Fluconazole prophylaxis for prevention of invasive fungal infections in targeted highest risk preterm infants limits drug exposure.

OBJECTIVE: Previous reports suggest a benefit of fluconazole prophylaxis in extremely low birth weight (ELBW) infants <1000 g. Our aim was to evaluate if limiting fluconazole prophylaxis to targeted highest risk infants effectively prevents invasive fungal infections, has no undesired side effects and limits unnecessary drug exposure. STUDY DESIGN: This nonrandomized retrospective pre-post intervention study compared two groups of infants: (1) Infants <26 weeks gestation and/or <750 g birth weight, requiring central vascular access and admitted to the Monroe Carell Jr Children's Hospital at Vanderbilt neonatal intensive care unit (NICU) prior to 5 days of age, who received fluconazole prophylaxis and (2) a matched control group from the year prior to prophylaxis. This target population was selected for fluconazole prophylaxis based on prior infection control data from our institution and a number needed to treat of <15 to prevent one episode of fungemia. Following implementation and integration through the institution's computerized physician order entry (CPOE) system, provider adherence to the protocol was assessed during the prophylaxis period. RESULT: A total of 86 patients were included in the study, 44 in the no-prophylaxis group and 42 in the prophylaxis group. In the targeted prophylaxis group, no invasive fungal infections were observed as compared to nine infants with invasive infections in the no-prophylaxis group (P=0.004). No significant adverse effects were recorded. Targeting the highest risk infants reduced the number of infants <1000 g requiring prophylaxis from 80 to 42 (48% reduction) with no preventable infection missed. Provider compliance was 91% following implementation of this protocol through the CPOE system using a standardized order set. CONCLUSION: Targeting the highest risk infants for fluconazole prophylaxis through CPOE can effectively prevent invasive fungal infections and limit drug exposure with no unwanted side effects.

Endogenous group B streptococcal endophthalmitis in a preterm infant.

Endogenous endophthalmitis is a rare complication of bacteremia. Proper intervention is critical, as the majority of affected patients lose vision in the infected eye. Treatment options include systemic antibiotics, intravitreous antibiotics and vitrectomy. We report a case of endogenous endophthalmitis presenting as leukocoria in a premature neonate with group B streptococcal meningitis.

Oral colostrum priming shortens hospitalization without changing the immunomicrobial milieu.

OBJECTIVE: Oral colostrum priming (OCP) after birth in preterm infants is associated with improved weight gain and modification of the oral immunomicrobial environment. We hypothesized that OCP would modify salivary immune peptides and the oral microbiota in preterm infants. STUDY DESIGN: We conducted a prospective, randomized clinical trial to determine the effects of OCP on salivary immune peptide representation in preterm infants (<32 weeks completed gestation at birth). Saliva samples were collected before and after OCP. Salivary immune peptide representation was determined via mass spectroscopy. Oral microbiota representation was determined via sequencing of the 16S rRNA gene. RESULTS: Neonates who received OCP (n=48) had a 16-day reduction in the median length of hospitalization as compared with infants who did not receive OCP (n=51). No differences in salivary immune peptide sequence representation before OCP between groups were found. Longitudinal changes in peptides were detected (lysozyme C, immunoglobulin A, lactoferrin) but were limited to a single peptide difference (α-defensin 1) between primed and unprimed infants after OCP. We found no difference in microbial diversity between treatment groups at any time point, but diversity decreased significantly over time in both groups. OCP treatment marginally modified oral taxa with a decline in abundance of Streptococci in the OCP group at 30 days of life. CONCLUSIONS: OCP had neither an effect on the salivary peptides we examined nor on overall oral bacterial diversity and composition. Infants who received OCP had a reduced length of hospitalization and warrants further investigation.

Genetic and structural determinants of virus neutralizing antibodies.

Neutralizing antibodies (Abs) are the principal protective mechanism against disease caused by reinfection with viruses. Ab-mediated neutralization of viruses is a complex process comprising multiple mechanisms. Every structural aspect of Abs is potentially capable of modulating the level of neutralizing activity or the mechanisms of neutralization. The focus of our laboratory is to understand the genetic and structural basis of Ab-mediated neutralization of human viral pathogens. We demonstrated the unexpected finding that virus antigen-binding fragments of Abs (Fabs) mediate potent virus neutralizing effects in vivo. This work has led to a broad investigation of the importance of the genetics, chemistry, and structure of the combining site to the neutralizing activity of antiviral Abs. Ongoing work in our laboratory reveals that effect or functions specified by the Ab isotype such as polymer formation, interactions with complement, interactions with Fc receptors, and the ability to transcytose mucosal epithelia, also modulate the mechanism and level of neutralizing effects mediated by antiviral Abs.

Abnormal heart rate characteristics before clinical diagnosis of necrotizing enterocolitis.

OBJECTIVE: Earlier diagnosis and treatment of necrotizing enterocolitis (NEC) in preterm infants, before clinical deterioration, might improve outcomes. A monitor that measures abnormal heart rate characteristics (HRC) of decreased variability and transient decelerations was developed as an early warning system for sepsis. As NEC shares pathophysiologic features with sepsis, we tested the hypothesis that abnormal HRC occur before clinical diagnosis of NEC. STUDY DESIGN: Retrospective review of Bells stage II to III NEC cases among infants <34 weeks gestation enrolled in a prospective randomized clinical trial of HRC monitoring at three neonatal intensive care units. RESULT: Of 97 infants with NEC and HRC data, 33 underwent surgical intervention within 1 week of diagnosis. The baseline HRC index from 1 to 3 days before diagnosis was higher in patients who developed surgical vs medical NEC (2.06±1.98 vs 1.22±1.10, P=0.009). The HRC index increased significantly 16 h before the clinical diagnosis of surgical NEC and 6 h before medical NEC. At the time of clinical diagnosis, the HRC index was higher in patients with surgical vs medical NEC (3.3±2.2 vs 1.9±1.7, P<0.001). CONCLUSION: Abnormal HRC occur before clinical diagnosis of NEC, suggesting that continuous HRC monitoring may facilitate earlier detection and treatment.

A silver-alginate-coated dressing to reduce peripherally inserted central catheter (PICC) infections in NICU patients: a pilot randomized controlled trial.

OBJECTIVE: Our aim was to evaluate the safety of a silver-alginate-containing dressing to reduce peripherally inserted central catheter (PICC) infections in neonatal intensive care unit (NICU) patients. STUDY DESIGN: Patients were randomized 3:1 to receive a patch containing silver, alginate and maltodextrin or standard of care. Patches were placed under the regular transparent retention dressing at the PICC exit site at insertion and were replaced with every dressing change at least every 2 weeks until PICC discontinuation. All study infants were monitored for adverse skin reactions. RESULT: A total of 100 infants were followed up for 1922 person-days, including 75 subjects with 89 PICCs who received the patch. The median birth weight (1330 g) and median gestational age (30 weeks) was lower in the patch group when compared with the controls (P=0.001 and 0.005, respectively). Study patients received the patch with their PICC at a median age of 5 days; the patch stayed in place for a median of 13 days. We noted no adverse skin reactions and found no evidence that the patch alters the microbiology of PICC-associated infections. CONCLUSION: This pilot trial suggests that silver-alginate-coated dressings are skin safe and their inclusion in future trials aimed at reduction of PICC-associated bloodstream infections in the NICU should be considered.

Pilot study assessing TNF gene polymorphism as a prognostic marker for disease progression in neonates with sepsis.

In adult postoperative intensive care patients, the biallelic Ncol polymorphism within the tumor necrosis factor (TNF) locus has been shown to be a genomic marker for individuals with increased TNF-alpha response and poor prognosis in severe sepsis. We characterized the genomic distribution and allele frequency of the Ncol polymorphism in 23 preterm and term neonatal intensive care unit (NICU) patients with culture-proven sepsis and compared it with clinical and laboratory characteristics to assess its prognostic value for disease progression. Genotype analysis demonstrated the following absolute (relative) frequencies: 7 (0.31) infants were homozygous for the allele TNFB2 (Group A). 12 (0.52) infants were heterozygous (TNFB1/TNFB2) and four (0.17) infants homozygous for the allele TNFB1 (Group B). There was no significant difference compared to adult intensive care patients with severe sepsis (p = 0.31). The median gestational age of all infants (13 female and ten male) as well as for either group was 28 weeks (range 23-37) with a median birth weight of 845 g (range 560-2,720). The study population included a total of 16 very low birth weight (VLBW) infants, four in Group A and 12 in Group B. However, there was no significant difference for gestational age and birth weight in both groups (p = 0.82 and 0.71, respectively). Laboratory parameters as maximum and minimum leukocyte and thrombocyte counts, maximum immature to total neutrophil ratios (ITR), maximum C-reactive protein (CRP) levels, days of CRP levels > 5 mg/l and total days of antibiotic treatment, were not statistically different in both groups. In total, three infants (13%) died in consequence of their underlying disease. Two infants belonged to Group A and one to Group B. The statistical analysis of outcome variables (mortality, neurological impairment, failure to thrive) was not possible, because the study population was small and the reasons for poor outcome and death in these high-risk patients had to be considered multifactorial. In conclusion, in this pilot study the biallelic Ncol polymorphism within the TNF locus was not a prognostic marker for disease progression in high-risk NICU-admitted term and preterm infants with culture-proven sepsis. In order to detect differences in outcome similar to adult postsurgical patients with severe sepsis, an unfeasibly high number of NICU patients with culture-proven sepsis would need to be included for a similar study.

Identification and characterization of Helicobacter pylori phospholipase C activity.

We analyzed 11 H. pylori isolates from humans using the artificial chromogenic substrate paranitrophenylphosphorylcholine to detect phospholipase C (PLC) activity. The range of PLC in sonicates was 8.8-92.3 (Mean 56.9 +/- 6.5) nmol of substrate hydrolysed min-1 mg-1 protein; the amount of activity was not associated with urease or cytotoxin levels. Addition of sorbitol or glycerol enhanced PLC activity of H. pylori sonicate and purified PLC from C. perfringens (PLC1) but not purified PLC from B. cereus (PLC3). H. pylori sonicates had little acid phosphatase and no detectable alkaline phosphatase activity, and H. pylori PLC showed markedly different biochemical characteristics from either phosphatase. In total, these studies indicate that activity measured in H. pylori sonicate by PLC assay is due to PLC and not phosphatase activity. The temperature optimum for PLC activity of H. pylori sonicate was 56 degrees C and for PLC 1 was 65 degrees C. For H. pylori PLC and PLC1, optimal activity occurred at pH 8. Despite multiple similarities between H. pylori PLC and PLC1, known PLC inhibitors show different interactions with each enzyme. Although PLC activity is present in many subcellular constituents of H. pylori, including culture supernatants and water extracts, highest specific activity is associated with a membrane-enriched fraction.

Recurrent Achromobacter xylosoxidans bacteremia associated with persistent lymph node infection in a patient with hyper-immunoglobulin M syndrome.

Achromobacter xylosoxidans (formerly Alcaligenes xylosoxidans) is a rare but important cause of bacteremia in immunocompromised patients, and strains are usually multiply resistant to antimicrobial therapy. We report an immunocompromised patient with hyper-immunoglobulin M syndrome who suffered from 14 documented episodes of A. xylosoxidans bacteremia. Each episode was treated and resulted in rapid clinical improvement, with blood cultures testing negative for bacteria. Between episodes, A. xylosoxidans was isolated from an excised right axillary lymph node, whereas the culture of the central venous catheter, removed at the same time, was negative. Multiple cultures from sputum, stool, and urine samples, as well as from gastrointestinal biopsies or environmental sources, were negative. Results from antibiotic sensitivity testing and pulsed-field gel electrophoresis suggested that a single strain of A. xylosoxidans caused the recurrent bacteremias in this patient; this strain originated from persistently infected lymph nodes. Lymphoid hyperplasia is a prominent characteristic of hyper-IgM syndrome and may serve as a source of bacteremia with low-pathogenicity organisms.

Candida infection in very low birth-weight infants: outcome and nephrotoxicity of treatment with liposomal amphotericin B (AmBisome).

Systemic fungal infection occurs in 2 to 4.5% of very low birth-weight (VLBW) infants (< 1,500 g) and may be fatal in 25 to 54%. Candida sp. is the major pathogen and amphotericin B the treatment of choice. To reduce side effects and optimize drug action, a formulation of amphotericin B encapsulated in liposomes (AmBisome) has been introduced. Data on 21 VLBW infants who received a full course of AmBisome was collected and its toxic effects with emphasis on nephrotoxicity and hypokalemia assessed. The median gestational age was 25 weeks (range 23-31) with a median birth-weight of 730 g (range 450-1,370). Antifungal therapy was started at a median age of 13 days (range 1-49). The median dose given was 2.6 mg/kg/day (range 1-5), and the median duration of therapy was 28 days (range 11-79), corresponding to a median cumulative dose of 71 mg/kg (range 12-271). Hypokalemia (< 3.0 mmol/l) was observed in 30% before, and 15% during AmBisome treatment. Twenty-one days after the termination of therapy, hypokalemia was not present in any patient. Median maximum daily potassium supplementation did not exceed doses usually recommended for VLBW infants. The median of the maximum creatinine levels before treatment was 121 mumol/l (range 71-221) and fell to 68 mumol/l (range 31-171) during treatment and 46 mumol/l (range 26-62) 21 days after the termination of therapy. All patients treated with AmBisome eradicated fungi and recovered clinically. AmBisome showed no certain nephrotoxicity in VLBW infants in this study.