Matthew S. Kelly

Moving CLABSI Prevention beyond the Intensive Care Unit: Risk Factors in Pediatric Oncology Patients

BACKGROUND AND OBJECTIVE Central line-associated bloodstream infections (CLABSIs) frequently complicate the use of central venous catheters (CVCs) among pediatric patients with cancer. Our objectives were to describe the microbiology and identify risk factors for hospital-onset CLABSI in this patient population. DESIGN Retrospective case-control study. SETTING Oncology and stem cell transplant units of a freestanding, 396-bed quaternary care pediatric hospital. PARTICIPANTS Case subjects ([Formula: see text]) were patients with a diagnosis of malignancy and/or stem cell transplant recipients with CLABSI occurring during admission. Controls ([Formula: see text]) were identified using risk set sampling of hospitalizations among patients with a CVC, matched on date of admission. METHODS Multivariate conditional logistic regression was used to identify independent predictors of CLABSI. RESULTS The majority of CLABSI isolates were gram-positive bacteria (58%). The most frequently isolated organism was Enterococcus faecium, and 6 of 9 isolates were resistant to vancomycin. In multivariate analyses, independent risk factors for CLABSI included platelet transfusion within the prior week (odds ratio [OR], 10.90 [95% confidence interval (CI), 3.02-39.38]; [Formula: see text]) and CVC placement within the previous month (<1 week vs ≥1 month: OR, 11.71 [95% CI, 1.98-69.20]; [Formula: see text]; ≥1 week and <1 month vs ≥1 month: OR, 7.37 [95% CI, 1.85-29.36]; [Formula: see text]). CONCLUSIONS Adjunctive measures to prevent CLABSI among pediatric oncology patients may be most beneficial in the month following CVC insertion and in patients requiring frequent platelet transfusions. Vancomycin-resistant enterococci may be an emerging cause of CLABSI in hospitalized pediatric oncology patients and are unlikely to be treated by typical empiric antimicrobial regimens.

The Epidemiology and Diagnosis of Invasive Candidiasis Among Premature Infants

Invasive candidiasis is a leading infectious cause of morbidity and mortality in premature infants. Improved recognition of modifiable risk factors and antifungal prophylaxis has contributed to the recent decline in the incidence of this infection among infants. Invasive candidiasis typically occurs in the first 6 weeks of life and presents with nonspecific signs of sepsis. Definitive diagnosis relies on the growth of Candida in blood culture or cultures from other normally sterile sites, but this may identify fewer than half of cases. Improved diagnostics are needed to guide the initiation of antifungal therapy in premature infants.

Treatment Failures and Excess Mortality Among HIV-Exposed, Uninfected Children With Pneumonia

BACKGROUND Human immunodeficiency virus (HIV)-exposed, uninfected (HIV-EU) children are at increased risk of infectious illnesses and mortality compared with children of HIV-negative mothers (HIV-unexposed). However, treatment outcomes for lower respiratory tract infections among HIV-EU children remain poorly defined. METHODS We conducted a hospital-based, prospective cohort study of N = 238 children aged 1-23 months with pneumonia, defined by the World Health Organization. Children were recruited within 6 hours of presentation to a tertiary hospital in Botswana. The primary outcome--treatment failure at 48 hours--was assessed by an investigator blinded to HIV exposure status. RESULTS Median age was 6.0 months; 55% were male. One hundred fifty-three (64%) children were HIV-unexposed, 64 (27%) were HIV-EU, and 20 (8%) were HIV-infected; the HIV exposure status of 1 child could not be established. Treatment failure at 48 hours occurred in 79 (33%) children, including in 36 (24%) HIV-unexposed, 30 (47%) HIV-EU, and 12 (60%) HIV-infected children. In multivariable analyses, HIV-EU children were more likely to fail treatment at 48 hours (risk ratio [RR]: 1.83, 95% confidence interval [CI]: 1.27-2.64, P = .001) and had higher in-hospital mortality (RR: 4.31, 95% CI: 1.44-12.87, P = .01) than HIV-unexposed children. Differences in outcomes by HIV exposure status were observed only among children under 6 months of age. HIV-EU children more frequently received treatment with a third-generation cephalosporin, but this did not reduce the risk of treatment failure in this group. CONCLUSIONS HIV-EU children with pneumonia have higher rates of treatment failure and in-hospital mortality than HIV-unexposed children during the first 6 months of life. Treatment with a third-generation cephalosporins did not improve outcomes among HIV-EU children.

Microbiology and risk factors for central line-associated bloodstream infections among pediatric oncology outpatients: a single institution experience of 41 cases.

Background: Risk factors for central line–associated bloodstream infections (CLABSI) among children with cancer in the outpatient setting remain poorly defined, and the microbiology may differ from hospital-onset CLABSI. Materials and Methods: We conducted a matched case-control study of oncology patients followed at the Dana Farber/Children’s Hospital Cancer Center. Cases (N=41) were patients with CLABSI as per National Healthcare Safety Network criteria who had not been hospitalized in the preceding 48 hours. For each case we randomly selected 2 oncology outpatients with a central venous catheter and a clinic visit within 30 days of the case subject’s CLABSI. Multivariate conditional logistic regression models were used to identify independent risk factors for CLABSI. We compared the microbiology to that of 54 hospital-onset CLABSI occurring at our institution during the study period. Results: Independent predictors of community-onset CLABSI included neutropenia in the prior week (odds ratio 17.46; 95% confidence interval, 4.71-64.67) and tunneled externalized catheter (vs. implantable port; odds ratio 10.30; 95% confidence interval, 2.42-43.95). Nonenteric gram-negative bacteria were more frequently isolated from CLABSI occurring among outpatients. Discussion: Pediatric oncology outpatients with recent neutropenia or tunneled externalized catheters are at increased risk of CLABSI. The microbiology of community-onset CLABSI differs from hospital-onset CLABSI.

Association of Respiratory Viruses with Outcomes of Severe Childhood Pneumonia in Botswana

Background The highest incidence of childhood acute lower respiratory tract infection (ALRI) is in low- and middle-income countries. Few studies examined whether detection of respiratory viruses predicts ALRI outcomes in these settings. Methods We conducted prospective cohort and case-control studies of children 1-23 months of age in Botswana. Cases met clinical criteria for pneumonia and were recruited within six hours of presentation to a referral hospital. Controls were children without pneumonia matched to cases by primary care clinic and date of enrollment. Nasopharyngeal specimens were tested for respiratory viruses using polymerase chain reaction. We compared detection rates of specific viruses in matched case-control pairs. We examined the effect of respiratory syncytial virus (RSV) and other respiratory viruses on pneumonia outcomes. Results Between April 2012 and August 2014, we enrolled 310 cases, of which 133 had matched controls. Median ages of cases and controls were 6.1 and 6.4 months, respectively. One or more viruses were detected from 75% of cases and 34% of controls. RSV and human metapneumovirus were more frequent among cases than controls, but only enterovirus/rhinovirus was detected from asymptomatic controls. Compared with non-RSV viruses, RSV was associated with an increased risk of treatment failure at 48 hours [risk ratio (RR): 1.85; 95% confidence interval (CI): 1.20, 2.84], more days of respiratory support [mean difference (MD): 1.26 days; 95% CI: 0.30, 2.22 days], and longer duration of hospitalization [MD: 1.35 days; 95% CI: 0.20, 2.50 days], but lower in-hospital mortality [RR: 0.09; 95% CI: 0.01, 0.80] in children with pneumonia. Conclusions Respiratory viruses were detected from most children hospitalized with ALRI in Botswana, but only RSV and human metapneumovirus were more frequent than among children without ALRI. Detection of RSV from children with ALRI predicted a protracted illness course but lower mortality compared with non-RSV viruses.

Chest Radiographic Findings and Outcomes of Pneumonia Among Children in Botswana.

Background: Chest radiography is increasingly used to diagnose pneumonia in low-income and middle-income countries. Few studies examined whether chest radiographic findings predict outcomes of children with clinically suspected pneumonia in these settings. Methods: This is a hospital-based, prospective cohort study of children 1–23 months of age meeting clinical criteria for pneumonia in Botswana. Chest radiographs were reviewed by 2 pediatric radiologists to generate a consensus interpretation using standardized World Health Organization criteria. We assessed whether final chest radiograph classification was associated with our primary outcome, treatment failure at 48 hours, and secondary outcomes. Results: From April 2012 to November 2014, we enrolled 249 children with evaluable chest radiographs. Median age was 6.1 months, and 58% were male. Chest radiograph classifications were primary endpoint pneumonia (35%), other infiltrate/abnormality (42%) or no significant pathology (22%). The prevalence of endpoint consolidation was higher in children with HIV infection (P = 0.0005), whereas endpoint pleural effusions were more frequent among children with moderate or severe malnutrition (P = 0.0003). Ninety-one (37%) children failed treatment, and 12 (4.8%) children died. Primary endpoint pneumonia was associated with an increased risk of treatment failure at 48 hours (P = 0.002), a requirement for more days of respiratory support (P = 0.002) and a longer length of stay (P = 0.0003) compared with no significant pathology. Primary endpoint pneumonia also predicted a higher risk of treatment failure than other infiltrate/abnormality (P = 0.004). Conclusions: Chest radiograph provides useful prognostic information for children meeting clinical criteria for pneumonia in Botswana. These findings highlight the potential benefit of expanded global access to diagnostic radiology services.

Use of Population Pharmacokinetics and Electronic Health Records to Assess Piperacillin–Tazobactam Safety in Infants

Background: Piperacillin, in combination with tazobactam, is frequently used in infants for treating nosocomial infections, although safety data in this population are limited. Electronic health record (EHR) data can be used to evaluate drug safety in infants, but measures of drug exposure are lacking. Methods: To relate simulated piperacillin exposure with adverse events (AEs) in infants using EHR data, we identified infants discharged from 333 neonatal intensive care units managed by the Pediatrix Medical Group between 1997 and 2012. Using a previously published population pharmacokinetic model in the target population, we simulated piperacillin steady state area under the concentration versus time curve from zero to &tgr; (AUCss,0-&tgr;) and steady state maximal drug concentration (Cmaxss). Next, we used multivariable logistic regression to evaluate the association between simulated AUCss,0-&tgr; and Cmaxss with clinical AEs (seizure and rash) and laboratory AEs controlling for gestational age. The odds ratios (95% confidence intervals) comparing the third versus the first tertiles for AUCss,0-&tgr; and Cmaxss were reported. Results: We identified 746 infants with a median (interquartile range) gestational age of 30 weeks (26–33) and postnatal age of 11 days (6–25). The median (interquartile range) piperacillin dose was 225 mg/kg/d (176–300). No significant associations were found between simulated piperacillin exposure (AUCss,0-&tgr; and Cmaxss) and clinical and laboratory AEs. Conclusions: We found no associations between predicted piperacillin exposures and the occurrence of AEs. This study confirms the feasibility of using population pharmacokinetics and EHR to relate drug exposure with safety.

The Nasopharyngeal Microbiota of Children with Respiratory Infections in Botswana.

Background: Nearly half of child pneumonia deaths occur in sub-Saharan Africa. Microbial communities in the nasopharynx are a reservoir for pneumonia pathogens and remain poorly described in African children. Methods: Nasopharyngeal swabs were collected from children with pneumonia (N = 204), children with upper respiratory infection symptoms (N = 55) and healthy children (N = 60) in Botswana between April 2012 and April 2014. We sequenced the V3 region of the bacterial 16S ribosomal RNA gene and used partitioning around medoids to cluster samples into microbiota biotypes. We then used multivariable logistic regression to examine whether microbiota biotypes were associated with pneumonia and upper respiratory infection symptoms. Results: Mean ages of children with pneumonia, children with upper respiratory infection symptoms and healthy children were 8.2, 11.4 and 8.0 months, respectively. Clustering of nasopharyngeal microbiota identified 5 distinct biotypes: Corynebacterium/Dolosigranulum-dominant (23%), Haemophilus-dominant (11%), Moraxella-dominant (24%), Staphylococcus-dominant (13%) and Streptococcus-dominant (28%). The Haemophilus-dominant [odds ratio (OR): 13.55; 95% confidence interval (CI): 2.10–87.26], the Staphylococcus-dominant (OR: 8.27; 95% CI: 2.13–32.14) and the Streptococcus-dominant (OR: 39.97; 95% CI: 6.63–241.00) biotypes were associated with pneumonia. The Moraxella-dominant (OR: 3.71; 95% CI: 1.09–12.64) and Streptococcus-dominant (OR: 12.26; 95% CI: 1.81–83.06) biotypes were associated with upper respiratory infection symptoms. In children with pneumonia, HIV infection was associated with a lower relative abundance of Dolosigranulum (P = 0.03). Conclusions: Pneumonia and upper respiratory infection symptoms are associated with distinct nasopharyngeal microbiota biotypes in African children. A lower abundance of the commensal genus Dolosigranulum may contribute to the higher pneumonia risk of HIV-infected children.

Rapid enteric testing to permit targeted antimicrobial therapy, with and without Lactobacillus reuteri probiotics, for paediatric acute diarrhoeal disease in Botswana: A pilot, randomized, factorial, controlled trial

Introduction Diarrhoeal disease is the second-leading cause of death in young children. Current guidelines recommend treating children with acute non-bloody diarrhea with oral rehydration solutions and zinc, but not antimicrobials. However, in many resource-limited settings, infections with treatable enteric bacterial and protozoan pathogens are common. Probiotics have shown promise as an adjunct treatment for diarrhoea but have not been studied in sub-Saharan Africa. Methods We conducted a pilot, factorial, randomized, placebo-controlled trial of children aged 2–60 months hospitalized in Botswana for acute non-bloody diarrhoea. A rapid test-and-treat intervention, consisting of multiplex PCR testing of rectal swabs taken at enrolment, accompanied by targeted antimicrobial therapy if treatable pathogens were detected, was compared to the reference standard of no stool testing. Additionally, Lactobacillus reuteri DSM 17938 x 60 days was compared to placebo treatment. The main objective of this pilot study was to assess feasibility. The primary clinical outcome was the increase in age-standardized height (HAZ) at 60 days adjusted for baseline HAZ. Results Seventy-six patients were enrolled over a seven-month study period. We judged that the recruitment rate, lab processing times, communication protocols, provision of specific antimicrobials, and follow-up rates were acceptable. Compared to the reference arm (no stool testing and placebo treatment), the combination of the rapid test-and-treat strategy plus L. reuteri DSM 17938 was associated with an increase of 0.61 HAZ (95% CI 0.09–1.13) and 93% lower odds of recurrent diarrhoea (OR 0.07, 95%CI 0.01–0.61) at 60 days. Discussion We demonstrated that it was feasible to evaluate the study interventions in Botswana. Despite the small sample size, we observed a statistically significant increase in HAZ at 60 days and significantly lower odds of recurrent diarrhoea in children receiving both rapid test-and-treat and L. reuteri. There is sufficient evidence to warrant proceeding with a larger follow-up trial in a similar setting.

Timing of Multiorgan Dysfunction among Hospitalized Infants with Fatal Fulminant Sepsis.

Objective Identify the progression of specific signs of multiorgan dysfunction among infants with fatal sepsis. Study Design Cohort study of 679 infants who died within 3 days of the start of a late‐onset sepsis (LOS) episode in neonatal intensive care units from 1997 to 2012. We extracted clinical and laboratory data on the day of death (day 0) and the preceding 5 days (days ‐5 to ‐1). Results Median (25th percentile‐75th percentile) gestational age was 25 (24‐28) weeks. Compared with day ‐1, day 0 was characterized by an increased requirement for mechanical ventilation and higher mean fraction of inspired oxygen. Measures of cardiorespiratory support and the proportion of infants with neutropenia began to rise on day ‐2. Conclusion Hospitalized infants with fatal LOS manifest respiratory, cardiovascular, renal, immune, and hematologic dysfunction. Knowledge of these factors and their timing may be important for the development and testing of novel therapeutics to reduce sepsis mortality.