Felice C. Adler-Shohet

Population Pharmacokinetics of Amphotericin B Lipid Complex in Neonates

ABSTRACT The pharmacokinetics of amphotericin B lipid complex (ABLC) were investigated in neonates with invasive candidiasis enrolled in a phase II multicenter trial. Sparse blood (153 samples; 1 to 9 per patient, 1 to 254 h after the dose) and random urine and cerebrospinal fluid (CSF) samples of 28 neonates (median weight [WT], 1.06 kg; range, 0.48 to 4.9 kg; median gestational age, 27 weeks; range, 24 to 41 weeks) were analyzed. Patients received intravenous ABLC at 2.5 (n = 15) or 5 (n = 13) mg/kg of body weight once a day over 1 or 2 h, respectively, for a median of 21 days (range, 4 to 47 days). Concentrations of amphotericin B were quantified as total drug by high-performance liquid chromatography. Blood data for time after dose (TAD) of <24 h fitted best to a one-compartment model with an additive-error model for residual variability, WT0.75 (where 0.75 is an exponent) as a covariate of clearance (CL), and WT as a covariate of volume of distribution (V). Prior amphotericin B, postnatal age, and gestational age did not further improve the model. The final model equations were CL (liters/h) = 0.399 × WT0.75 (interindividual variability, 35%) and V (liters) = 10.5 × WT (interindividual variability, 43%). Noncompartmental analysis of pooled data with a TAD of >24 h revealed a terminal half-life of 395 h. Mean concentrations in the urine after 1, 2, and 3 weeks ranged from 0.082 to 0.430 μg/ml, and those in CSF ranged from undetectable to 0.074 μg/ml. The disposition of ABLC in neonates was similar to that observed in other age groups: weight was the only factor that influenced clearance. Based on these results and previously published safety and efficacy data, we recommend a daily dosage between 2.5 and 5.0 mg/kg for treatment of invasive Candida infections in neonates.

Aseptic meningitis in infants younger than six months of age hospitalized with urinary tract infections

Background. Aseptic meningitis associated with urinary tract infection (UTI) in young infants has not been described in detail in the literature. We performed a retrospective study to determine the incidence and clinical features of aseptic meningitis accompanying UTI. Methods. We retrospectively reviewed the medical records of all infants younger than 6 months of age hospitalized with a UTI at Miller Children’s Hospital from March 1995 through March 2000. UTI was defined as a urine culture growing ≥10 000 colony-forming units/ml of a single organism from a catheterized specimen or ≥100 000 colony-forming units/ml of a single organism from a bagged urine specimen. Meningitis was defined as a positive cerebrospinal fluid culture or cerebrospinal fluid with >35 white blood cells/mm3 in infants ≤30 days of age or with >10 white blood cells/mm3 in infants >30 days of age. Results. Of 386 infants with UTI, a lumbar puncture was performed in 260, and 31 (11.9%) had aseptic meningitis. One infant had bacterial meningitis. None of the 26 infants with UTI and bacteremia had aseptic meningitis. Two infants with meningitis had confirmed enteroviral infections, but aseptic meningitis did not occur more frequently in any particular month or during times of peak enteroviral activity. Conclusions. A cerebrospinal fluid pleocytosis is relatively common in hospitalized infants <6 months of age who have a UTI and usually does not reflect bacterial meningitis. Knowledge of this may prevent unnecessary courses of antibiotics for presumed bacterial meningitis and lead to evaluation for other possible causes of aseptic meningitis including viral or congenital infections.

Motavizumab treatment of infants hospitalized with respiratory syncytial virus infection does not decrease viral load or severity of illness

Background: This study was conducted to determine whether treatment with motavizumab, an anti-respiratory syncytial virus (RSV) monoclonal antibody, would decrease viral load and improve clinical outcomes in previously healthy term infants hospitalized with RSV lower respiratory tract infection. Methods: Infants hospitalized with lower respiratory tract infection and a positive RSV test performed locally were randomized to receive 1 intravenous dose of motavizumab (30 or 100 mg/kg) or placebo. Nasal wash samples were tested by real-time reverse transcriptase polymerase chain reaction at a central laboratory to determine viral load. Clinical data were collected during RSV hospitalization and at 12-month follow up. Results: Of 118 infants, 112 were confirmed RSV positive by real-time reverse transcriptase polymerase chain reaction. In each study group, median (range) RSV load (log10 copies/mL) decreased at a similar rate from baseline to study day 7 [motavizumab 30 mg/kg: 8.35 (2.5–9.5) to 5.03 (2.5–6.8); motavizumab 100 mg/kg: 8.22 (5.5–9.7) to 4.25 (2.5–8.0); placebo: 8.02 (6.7–9.8) to 5.17 (2.5–7.3)]. Median (range) duration of hospitalization was 3.05 (0.8–16.0), 2.99 (1.0–25.0) and 2.88 (0.8–11.7) days for the motavizumab 30 mg/kg, motavizumab 100 mg/kg and placebo groups, respectively. Six (8%) motavizumab and 0 placebo recipients were admitted to the intensive care unit and 4 required mechanical ventilation. The incidence of wheezing episodes during the 12-month follow up was comparable for all 3 groups. Conclusions: Motavizumab had no appreciable effect on RSV viral load measured in the upper respiratory tract of children hospitalized for RSV lower respiratory tract infection. No differences were observed for duration of hospitalization, severity of illness measures or wheezing episodes during 12-month follow up in children treated with motavizumab or placebo.

Nephrotoxicity associated with amphotericin B deoxycholate in neonates.

Background: The prevalence of nephrotoxicity in neonates receiving amphotericin B deoxycholate (amphoB) is not well-defined. While some studies report a lack of toxicity, others claim a frequency as high as 85%. Methods: We reviewed medical records of all infants ≤90 days of age in the neonatal intensive care unit who received at least 3 doses of amphoB between January 1990 and December 2004. A standardized form was used to collect demographic, therapeutic, microbiologic, and laboratory data for each patient. Nephrotoxicity was defined as a rise in serum creatinine (SCr) of at least 0.4 mg/dL any time during amphoB therapy. Results: A total of 92 infants met entry criteria. Median gestational age was 26 (range: 23–41) weeks and median birth weight was 863 (range: 546–4000) grams. Overall, 15 (16%) infants experienced nephrotoxicity, and 16 (17%) developed hypokalemia (<3.0 mmol/L). There were no differences between infants who did or did not develop nephrotoxicty in terms of gestational age, birth weight, gender, underlying medical conditions, or use of other potentially nephrotoxic medications. AmphoB exposure and duration of therapy were similar between infants who developed nephrotoxicity and those who did not, with a mean cumulative dose of 13.5 ± 9.6 mg/kg and duration of 16.3 ± 10.4 days. With the exception of 1 infant, the elevated SCr values resolved in all infants by the end of amphoB therapy. Conclusion: AmphoB administration does not appear to be associated with lasting measurable nephrotoxicity in neonates. Because of changes in serum creatinine and potassium, renal function and potassium levels should be monitored closely in infants receiving amphoB.

Management of latent tuberculosis infection in child contacts of multidrug-resistant tuberculosis.

After exposure to a teacher with multidrug-resistant pulmonary tuberculosis, 31 children developed latent infection. Twenty-six were treated with levofloxacin and pyrazinamide. Twelve required a change in therapy secondary to adverse effects. The most common adverse effects included abdominal pain, arthralgias/myalgias and elevated transaminases. All children reported at least 1 adverse effect. Fifteen children completed treatment. All adverse effects were transient.

Clinical and Laboratory Features of Pertussis in Infants at the Onset of a California Epidemic

We report clinical characteristics and outcome of infants <3 months of age hospitalized with pertussis compared with viral respiratory infection (respiratory syncytial virus and influenza). Patients with pertussis more often were afebrile, had more visits before admission, and had longer hospital stays. Household coughing contacts were common.

Complications Associated With Outpatient Parenteral Antibiotic Therapy in Children

Background. The authors sought to determine the prevalence, risk factors, and clinical impact of complications associated with outpatient parenteral antimicrobial therapy (OPAT) in children. Methods. A cohort of patients ≤18 years old with infections, who received OPAT were evaluated retrospectively. Antibiotic-associated complications (AACs), catheter-associated complications (CACs), and unplanned medical care visits were the main outcome measures. Results. Overall, 36 complications (25 CACs and 11 AACs) occurred in 32 of 98 patients. Mean age of patients, race, gender, and infecting organism did not differ between study groups. The use of OPAT for osteomyelitis was associated with complications (odds ratio = 2.69; 95% confidence interval = 0.99-7.35; P = .05). All patients, except for 4 who had complications, clinically improved by the end of OPAT. Unplanned medical visits occurred in 17 patients, 15 of which were because of CACs. Conclusion. Complications occurred commonly in children receiving OPAT and resulted in unplanned medical visits.

Evaluation of indirect fluorescent antibody assays compared to rapid influenza diagnostic tests for the detection of pandemic influenza A (H1N1) pdm09.

Performance of indirect fluorescent antibody (IFA) assays and rapid influenza diagnostic tests (RIDT) during the 2009 H1N1 pandemic was evaluated, along with the relative effects of age and illness severity on test accuracy. Clinicians and laboratories submitted specimens on patients with respiratory illness to public health from April to mid October 2009 for polymerase chain reaction (PCR) testing as part of pandemic H1N1 surveillance efforts in Orange County, CA; IFA and RIDT were performed in clinical settings. Sensitivity and specificity for detection of the 2009 pandemic H1N1 strain, now officially named influenza A(H1N1)pdm09, were calculated for 638 specimens. Overall, approximately 30% of IFA tests and RIDTs tested by PCR were falsely negative (sensitivity 71% and 69%, respectively). Sensitivity of RIDT ranged from 45% to 84% depending on severity and age of patients. In hospitalized children, sensitivity of IFA (75%) was similar to RIDT (84%). Specificity of tests performed on hospitalized children was 94% for IFA and 80% for RIDT. Overall sensitivity of RIDT in this study was comparable to previously published studies on pandemic H1N1 influenza and sensitivity of IFA was similar to what has been reported in children for seasonal influenza. Both diagnostic tests produced a high number of false negatives and should not be used to rule out influenza infection.

Bacterial pneumonia in children

Pneumonia is the leading cause of death in children around the world. This article reviews the clinical manifestations, diagnoses, and management of the major causes of bacterial pneumonia in children of different ages. Major pathogens causing pneumonia in newborns include group B streptococcus, Listeria monocytogenes , and Chlamydia trachomatis , organisms that can infect infants born to mothers who have genital tract colonization. Streptococcus pneumoniae remains the most common cause of serious bacterial pneumonia in children, and the increasing incidence of penicillin-resistant strains can complicate therapy. Mycoplasma pneumoniae and Chlamydia pneumoniae are the most common causes of pneumonia in school-aged children. In most cases of bacterial pneumonia, a specific cause is not determined, and empiric therapy is based on the likely pathogens as determined by the childs age and the clinical presentation. Prevention, through simple measures such as breast-feeding and avoidance of exposure to passive smoke, as well as widespread use of available vaccines, is the most effective means of reducing the morbidity and mortality associated with bacterial pneumonia.

Time to Initiation of Antifungal Therapy for Neonatal Candidiasis

ABSTRACT The effect of delayed antifungal therapy in critically ill infants with invasive candidiasis has not been studied. Our objective was to evaluate the effect of time to initiation of antifungal therapy (TIA) on mortality, disseminated disease, and postinfection hospital stay. We conducted a cohort study of critically ill infants with cultures positive for Candida from 1990 to 2008. TIA was defined as the number of hours from the collection of the first positive culture until the start of antifungal therapy. Of 96 infants, 57% were male, the median gestational age was 27 weeks (range, 23 to 41 weeks), and the median birth weight was 956 g (range, 415 to 6,191 g). Most subjects received amphotericin B deoxycholate. TIA was ≤24 h for 35% of infants, between 25 and 48 h for 42%, and >48 h for 23%. Eleven subjects died during hospitalization, and 22% had disseminated candidiasis. The median duration of hospital stay postinfection was 53 days (range, 6 to 217 days). Both univariate and multivariate analyses demonstrated that TIA was not associated with mortality, disseminated disease, or hospital stay postinfection. However, ventilator use for >60 days significantly increased the risk of death (odds ratio [OR], 9.5; 95% confidence interval [CI], 2.2 to 66.7; P = 0.002). Prolonged candidemia increased the risk of disseminated disease by 10% per day of positive culture (OR, 1.1; 95% CI, 1.08 to 1.2; P = 0.007), and low gestational age was associated with increased neonatal intensive care unit (NICU) stay after the first positive Candida culture by 0.94 weeks (95% CI, 0.70 to 0.98; P < 0.001). The TIA was not associated with all-cause mortality, disseminated candidiasis, and postinfection length of hospital stay.