Jaime G. Deville

Linezolid versus vancomycin for treatment of resistant Gram-positive infections in children

Background. Pediatric infections caused by resistant Gram-positive infections are an increasing concern with limited treatment options. Linezolid, a new oxazolidinone, is active against staphylococci, streptococci and enterococci. Objective. To assess clinical efficacy and safety of linezolid vs. vancomycin in antibiotic-resistant Gram-positive infections in children. Design. Hospitalized children (birth to 12 years of age) with nosocomial pneumonia, complicated skin/skin structure infections, catheter-related bacteremia, bacteremia of unknown source or other infections caused by Gram-positive bacteria were randomized 2:1 to receive linezolid intravenously followed by oral linezolid or vancomycin and then by an appropriate oral agent. Treatment duration was 10 to 28 days. Results. There were 321 patients enrolled (linezolid 219, vancomycin 102). Clinical cure rates were 79% vs. 74% (P = 0.36) and 89% vs. 85% (P = 0.31) for linezolid and vancomycin in intent-to-treat and clinically evaluable patients, respectively. Cure rates were similar by age and infection diagnosis. Pathogen eradication rates in microbiologically evaluable patients were high for linezolid and vancomycin, respectively, for methicillin-susceptible S. aureus (95% vs. 94%; P = 0.82), methicillin-resistant S. aureus (88% vs. 90%; P = 0.89) and methicillin-resistant coagulase-negative staphylococci (85% vs. 83%, P = 0.87). In clinically evaluable patients, linezolid-treated patients required significantly fewer days of intravenous therapy compared with vancomycin-treated patients (8.0 ± 4.8; 10.9 ± 5.8 days, respectively; P < 0.001). In addition significantly fewer linezolid-treated patients had drug-related adverse events than did vancomycin-treated patients (19% vs. 34%, respectively; P = 0.003). Hematologic events were uncommon and similar between treatment groups. Conclusions. Linezolid was well-tolerated and as effective as vancomycin in treating serious Gram-positive infections in children.

Invasive fungal infections in pediatric oncology patients: 11-year experience at a single institution.

The purpose of this study was to determine the incidence of fungal infections in pediatric hematology and oncology (PHO) patients and to describe variations regarding site of infection, organisms, and mortality. The records of 1,052 patients presenting to the UCLA PHO service with various malignancies from 1991 to 2001 were retrospectively reviewed. No patient received invasive antifungal prophylaxis. Transplant patients were excluded. The 11-year incidence of fungal infections in this pediatric oncology cohort was 4.9%. There was a linear increase in the incidence of fungal infections from 2.9% to 7.8% between 1996 and 2001 (P = 0.001). Patients with acute leukemia represented 36% of the population but had a disproportionate incidence (67%) of fungal infections. Adolescents had twice the expected incidence of infection (P < 0.0001). Overall, Candida sp. was the major pathogen. Over time, a trend of fewer infections caused by Candida and more due to Aspergillus was noted. Blood-borne infections decreased over time, while those in the urinary and respiratory tracts increased (P = 0.04). Sixty-two percent of infections occurred in neutropenic patients. PHO patients had an overall mortality of 21%, but those with fungal infections experienced a 2.6-fold higher mortality that was not attributable to infections alone. Empiric antifungal therapy had no effect on mortality rates. Concurrent nonfungal infections did not increase mortality rates. The incidence of fungal infections increased over time, possibly as a result of advances in antibacterial and chemotherapeutic regimens. Adolescents and patients with leukemia were especially at risk. Fungal infections are a poor prognostic factor, independent of fungal-related mortality. New diagnostic methods allowing for early detection and treatment as well as more effective therapies are needed.

Decrease in Hospitalization and Mortality Rates among Children with Perinatally Acquired HIV Type 1 Infection Receiving Highly Active Antiretroviral Therapy

BACKGROUND The impact of highly active antiretroviral therapy (HAART) on human immunodeficiency virus type 1 (HIV-1) disease progression in perinatally infected children is not well documented. This study aims to identify the effect of evolving antiretroviral therapy on the immunologic and virologic status of and hospitalization and mortality rates among perinatally infected children. METHODS Children receiving outpatient care during 1994-2001 at 3 HIV clinics in southern California were observed longitudinally for CD4+ cell percentage, plasma HIV-1 RNA load, antiretroviral treatment, Pneumocystis jiroveci pneumonia (PCP) prophylaxis, and rate of hospital admissions. RESULTS A total of 129 children were observed during the study period; 51% were girls, and 40.3% were Hispanic, 29.5% were African American, and 27.1% were white. The mean CD4+ cell percentage increased from 22.5% in 1994 to 31.2% in 2001 (P<.01), and the mean plasma HIV-1 RNA load decreased from 4.53 log10 copies/mL in 1996 to 3.27 log10 copies/mL in 2001 (P<.001). The use of HAART increased from 0% in 1994 to 93% in 2001 (P<.01), whereas the use of PCP prophylaxis decreased from 55% to 16% during this time (P<.001). The hospitalization rate decreased from 6.49 to 0.60 admissions per 100 person-years during 1994-2001 (P<.001). Acquired immunodeficiency syndrome-associated hospital admission rates decreased from 15.6% in 1994 to 0% in 2001 (P<.0001). Similarly, the admission rate for patients with Centers for Disease Control and Prevention category B decreased from 29.7% in 1994 to 5.9% in 2001 (P<.0001). Logistic regression analysis showed that CD4+ cell percentage and viral load were independently associated with risk of hospitalization. Survival was significantly longer for those who received HAART. CONCLUSIONS HIV-1-associated mortality and hospitalization rates decreased significantly between 1994 and 2001 in perinatally infected children. This correlated with an increase in CD4+ cell percentage and a decrease in HIV-1 RNA load concurrently with the expanded use of HAART.

Safety, vaccine virus shedding and immunogenicity of trivalent, cold-adapted, live attenuated influenza vaccine administered to human immunodeficiency virus-infected and noninfected children.

OBJECTIVE To assess the safety of live, attenuated influenza vaccine (LAIV) administered to relatively asymptomatic or mildly symptomatic HIV-infected children and non-HIV-infected children. METHODS Twenty-five non-HIV and 24 HIV-infected children (CDC Class N or A1,2) were enrolled into this double blind, placebo-controlled study. Children were randomized within each HIV status group to one of two dosing regimens: Regimen 1, Dose 1 = LAIV, Dose 2 = placebo, Dose 3 = LAIV; or Regimen 2, Dose 1 = placebo, Dose 2 = LAIV, Dose 3 = LAIV. Study doses were separated by 28 to 35 days. Reactogenicity events within 10 days and adverse events within 28 to 35 days after each study dose were recorded. Blood HIV RNA concentrations, CD4 counts and CD4% were measured throughout the study on HIV-infected children. Quantitative influenza cultures were performed on nasal aspirates collected periodically from all children up to 28 to 35 days after each study dose. Influenza isolates were assessed for retention of the temperature-sensitive phenotype. Serum influenza HAI antibodies were measured before and after each LAIV vaccination. RESULTS No significant differences were found in rates of reactogenicity events and vaccine-related adverse events after placebo or the first dose of LAIV within each HIV status group, nor were differences found between HIV-infected and HIV-uninfected children after each dose of LAIV. Overall none of the HIV-infected children experienced a significant LAIV-related serious adverse event or influenza-like illness, making the one sided 95% CI of such a serious event occurring after LAIV 0 to 12%. No significant changes in geometric mean HIV RNA concentrations, CD4 counts or CD4% or prolonged or increased quantity of LAIV virus shedding occurred in HIV-infected children after receiving either dose of LAIV. All recovered influenza isolates retained the temperature-sensitive phenotype. After two doses of LAIV, 83% of the non-HIV-infected and 77% of the HIV-infected children had a > or = 4-fold rise in influenza antibody to at least one of the three LAIV strains. CONCLUSION If relatively healthy HIV-infected children become exposed to LAIV inadvertently, then serious adverse outcomes would not be expected to occur frequently.

Linezolid versus vancomycin in the treatment of known or suspected resistant gram-positive infections in neonates.

Background. Gram-positive infections caused by susceptible and resistant strains of Staphylococcus aureus, coagulase-negative staphylococci and enterococci are increasing problems in neonates. Linezolid, a new oxazolidinone, is active against these pathogens and has recently been approved by the Food and Drug Administration for treating Gram-positive infections in pediatric patients. Objective. To compare the clinical efficacy and safety of intravenous and oral linezolid with vancomycin (10 to 15 mg/kg every 6 to 24 h) in neonates (age 0 to 90 days). Methods. Hospitalized infants with known or suspected hospital-acquired pneumonia, complicated skin or skin structure infections, bacteremia or other infections (e.g. pyelonephritis, abdominal abscess) were eligible. Test-of-cure clinical response was evaluated at follow-up. Results. Sixty-three neonates, randomized 2:1 to linezolid (n = 43) or vancomycin (n = 20) were included in the intent-to-treat group. Clinical cure rates at follow-up in the intent-to-treat group were higher, but not significantly different, for linezolid vs. vancomycin (78%vs. 61%; P = 0.196). Corresponding cure rates in clinically evaluable patients were 84%vs. 77% (P = 0.553) for linezolid and vancomycin, respectively. Pathogen eradication rates were as follows in the linezolid and vancomycin groups, respectively:S. aureus (67% vs. 60%; P = 0.850); coagulase-negative staphylococci (88%vs. 100%; P = 0.379); and enterococci (71%vs. 0%; P = 0.168). Results for hematology and chemistry assays were similar between treatment groups. Fewer linezolid-treated neonates had drug-related adverse events than vancomycin-treated neonates (12%vs. 32%; P = 0.058). Conclusions. Linezolid is well-tolerated and as effective as vancomycin in the treatment of resistant Gram-positive infections in neonates.

Recombinant CD4-IgG2 in Human Immunodeficiency Virus Type 1—Infected Children: Phase 1/2 Study

The use of recombinant CD4-IgG2 in pediatric human immunodeficiency virus type 1 (HIV-1) infection was evaluated by single and multidose intravenous infusions in 18 children in a phase 1/2 study. The study drug was well tolerated, and dose proportionality was observed in terms of area under time-concentration curve and peak serum concentration. Acute decreases of >0.7 log(10) copies/mL in serum HIV-1 RNA concentration were seen in 4 of the 6 children treated with 4 weekly 10 mg/kg doses. At 14 days after treatment, 3 children had sustained reductions in serum HIV-1 RNA; the other children had rebounded to baseline levels or above. By 28 days after therapy, the peak HIV-1 cellular infectious units was reduced in all 6 children, including the 2 who had experienced an earlier transient increase in values. Thus, recombinant CD4-IgG2 treatment of HIV-1-infected children appears to be well tolerated and capable of reducing HIV-1 burden.

Frequency of fungemia in hospitalized pediatric inpatients over 11 years at a tertiary care institution.

Objectives. To determine the frequency of bloodstream fungal infections in children who were admitted to our tertiary institution over an 11-year period. Methods. We conducted a retrospective cohort study of patients who were aged 0 to 21 years, had bloodstream fungal infections, and were admitted to the University of California, Los Angeles from 1991 through 2001. Patients were identified through the microbiology laboratory database. All positive fungal cultures for pediatric inpatients were reviewed. For each fungemic patient, a review of clinical course, cause, and outcome was performed. Results. Over 11 years, 1124 pediatric inpatients with 3633 positive cultures had evidence of fungal colonization or infection. The mean incidence of positive fungal cultures increased from 105 between 1991 and 1996 to 129 patients per year between 1997 and 2001. Fungal isolates were mainly Candida species (85%) obtained primarily from respiratory (41%) and urine (27%) cultures. Only 7.5% of positive fungal cultures were from blood, although 24490 pediatric admissions prompted 72960 bacterial and fungal blood cultures, at charges of

HIV-1 vaccine induced immune responses in newborns of HIV-1 infected mothers.

2.52 million. Of 14592 fungal blood cultures, <2% (n = 272) were positive, involving <1% (n = 97) of patients. The mean rise in number of children with fungemia was significant, from 6.8 between 1991 and 1996 to 13.0 patients per year between 1997 and 2001. Fungemia was associated with a high all-cause mortality rate (46%), particularly in immunocompromised patients (57%). Organisms recovered were primarily Candida species (91%). There was a decline in C albicans and C glabrata fungemia and an increase in C parapsilosis organisms. In 84% of patients, fungal organisms were isolated from both bacterial and fungal blood cultures, and in 74%, the same organism was isolated from additional body sites. Conclusions. Episodes of fungemia increased significantly over 11 years as compared with a moderate increase in positive fungal cultures and were associated with high all-cause mortality rates. More sensitive assays for early identification of fungal bloodstream infections are warranted.

Linezolid for the treatment of children with bacteremia or nosocomial pneumonia caused by resistant gram-positive bacterial pathogens.

Objective:Breast milk transmission continues to account for a large proportion of cases of mother-to-child transmission of HIV-1 worldwide. An effective HIV-1 vaccine coupled with either passive immunization or short-term antiretroviral prophylaxis represents a potential strategy to prevent breast milk transmission. This study evaluated the safety and immunogenicity of ALVAC HIV-1 vaccine with and without a subunit envelope boost in infants born to HIV-1-infected women. Design:Placebo-controlled, double-blinded study. Methods:Infants born to HIV-1-infected mothers in the US were immunized with a prime-boost regimen using a canarypox virus HIV-1 vaccine (vCP1452) and a recombinant glycoprotein subunit vaccine (rgp120). Infants (n = 30) were randomized to receive: vCP1452 alone, vCP1452 + rgp120, or corresponding placebos. Results:Local reactions were mild or moderate and no significant systemic toxicities occurred. Subjects receiving both vaccines had gp120-specific binding serum antibodies that were distinguishable from maternal antibody. Repeated gp160-specific lymphoproliferative responses were observed in 75%. Neutralizing activity to HIV-1 homologous to the vaccine strain was observed in 50% of the vCP1452 + rgp120 subjects who had lost maternal antibody by week 24. In some infants HIV-1-specific proliferative and antibody responses persisted until week 104. HIV-1-specific cytotoxic T lymphocyte responses were detected in two subjects in each treatment group; the frequency of HIV-1 specific cytotoxic T lymphocyte responses did not differ between vaccine and placebo recipients. Conclusion:The demonstration of vaccine-induced immune responses in early infancy supports further study of HIV-1 vaccination as a strategy to reduce breast milk transmission.

Clearance of Cellulosimicrobium cellulans bacteremia in a child without central venous catheter removal.

Background. Nosocomial infections, particularly hospital-acquired pneumonia (HAP) and bacteremia, are an increasing concern in pediatric hospitals and pediatric intensive care units. Gram-positive pathogens are a leading cause of these infections in children. Linezolid is well-tolerated and as effective as vancomycin in the treatment of these infections in adults. Objective. To evaluate the clinical effectiveness and safety of iv/oral linezolid and iv vancomycin in children with resistant Gram-positive HAP or bacteremia. Methods. Hospitalized children <12 years of age were randomized 2:1 to linezolid or vancomycin. Patients received linezolid 10 mg/kg iv every 8 h with the option to change treatment to oral linezolid suspension 10 mg/kg every 8 h or iv vancomycin 10 to 15 mg/kg every 6 to 24 h. Clinical response was evaluated at follow-up. Results from an analysis of patients with HAP or bacteremia are presented. Results. Thirty-nine patients (linezolid, 23; vancomycin, 16) with HAP and 113 patients with bacteremia (linezolid, 81; vancomycin, 32) were included in the intent-to-treat group. Clinical cure rates for clinically evaluable patients with HAP did not differ between treatment groups (linezolid, 90.0% and vancomycin, 100%; P = 0.305). No significant difference was seen in clinical cure rates in the clinically evaluable population between the linezolid and vancomycin groups for patients with catheter-related bacteremia (84.8 and 80.0%, respectively; P = 0.716) or patients with bacteremia of unknown source (79.2 and 69.2%, respectively; P = 0.501). In this subset fewer linezolid-treated patients had drug-related adverse events than did vancomycin-treated patients (19.4%vs. 28.3%; P = 0.230). Similar percentages of patients with laboratory abnormalities, including selected hematologic parameters, were seen in both treatment groups. Conclusions. Intravenous/oral linezolid was well-tolerated and as effective as vancomycin in treating children with resistant Gram-positive HAP or bacteremia.