Priya A. Prasad

Epidemiological Features of Clostridium difficile-Associated Disease Among Inpatients at Children's Hospitals in the United States, 2001–2006

OBJECTIVE. Clostridium difficile is the main cause of nosocomial and antibiotic-associated diarrhea in adults. Recently, the incidence and severity of C difficile-associated disease in adults have been increasing. Whether similar phenomena are occurring among children remains unknown. Our study describes the epidemiological features of C difficile-associated disease in hospitalized children. METHODS. We conducted a retrospective cohort study of hospitalized children with C difficile-associated disease at 22 freestanding childrens hospitals in the United States, from 2001 to 2006. Cases of C difficile-associated disease were defined as a hospitalized child with a discharge code for C difficile infection, a laboratory billing charge for a C difficile toxin assay, and receipt of antimicrobial therapy for C difficile-associated disease. RESULTS. We identified 4895 patients with C difficile-associated disease. Over the study period, the annual incidence of C difficile-associated disease increased from 2.6 to 4.0 cases per 1000 admissions and from 4.4 to 6.5 cases per 10 000 patient-days. The median age of children with C difficile-associated disease was 4 years. Twenty-six percent of patients were <1 year of age. The majority of patients (67%) had underlying chronic medical conditions. The colectomy and all-cause mortality rates among children with C difficile-associated disease did not increase during the study period. CONCLUSIONS. The annual incidence of C difficile-associated disease in hospitalized children increased significantly from 2001 to 2006. However, the rates of colectomy and in-hospital death have not increased in children with C difficile-associated disease as they have among adults. The risk factors and outcomes for children with C difficile-associated disease remain to be defined in future studies.

Pediatric Invasive Aspergillosis: A Multicenter Retrospective Analysis of 139 Contemporary Cases

OBJECTIVE. Invasive aspergillosis is a major cause of morbidity and mortality in immunocompromised children. Invasive aspergillosis has been well characterized in adults; however, the incidence and analysis of risk factors, diagnostic tools, treatments, and outcomes have not been well described for a large cohort of pediatric patients. METHODS. We conducted the largest retrospective review of contemporary cases of proven and probable pediatric invasive aspergillosis diagnosed at 6 major medical centers (January 1, 2000, to July 1, 2005). RESULTS. Aspergillus fumigatus was the species most frequently recovered (52.8%) for the 139 patients analyzed. The majority of the children had a malignancy with or without hematopoietic stem cell transplant. Significant risk factors that impacted survival were immunosuppressive therapies and allogeneic stem cell transplant. The most common clinical site of invasive aspergillosis was the lungs (59%), and the most frequent diagnostic radiologic finding was nodules (34.6%). Only 2.2% of children showed the air crescent sign, 11% demonstrated the halo sign, and cavitation was seen in 24.5% of patients. Before the diagnosis of invasive aspergillosis, 43.1% of patients received fluconazole, and 39.2% received liposomal amphotericin B. After the diagnosis of invasive aspergillosis, 57% were treated with a lipid formulation of amphotericin B; however, 45.8% received ≥3 concomitant antifungal agents. Analysis did not show superiority of any 1 antifungal related to overall mortality. A total of 52.5% (73 of 139) died during treatment for invasive aspergillosis. Of all the interventions implemented, surgery was the only independent predictor of survival. CONCLUSIONS. Our analyses revealed common findings between adult and pediatric invasive aspergillosis. However, one key difference is diagnostic radiologic findings. Unlike adults, children frequently do not manifest cavitation or the air crescent or halo signs, and this can significantly impact diagnosis. Immune reconstitution, rather than specific antifungal therapy, was found to be the best predictor of survival.

Effect of an outpatient antimicrobial stewardship intervention on broad-spectrum antibiotic prescribing by primary care pediatricians: a randomized trial.

IMPORTANCE Antimicrobial stewardship programs have been effective for inpatients, often through prescribing audit and feedback. However, most antimicrobial use occurs in outpatients with acute respiratory tract infections (ARTIs). OBJECTIVE To evaluate the effect of an antimicrobial stewardship intervention on antibiotic prescribing for pediatric outpatients. DESIGN Cluster randomized trial of outpatient antimicrobial stewardship comparing prescribing between intervention and control practices using a common electronic health record. After excluding children with chronic medical conditions, antibiotic allergies, and prior antibiotic use, we estimated prescribing rates for targeted ARTIs standardized for age, sex, race, and insurance from 20 months before the intervention to 12 months afterward (October 2008-June 2011). SETTING AND PARTICIPANTS A network of 25 pediatric primary care practices in Pennsylvania and New Jersey; 18 practices (162 clinicians) participated. INTERVENTIONS One 1-hour on-site clinician education session (June 2010) followed by 1 year of personalized, quarterly audit and feedback of prescribing for bacterial and viral ARTIs or usual practice. MAIN OUTCOMES AND MEASURES Rates of broad-spectrum (off-guideline) antibiotic prescribing for bacterial ARTIs and antibiotics for viral ARTIs for 1 year after the intervention. RESULTS Broad-spectrum antibiotic prescribing decreased from 26.8% to 14.3% (absolute difference, 12.5%) among intervention practices vs from 28.4% to 22.6% (absolute difference, 5.8%) in controls (difference of differences [DOD], 6.7%; P = .01 for differences in trajectories). Off-guideline prescribing for children with pneumonia decreased from 15.7% to 4.2% among intervention practices compared with 17.1% to 16.3% in controls (DOD, 10.7%; P < .001) and for acute sinusitis from 38.9% to 18.8% in intervention practices and from 40.0% to 33.9% in controls (DOD, 14.0%; P = .12). Off-guideline prescribing was uncommon at baseline and changed little for streptococcal pharyngitis (intervention, from 4.4% to 3.4%; control, from 5.6% to 3.5%; DOD, -1.1%; P = .82) and for viral infections (intervention, from 7.9% to 7.7%; control, from 6.4% to 4.5%; DOD, -1.7%; P = .93). CONCLUSIONS AND RELEVANCE In this large pediatric primary care network, clinician education coupled with audit and feedback, compared with usual practice, improved adherence to prescribing guidelines for common bacterial ARTIs, and the intervention did not affect antibiotic prescribing for viral infections. Future studies should examine the drivers of these effects, as well as the generalizability, sustainability, and clinical outcomes of outpatient antimicrobial stewardship. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01806103.

Zygomycosis in Children: A Systematic Review and Analysis of Reported Cases

Background: Zygomycosis has emerged as an increasingly important infection with a high mortality especially in immunocompromised patients. No comprehensive analysis of pediatric zygomycosis cases has been published to date. Methods: We used a PUBMED search for English publications of pediatric (0–18 years) zygomycosis cases and references from major books as well as single case reports or case series. Individual references were reviewed for additional cases. Data were entered into Filemaker-pro database and analyzed by logistic regression analysis. Results: One hundred fifty-seven cases (64% male) were found with median age 5 years (range, 0.16–13). Underlying conditions included neutropenia (18%), prematurity (17%), diabetes mellitus (15%), ketoacidosis (10%), and no apparent underlying condition (14%). The most common patterns of zygomycosis were cutaneous (27%), gastrointestinal (21%), rhinocerebral (18%), and pulmonary (16%). Among 77 culture-confirmed cases, Rhizopus spp. (44%) and Mucor spp. (15%) were most commonly identified. Of 81 patients who were given antifungal therapy, 73% received an amphotericin B formulation only. The remaining patients received mostly amphotericin B in combination with other antifungal agents. Mortality in patients without antifungal therapy was higher than in those with therapy (88% versus 36%, P < 0.0001). Ninety-two (59%) patients underwent surgery. Cerebral, gastrointestinal, disseminated and cutaneous zygomycosis were associated with mortality rates of 100, 100, 88, and 0%, respectively. Independent risk factors for death were disseminated infection (OR: 7.18; 95% CI: 3.02–36.59) and age <1 year (OR: 3.85; 95% CI: 1.05–7.43). Antifungal therapy and particularly surgery reduced risk of death by 92% (OR: 0.07; 95% CI: 0.04–0.25) and 84% (OR: 0.16; 95% CI: 0.09–0.61), respectively. Conclusions: Zygomycosis is a life-threatening infection in children with neutropenia, diabetes mellitus, and prematurity as common predisposing factors, and there is high mortality in untreated disease, disseminated infection, and age <1 year. Amphotericin B and surgery significantly improve outcome.

Risk Factors and Predictors for Candidemia in Pediatric Intensive Care Unit Patients: Implications for Prevention

BACKGROUND Candida species are the leading cause of invasive fungal infections in hospitalized children and are the third most common isolates recovered from patients with healthcare-associated bloodstream infection in the United States. Few data exist on risk factors for candidemia in pediatric intensive care unit (PICU) patients. METHODS We conducted a population-based case-control study of PICU patients at Childrens Hospital of Philadelphia during the period from 1997 through 2004. Case patients were identified using laboratory records, and control patients were selected from PICU rosters. Control patients were matched to case patients by incidence density sampling, adjusting for time at risk. Following conditional multivariate analysis, we performed weighted multivariate analysis to determine predicted probabilities for candidemia given certain risk factor combinations. RESULTS We identified 101 case patients with candidemia (incidence, 3.5 cases per 1000 PICU admissions). Factors independently associated with candidemia included presence of a central venous catheter (odds ratio [OR], 30.4; 95% confidence interval [CI], 7.7-119.5), malignancy (OR, 4.0; 95% CI, 1.23-13.1), use of vancomycin for >3 days in the prior 2 weeks (OR, 6.2; 95% CI, 2.4-16), and receipt of agents with activity against anaerobic organisms for >3 days in the prior 2 weeks (OR, 3.5; 95% CI, 1.5-8.4). Predicted probability of having various combinations of the aforementioned factors ranged from 10.7% to 46%. The 30-day mortality rate was 44% among case patients and 14% among control patients (OR, 4.22; 95% CI, 2.35-7.60). CONCLUSIONS To our knowledge, this is the first study to evaluate independent risk factors and to determine a population of children in PICUs at high risk for developing candidemia. Future efforts should focus on validation of these risk factors identified in a different PICU population and development of interventions for prevention of candidemia in critically ill children.

Variability in Antibiotic Use at Children's Hospitals

BACKGROUND: Variation in medical practice has identified opportunities for quality improvement in patient care. The degree of variation in the use of antibiotics in childrens hospitals is unknown. METHODS: We conducted a retrospective cohort study of 556 692 consecutive pediatric inpatient discharges from 40 freestanding childrens hospitals between January 1, 2008, and December 31, 2008. We used the Pediatric Health Information System to acquire data on antibiotic use and clinical diagnoses. RESULTS: Overall, 60% of the children received at least 1 antibiotic agent during their hospitalization, including >90% of patients who had surgery, underwent central venous catheter placement, had prolonged ventilation, or remained in the hospital for >14 days. Even after adjustment for both hospital- and patient-level demographic and clinical characteristics, antibiotic use varied substantially across hospitals, including both the proportion of children exposed to antibiotics (38%–72%) and the number of days children received antibiotics (368–601 antibiotic-days per 1000 patient-days). In general, hospitals that used more antibiotics also used a higher proportion of broad-spectrum antibiotics. CONCLUSIONS: Childrens hospitals vary substantially in their use of antibiotics to a degree unexplained by patient- or hospital-level factors typically associated with the need for antibiotic therapy, which reveals an opportunity to improve the use of these drugs.

Antibiotic Use in Neonatal Intensive Care Units and Adherence with Centers for Disease Control and Prevention 12 Step Campaign to Prevent Antimicrobial Resistance

Background: The Centers for Disease Control and Prevention (CDC) 12-Step Campaign to Prevent Antimicrobial Resistance was launched to educate clinicians about antimicrobial resistance and provide strategies to improve clinical practice, including antimicrobial utilization. Methods: A multicenter retrospective observational study of antibiotic use was performed in 4 tertiary care NICUs to assess adherence to the guidelines defined by the CDC 12-Step Campaign using predetermined criteria. Fifty infants per NICU were identified who received intravenous antibiotics at greater than 72 hours of age. Antibiotic regimens, clinical and microbiologic data, and indications for initiation and continuation of antibiotics (after 72 hours of use) were recorded. Inappropriate utilization was characterized at initiation, continuation, by agent, and by CDC 12-Step. Results: Two hundred neonates received 323 antibiotic courses totaling 3344 antibiotic-days. Ninety (28%) courses and 806 (24%) days were judged to be nonadherent to a CDC 12-Step. Inappropriate use was more common with continuation of antibiotics (39%) than with initiation (4%) of therapy. Vancomycin was the most commonly used drug (n = 895 antibiotic-days) of which 284 (32%) days were considered inappropriate. Carbapenems were used less frequently (n = 310 antibiotic-days), and 132 (43%) of these days were inappropriate. Common reasons for nonadherence at the time of continuation included failure to narrow antibiotic coverage after microbiologic results were known and prolonged antibiotic prophylaxis after surgery with chest tube placement. Conclusions: The CDC 12-Step Campaign can be modified for neonatal populations. Inappropriate antibiotic prescribing was common in the study NICUs. Improvement efforts should target antibiotic use 72 hours after initiation, particularly focusing on narrowing therapy and instituting protocols to limit prophylaxis.

Evaluation of an antimicrobial stewardship program at a pediatric teaching hospital.

Background: Thirty to 50% of hospitalized patients receive antimicrobial therapy. Previous data suggest that inappropriate use results in higher mortality rates, longer lengths of stay, and increased medical costs. Antimicrobial Stewardship Programs (ASPs) reduce the improper use of antimicrobials and improve patient safety. Despite increased awareness about the benefits of these programs, few pediatric ASPs exist and fewer comprehensive studies evaluate their effects. Methods: A prospective observational study was conducted to describe the use and impact of a pediatric ASP. Data were collected on the clinicians request for targeted antibiotics and the interventions made by the ASP. Retrospective chart review was performed to assess outcomes and compliance on empiric antimicrobial therapy decisions and recommendations to discontinue antimicrobial therapy. Results: During the 4-month study period, calls were placed to the ASP for 652 patients. Forty-five percent of those calls required an intervention by the ASP. These interventions included: (1) Targeting the known or suspected pathogens (20%); (2) Consultation (43%); (3) Optimize antimicrobial treatment (33%); and (4) Stop antimicrobial treatment (4%). Three of the 84 (3.5%) patients recommended to receive alternative therapy developed an infection not covered by the ASP recommendations or the antimicrobial initially requested by the clinician. Conclusions: Our data demonstrate that an ASP improves the appropriate use of antimicrobial medications in hospitalized children. In addition, the ASP plays an integral role in providing guidance to clinicians and ensures that the appropriate antimicrobial agents are used.

Risk factors and outcomes associated with severe Clostridium difficile infection in children

Background: The incidence and severity of Clostridium difficile infection (CDI) is increasing among adults; however, little is known about the epidemiology of CDI among children. Methods: We conducted a nested case-control study to identify the risk factors for and a prospective cohort study to determine the outcomes associated with severe CDI at 2 childrens hospitals. Severe CDI was defined as CDI and at least 1 complication or ≥2 laboratory or clinical indicators consistent with severe disease. Studied outcomes included relapse, treatment failure, and CDI-related complications. Isolates were tested to determine North American pulsed-field gel electrophoresis type 1 lineage. Results: We analyzed 82 patients with CDI, of whom 48 had severe disease. Median age in years was 5.93 (1.78–12.16) and 1.83 (0.67–8.1) in subjects with severe and nonsevere CDI, respectively (P = 0.012). All patients with malignancy and CDI had severe disease. Nine subjects (11%) had North American pulsed-field gel electrophoresis type 1 isolates. Risk factors for severe disease included age (adjusted odds ratio [95% confidence interval]: 1.12 [1.02, 1.24]) and receipt of 3 antibiotic classes in the 30 days before infection (3.95 [1.19, 13.11]). If infants less than 1 year of age were excluded, only receipt of 3 antibiotic classes remained significantly associated with severe disease. Neither the rate of relapse nor treatment failure differed significantly between patients with severe and nonsevere CDI. There was 1 death. Conclusions: Increasing age and exposure to multiple antibiotic classes were risk factors for severe CDI. Although most patients studied had severe disease, complications were infrequent. Relapse rates were similar to those reported in adults.

Surveillance Cultures for Detection of Methicillin-Resistant Staphylococcus aureus: Diagnostic Yield of Anatomic Sites and Comparison of Provider- and Patient-Collected Samples

We studied provider- and patient-collected samples from multiple anatomic sites to determine the yield for detection of methicillin-resistant Staphylococcus aureus (MRSA). Sampling of multiple sites was required to achieve a sensitivity of more than 90% for MRSA colonization. Groin and perineum samples yielded positive results significantly more often for community-onset MRSA than for hospital-onset MRSA. Agreement rates between provider- and patient-collected swab specimens were excellent.