating vaccine science to the public.

Communicating science to the public is not always a straightforward process. In the case of vaccines, fear and lack of knowledge makes it even more challenging. We present some suggestions on how to defend the methods and fruits of scientific investigation to the public: 1) stand up for science, even if it not an easy task, 2) remember that no venue it too small, 3) don't let bad information go unchallenged, 4) don't assume other people are doing it, they are not and 5) remember that scientist have a responsibility to the public.

Cutaneous bacterial infections caused by Staphylococcus aureus and Streptococcus pyogenes in infants and children.

Acute bacterial skin and skin structure infections (SSSIs) are among the most common bacterial infections in children. The medical burden of SSSIs, particularly abscesses, has increased nationwide since the emergence of community-acquired methicillin-resistant Staphylococcus aureus. SSSIs represent a wide spectrum of disease severity. Prompt recognition, timely institution of appropriate therapy, and judicious antimicrobial use optimize patient outcomes. For abscesses, incision and drainage are paramount and might avoid the need for antibiotic treatment in uncomplicated cases. If indicated, empiric antimicrobial therapy should target Streptococcus pyogenes for nonpurulent SSSIs, such as uncomplicated cellulitis, and S aureus for purulent SSSIs such as abscesses.

Antiretroviral treatment in HIV-1 infected pediatric patients: focus on efavirenz.

Efavirenz is a non-nucleoside reverse transcriptase inhibitor (NNRTI), used for the treatment of human immunodeficiency virus (HIV)-1 infection. Approved by the US Food and Drug Administration in 1998, its indication was recently extended to include children as young as 3 months of age. The World Health Organization and many national guidelines consider efavirenz to be the preferred NNRTI for first-line treatment of children over the age of 3 years. Clinical outcomes of patients on three-drug antiretroviral regimens which include efavirenz are as good as or better than those for patients on all other currently approved HIV medications. Efavirenz is dosed once daily and has pediatric-friendly formulations. It is usually well tolerated, with central nervous system side effects being of greatest concern. Efavirenz increases the risk of neural tube defects in nonhuman primates and therefore its use during the first trimester of pregnancy is limited in some settings. With minimal interactions with antituberculous drugs, efavirenz is preferred for use among patients with HIV/tuberculosis coinfection. Efavirenz can be rendered inactive by a single point mutation in the reverse transcriptase enzyme. Newer NNRTI drugs such as etravirine, not yet approved for use in children under the age of 6 years, may maintain their activity following development of efavirenz resistance. This review highlights key points from the existing literature regarding the use of efavirenz in children and suggests directions for future investigation.

Candida krusei arthritis in an adolescent with acute myelogenous leukemia.

We report a case of Candida krusei arthritis in an adolescent with secondary acute myelogenous leukemia, who underwent an allogeneic bone marrow transplant complicated by C. krusei fungemia 4 months before her presentation. The infection was successfully treated with voriconazole.

Medical treatment failure and complete left pneumonectomy after Legionella pneumophila pneumonia in a bone marrow transplant recipient.

Legionnaire disease (LD) is infrequently considered in the differential diagnoses for hospital- and community-acquired pneumonia in pediatrics. We report a case of Legionnaire disease in a 19-year-old male with aplastic anemia after bone marrow transplant, who was being treated in a children's hospital. Severe, refractory pulmonary disease necessitated pneumonectomy to control the infection.

HIV-infected adolescents: relationship between atazanavir plasma levels and bilirubin concentrations.

The use of atazanavir (ATV) in adolescents infected with human immunodeficiency virus was analyzed in this study. ATV morning plasma concentrations were determined during regular visits to the outpatient department. Results showed that bilirubin levels were higher among patients with higher ATV plasma concentrations (p = .018). Monitoring plasma levels of ATV could avoid toxicity in these patients.

Association between lipodystrophy and leptin in human immunodeficiency virus-1-infected children receiving lopinavir/ritonavir-based therapy.

Highly active antiretroviral therapy might lead to the development of dyslipidemia and lipodystrophy (LD) syndrome. We carried out a multicenter prospective study of 22 human immunodeficiency virus (HIV)-1-infected children treated during 48 months with lopinavir/ritonavir-based highly active antiretroviral therapy to evaluate the trend of serum lipids and adipokines. Increase in plasma leptin levels and leptin/adiponectin ratio was associated with LD. These adipokines may be surrogate markers of LD.

Comparison of levels of antiretroviral drugs with efficacy in children with HIV infection.

OBJECTIVE: To determine the prevalence of low and high antiretroviral (ARV) plasma levels and to analyze correlation between ARV concentrations and the appearance of therapeutic failure and toxicity. METHODS: The authors present here a study evaluating antiretroviral plasma concentrations in HIV infected children on nonnucleoside reverse transcriptase inhibitors and protease inhibitors based therapy. The authors carried out a multicentre, cross-sectional study, including HIV-infected children from five large Hospitals in Madrid, Spain. Clinical, haematological, biochemical and immuno-virological parameters were assessed. Antiretroviral plasma trough levels were performed using a validated high performance liquid chromatography method. RESULTS: Between April 2006 and April 2008, 129 children were enrolled in the present study, with median treatment duration of 39.2 months. 25.5% of the non-nucleoside reverse transcriptase inhibitors levels were low and 17.6%, high. 27.9% percent of the protease inhibitors levels were low and 12.5%, high. A correlation was found among adequate or high levels of antiretrovirals and normal CD4 percentage and low viral load. Lopinavir/ritonavir plasma levels were correlated with an increase in lipodystrophy. Patients with Tanner stage 1 presented the lowest ARV plasma levels. Full adherence was reported for all the participants by a questionnaire. CONCLUSION: Many HIV-infected children show ARV plasma levels out of the therapeutic range which demands a child-adjusted approach. However, larger studies are urgently needed in pediatric populations to define optimal reference values.