Mohan Pammi

Candida parapsilosis is a significant neonatal pathogen a systematic review and meta-analysis

Background: Candida is the third most common cause of late-onset neonatal sepsis in infants born at <1500 g. Candida parapsilosis infections are increasingly reported in preterm neonates in association with indwelling catheters. Methods: We systematically reviewed neonatal literature and synthesized data pertaining to percentage of C. parapsilosis infections and mortality by meta-analyses. We also reviewed risk factors, virulence determinants, antimicrobial susceptibility patterns and outlined clinical management strategies. Results: C. parapsilosis infections comprised 33.47% (95% confidence interval [CI]: 30.02, 37.31) of all neonatal Candida infections. C. parapsilosis rates were similar in studies performed before the year 2000, 33.53% (95% CI: 30.06, 37.40) (28 studies), to those after 2000, 27.00% (95% CI: 8.25, 88.37) (8 studies). The mortality due to neonatal C. parapsilosis infections was 10.02% (95% CI: 7.66, 13.12). Geographical variations in C. parapsilosis infections included a low incidence in Europe and higher incidence in North America and Australia. Biofilm formation was a significant virulence determinant and predominant risk factors for C. parapsilosis infections were prematurity, prior colonization and catheterization. Amphotericin B remains the antifungal drug of choice and combination therapy with caspofungin or other echinocandins may be considered in resistant cases. Conclusion: C. parapsilosis is a significant neonatal pathogen, comprises a third of all Candida infections and is associated with 10% mortality. Availability of tools for genetic manipulation of this organism will identify virulence determinants and organism characteristics that may explain predilection for preterm neonates. Strategies to prevent horizontal transmission in the neonatal unit are paramount in decreasing infection rates.

Molecular assays in the diagnosis of neonatal sepsis: A systematic review and meta-analysis

BACKGROUND: Microbial cultures for diagnosis of neonatal sepsis suffer from low sensitivity and reporting delay. Advances in molecular microbiology have fostered new molecular assays that are rapid and may improve neonatal outcomes. OBJECTIVES: We assessed whether molecular assays have sufficient sensitivity (>0.98) and specificity (>0.95) to replace microbial cultures in the diagnosis of neonatal sepsis and explored heterogeneity by use of subgroup analyses based on the type of assay, gestational age of the neonate, and type of sepsis onset. METHODS: We performed the systematic review as recommended by the Cochrane Diagnostic Test Accuracy Working Group. Electronic bibliographic databases, conference abstracts, personal files, and reference lists of identified articles were searched. We included studies of case-control or consecutive series design, which evaluated molecular assays (index test) in neonates with suspected sepsis (participants) in comparison with microbial cultures (reference standard). Two reviewers independently assessed the methodologic quality of the studies and extracted data. RESULTS: A bivariate random-effects model was used for meta-analysis of the 23 included studies, and summary estimates of sensitivity and specificity with 95% confidence intervals (CIs) were generated. Mean sensitivity and specificity were 0.90 (95% CI: 0.78–0.95) and 0.96 (95% CI: 0.94–0.97), respectively. Real-time polymerase chain reaction (PCR) and broad-range conventional PCR had higher sensitivity and specificity than other assays. Sufficient data were not available to evaluate gestational-age and sepsis-type subgroups. CONCLUSION: Molecular assays do not have sufficient sensitivity to replace microbial cultures in the diagnosis of neonatal sepsis but may perform well as “add-on” tests.

Biofilm extracellular DNA enhances mixed species biofilms of Staphylococcus epidermidis and Candida albicans

BackgroundPolymicrobial infections are responsible for significant mortality and morbidity in adults and children. Staphylococcus epidermidis and Candida albicans are the most frequent combination of organisms isolated from polymicrobial infections. Vascular indwelling catheters are sites for mixed species biofilm formation and pose a significant risk for polymicrobial infections. We hypothesized that enhancement of biofilms in a mixed species environment increases patient mortality and morbidity.ResultsMixed species biofilms of S. epidermidis and C. albicans were evaluated in vitro and in a subcutaneous catheter infection model in vivo. Mixed species biofilms were enhanced compared to single species biofilms of either S. epidermidis or C. albicans. A mixed species environment increased catheter infection and increased dissemination of S. epidermidis in mice. Microarrays were used to explore differential gene expression of S. epidermidis in the mixed species biofilms. In mixed species biofilms, compared to single species S. epidermidis biofilms, 2.7% of S. epidermidis genes were upregulated and 6% were down regulated. Staphylococcal autolysis repressors lrgA and lrgB were down regulated 36-fold and 27-fold respectively. The role of biofilm extracellular DNA was investigated by quantitation and by evaluating the effects of DNAse in a concentration and time dependent manner. S. epidermidis specific eDNA was increased in mixed species biofilms and further confirmed by degradation with DNAse.ConclusionsMixed-species biofilms are enhanced and associated with increased S. epidermidis-specific eDNA in vitro and greater systemic dissemination of S. epidermidis in vivo. Down regulation of the lrg operon, a repressor of autolysis, associated with increased eDNA suggests a possible role for bacterial autolysis in mixed species biofilms. Enhancement and systemic dissemination of S. epidermidis may explain adverse outcomes after clinical polymicrobial infections of S. epidermidis and C. albicans.

Farnesol Decreases Biofilms of Staphylococcus epidermidis and Exhibits Synergy With Nafcillin and Vancomycin

Biofilm infections are frequently caused by Staphylococcus epidermidis, are resistant to antimicrobial agents, and adversely affect patient outcomes. We evaluated farnesol (FSL), the Candida quorum-sensing molecule, on S. epidermidis biofilms, in vitro and in vivo. We evaluated ED50, ED75, and ED90 (drug concentrations causing 50%, 75%, and 90% inhibition, respectively) of FSL and evaluated synergy with nafcillin and vancomycin. FSLs effects on morphology of S. epidermidis biofilms were analyzed using confocal microscopy and real-time changes using a bioluminescent strain of S. epidermidis, Xen 43. In mice, effects of FSL treatment on s.c. catheter biofilms; cultures of blood, kidney, and catheter and pericatheter tissues; and bioluminescence in strain Xen 43 were evaluated. FSL inhibited biofilms (ED50 ranged from 0.625 to 2.5 mM) and was synergistic with nafcillin and vancomycin at most combination ratios. FSL significantly decreased biovolume, substratum coverage, and mean thickness of S. epidermidis biofilms. In mice, FSL significantly decreased viable colony counts of S. epidermidis from blood, kidney, and catheter and pericatheter tissues and decreased Xen 43 bioluminescence. We confirmed the antibiofilm effects of FSL both in vitro and in vivo, in a bioluminescent strain and its synergy with antibiotics. FSL may be effective against clinical S. epidermidis biofilm infections.

Diagnosing Significant PDA Using Natriuretic Peptides in Preterm Neonates: A Systematic Review

BACKGROUND AND OBJECTIVES: Echocardiogram is the gold standard for the diagnosis of hemodynamically significant patent ductus arteriosus (hsPDA) in preterm neonates. A simple blood assay for brain natriuretic peptide (BNP) or amino-terminal pro-B-type natriuretic peptide (NT-proBNP) may be useful in the diagnosis and management of hsPDA. Our objectives were to determine the diagnostic accuracy of BNP and NT-proBNP for hsPDA in preterm neonates and to explore heterogeneity by analyzing subgroups. METHODS: The systematic review was performed as recommended by the Cochrane Diagnostic Test Accuracy Working Group. Electronic databases, conference abstracts, and cross-references were searched. We included studies that evaluated BNP or NT-proBNP (index test) in preterm neonates with suspected hsPDA (participants) in comparison with echocardiogram (reference standard). A bivariate random effects model was used for meta-analysis, and summary receiver operating characteristic curves were generated. RESULTS: Ten BNP and 11 NT-proBNP studies were included. Studies varied by methodological quality, type of commercial assay, thresholds, age at testing, gestational age, and whether the assay was used to initiate medical or surgical therapy. Sensitivity and specificity for BNP at summary point were 88% and 92%, respectively, and for NT-proBNP they were 90% and 84%, respectively. CONCLUSIONS: The studies evaluating the diagnostic accuracy of BNP and NT-proBNP for hsPDA varied widely by assay characteristics (assay kit and threshold) and patient characteristics (gestational and chronological age); therefore, generalizability between centers is not possible. We recommend that BNP or NT-proBNP assays be locally validated for specific patient population and outcomes, to initiate therapy or follow response to therapy.

Use of Exome Sequencing for Infants in Intensive Care Units: Ascertainment of Severe Single-Gene Disorders and Effect on Medical Management

Importance While congenital malformations and genetic diseases are a leading cause of early infant death, to our knowledge, the contribution of single-gene disorders in this group is undetermined. Objective To determine the diagnostic yield and use of clinical exome sequencing in critically ill infants. Design, Setting, and Participants Clinical exome sequencing was performed for 278 unrelated infants within the first 100 days of life who were admitted to Texas Children’s Hospital in Houston, Texas, during a 5-year period between December 2011 and January 2017. Exome sequencing types included proband exome, trio exome, and critical trio exome, a rapid genomic assay for seriously ill infants. Main Outcomes and Measures Indications for testing, diagnostic yield of clinical exome sequencing, turnaround time, molecular findings, patient age at diagnosis, and effect on medical management among a group of critically ill infants who were suspected to have genetic disorders. Results The mean (SEM) age for infants participating in the study was 28.5 (1.7) days; of these, the mean (SEM) age was 29.0 (2.2) days for infants undergoing proband exome sequencing, 31.5 (3.9) days for trio exome, and 22.7 (3.9) days for critical trio exome. Clinical indications for exome sequencing included a range of medical concerns. Overall, a molecular diagnosis was achieved in 102 infants (36.7%) by clinical exome sequencing, with relatively low yield for cardiovascular abnormalities. The diagnosis affected medical management for 53 infants (52.0%) and had a substantial effect on informed redirection of care, initiation of new subspecialist care, medication/dietary modifications, and furthering life-saving procedures in select patients. Critical trio exome sequencing revealed a molecular diagnosis in 32 of 63 infants (50.8%) at a mean (SEM) of 33.1 (5.6) days of life with a mean (SEM) turnaround time of 13.0 (0.4) days. Clinical care was altered by the diagnosis in 23 of 32 patients (71.9%). The diagnostic yield, patient age at diagnosis, and medical effect in the group that underwent critical trio exome sequencing were significantly different compared with the group who underwent regular exome testing. For deceased infants (n = 81), genetic disorders were molecularly diagnosed in 39 (48.1%) by exome sequencing, with implications for recurrence risk counseling. Conclusions and Relevance Exome sequencing is a powerful tool for the diagnostic evaluation of critically ill infants with suspected monogenic disorders in the neonatal and pediatric intensive care units and its use has a notable effect on clinical decision making.

Zika Virus-Associated Microcephaly and Eye Lesions in the Newborn

On February 1, 2016, Zika virus (ZIKV) was designated as a Public Health Emergency of International Concern by the director of the World Health Organization. Zika virus has spread to numerous countries throughout the Americas, affecting up to an estimated 1.3 million people since the first reports from Brazil in early 2015. Although ZIKV infections are self-limiting, fetal microcephaly and ophthalmic anomalies have been associated with ZIKV infection as a possible result of perinatal transmission. The causal link between maternal ZIKV infection and newborn microcephaly and eye lesions has not been proven beyond doubt and is currently debated. We discuss the possibility of causality by ZIKV using Kochs postulates and the more appropriate Bradford Hill criteria. In this review, we summarize and consolidate the current literature on newborn microcephaly and eye lesions associated with ZIKV infection and discuss current perspectives and controversies.

Pathogenesis of NEC: Impact of an altered intestinal microbiome

Necrotizing enterocolitis (NEC), a disease most commonly seen in preterm infants, often presents without warning and is associated with very high mortality and morbidity. Progress in the prevention and treatment of NEC has been slow. In this article, we will discuss some of the reasons as to why this progress has been slow. We will describe some of the factors that appear to be highly associated and important components in the pathophysiology of NEC. We will discuss the intestinal microbial environment of the fetus as well as the preterm infant and how interaction of dysbiosis with an immature gastrointestinal tract combined with dietary factors play a role in the pathogenesis of NEC. Testable hypotheses are discussed as well as how these may lead to not only a better understanding of the pathophysiology of the disease but also the preventative strategies.

Late-onset sepsis in preterm infants: update on strategies for therapy and prevention

Late-onset sepsis occurs in 15–25% of very low birth weight neonates. Early diagnosis and therapy optimize patient outcomes. Despite these efforts, mortality remains high (18–36%) and survivors suffer significant neurological and pulmonary morbidity. Although rapid diagnostics are improving, more are needed. Current therapy remains antibiotics and supportive care. Adjunctive therapies have either limited data (e.g., pentoxifylline) or have been found ineffective (e.g., granulocyte transfusions, granulocyte macrophage colony-stimulating factor/granulocyte colony-stimulating factor, and intravenous immunoglobulin). Preventive strategies that have proven beneficial include infection control measures (e.g., hand hygiene and universal precautions), early enteral feeds with human milk, early removal of central lines, catheter infection prevention bundles, antibiotic stewardship and focused quality improvement measures. Promising strategies to prevent late-onset sepsis include oral lactoferrin, and pathogen-specific monoclonal antibodies but more evidence is required to make practice recommendations.

A Systematic Review of Controlled Trials of Lower-Protein or Energy-Containing Infant Formulas for Use by Healthy Full-Term Infants

Infant formulas have historically been developed based on providing macronutrients at intake concentrations approximately matching the composition of human milk. In most countries, targets of 1.4-1.5 g of protein/dL and 20 kcal/oz (67-68 kcal/dL) have been set as the protein and energy concentrations for formulas during the first year of life, although this may be an overestimation of these contents. Recent introduction of lower-protein and -energy formulas in full-term infants led us to systematically review the literature for its effects on growth. Following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines, our inclusion criteria were studies that enrolled healthy full-term infants and evaluated lower-protein or lower-energy formula, reported anthropometric outcomes including weight and length, and followed infants for at least 6 mo. Six studies were eligible for inclusion. These studies varied in the content of nutrients provided in the intervention and control groups, by additional dietary components in the study groups, and the timing and length of the intervention, which limit their usefulness for interpreting newly introduced lower-protein and -energy formulas in the United States. These studies suggest adequate growth during infancy and early childhood with infant formulas with concentrations of protein and energy slightly below historical standards in the United States. Further long-term research is needed to assess the impact of the use of lower-protein and/or lower-energy products, especially for nutritionally at-risk populations such as preterm infants and infants who are born small for gestational age.