Jennifer E Girotto

Persistent and Relapsing Babesiosis in Immunocompromised Patients

BACKGROUND Human babesiosis is a tickborne malaria-like illness that generally resolves without complication after administration of atovaquone and azithromycin or clindamycin and quinine. Although patients experiencing babesiosis that is unresponsive to standard antimicrobial therapy have been described, the pathogenesis, clinical course, and optimal treatment regimen of such cases remain uncertain. METHODS We compared the immunologic status, clinical course, and treatment of 14 case patients who experienced morbidity or death after persistence of Babesia microti infection, despite repeated courses of antibabesial treatment, with those of 46 control subjects whose infection resolved after a single course of standard therapy. This retrospective case-control study was performed in southern New England, New York, and Wisconsin. RESULTS All case patients were immunosuppressed at the time of acute babesiosis, compared with <10% of the control subjects. Most case patients experienced B cell lymphoma and were asplenic or had received rituximab before babesial illness. The case patients were more likely than control subjects to experience complications, and 3 died. Resolution of persistent infection occurred in 11 patients after 2-10 courses of therapy, including administration of a final antimicrobial regimen for at least 2 weeks after babesia were no longer seen on blood smear. CONCLUSIONS Immunocompromised people who are infected by B. microti are at risk of persistent relapsing illness. Such patients generally require antibabesial treatment for >or=6 weeks to achieve cure, including 2 weeks after parasites are no longer detected on blood smear.

Optimizing bactericidal exposure for β‐lactams using prolonged and continuous infusions in the pediatric population

Administration of β‐lactams via prolonged or continuous infusion has been utilized in adults to optimize drug exposure and clinical outcomes. As children exhibit increased drug clearance, this may further the benefit of prolonged or continuous infusions. This dosing approach was applied to several β‐lactams commonly utilized in children.

Increased Clinical Failures When Treating Acute Otitis Media with Macrolides: A Meta-Analysis

Background: Macrolide antibiotics are often used to treat children with acute otitis media (AOM); however, the 2004 American Academy of Pediatrics (AAP) and American Academy of Family Physicians guidelines recommend against their use in patients without history of a type I allergic reaction to penicillins. Objective: To evaluate via meta-analysis the comparative efficacy of amoxicillin or amoxicillin/clavulanate to that of macrolide antibiotics in the treatment of children with AOM. Methods: A systematic literature search of MEDLINE, EMBASE, and International Pharmaceutical Abstracts was conducted from the earliest available date through September 2008. We used the following MeSH and key words: amoxicillin, amoxlcillin/clavulanate, Augmentin, azithromycin, ceftriaxone, clarithromycin, macrolides, AND media, otitis media, and effusion. Included studies were randomized, blinded, and controlled trials evaluating guideline-recommended antibiotics (amoxicillin or amoxicillin/clavulanate) compared to macrolide antibiotics (azithromycin or clarithromycin) in AOM in children. The primary outcome assessed was clinical failure measured between days 10 and 16 after starting antibiotic therapy. Results are reported as relative risks (RRs) with 95% confidence intervals and were calculated using a random-effects model. Results: A total of 10 trials (N = 2766) evaluating children 6 months–15 years old were included in the meta-analysis. Upon meta-analysis, the use of macrolide antibiotics was associated with an increased risk of clinical failure (RR 1.31 [95% CI 1.07 to 1.60]: p = 0.008) corresponding to a number needed to harm of 32. Upon safety analysis, rates of any adverse reaction (RR 0.74 [95% CI 0.60 to 0.90]: p = 0.003) and diarrhea (RR 0.41 [95% CI 0.32 to 0.52]: p < 0.0001) were significantly lower in the macrolide group. Conclusions: The meta-analysis suggests that patients treated with macrolides for AOM may be more likely to have clinical failures. As such, it supports the current AAP AOM recommendation that macrolides be reserved for patients who can not receive amoxicillin or amoxicillin/clavulanate.

Recombinant Human Growth Hormone in the Treatment of Patients With Cystic Fibrosis

CONTEXT: Recombinant human growth hormone (rhGH) improves growth in patients with growth hormone deficiency or idiopathic short stature. Its role in patients with cystic fibrosis (CF) is unclear. OBJECTIVE: To review the effectiveness of rhGH in the treatment of patients with CF. METHODS: Medline and the Cochrane Central Register of Controlled Trials were searched from the earliest date through April 2010. Randomized controlled trials, observational studies, systematic reviews/meta-analyses, or case reports were included if rhGH therapy was administered to patients with CF and data on prespecified harms, intermediate outcomes, or final health outcomes were reported. When applicable, end points were pooled by using a random-effects model. The overall body of evidence was graded for each outcome as insufficient, low, moderate, or high. RESULTS: Ten unique controlled trials (n = 312) and 8 observational studies (n = 58) were included. On quantitative synthesis of controlled trials, several markers of pulmonary function, anthropometrics, and bone mineralization were significantly improved versus control. Results of single-arm observational studies for the aforementioned outcomes were generally supportive of findings in clinical trials. There is insufficient evidence to determine the effect of rhGH on intravenous antibiotic use during therapy, pulmonary exacerbations, health-related quality-of-life, bone consequences, or total mortality, but moderate evidence suggests that rhGH therapy reduces the rate of hospitalization versus control. CONCLUSIONS: rhGH improved almost all intermediate measures of pulmonary function, height, and weight in patients with CF. Improvements in bone mineral content are also promising. However, with the exception of hospitalizations, the benefits on final health outcomes cannot be directly determined at this time.

Making a Case for Pediatric Antimicrobial Stewardship Programs

Although antimicrobials are commonly used in children, it is important to remember that they can have a profound impact on this unique patient population. Inadvertent consequences of antiinfective use in children include antimicrobial resistance, infection caused by Clostridium difficile, increased risk of obesity, and adverse drug events. In addition, compared with adults, children have different dosing requirements, antimicrobial formulation needs, pharmacokinetics, and antimicrobial susceptibility profiles. Therefore, pediatric‐specific antimicrobial stewardship efforts are needed to promote appropriate use of antimicrobials in children. The primary purposes of this review article are to provide a rationale behind pediatric‐focused antimicrobial stewardship and to describe currently available evidence regarding the initiatives of pediatric antimicrobial stewardship programs (ASPs). A literature search of the Medline database was performed (from inception through March 2015). The studies included in this review focus on antimicrobial stewardship interventions in inpatient pediatric settings. Ten inpatient studies involving pediatric‐focused antimicrobial stewardship interventions were identified from the published literature. Four studies used the core strategy of prospective audit with feedback; two used prior approval. The remaining four used supplemental antimicrobial stewardship strategies (guidelines, clinical pathways, and computerized decision support tools). In general, the interventions resulted in decreased antimicrobial use, reduced antimicrobial costs, and fewer prescribing errors. Children have unique medical needs related to antimicrobials and deserve focused ASP efforts. The literature regarding pediatric antimicrobial stewardship interventions is limited, but published interventions may serve as paradigms for developing pediatric ASPs as demonstrated by the general success of these interventions.

Pharmacodynamic Target Attainment of Oral β-Lactams for the Empiric Treatment of Acute Otitis Media in Children

AbstractObjective: To determine the probability of oral β-lactam regimens achieving bactericidal pharmacodynamic exposure against pathogens causing acute otitis media (AOM) given contemporary prevalence and resistance rates. Methods: A 5000-patient Monte Carlo simulation was used to recreate steady-state concentration-time profiles for oral drug administration regimens of amoxicillin, amoxicillin/clavulanic acid, cefpodoxime, cefprozil, ceftibuten, and cefuroxime in a population of 12.5-month-old children. The percent of simulated children in whom free drug concentrations above the minimum inhibitory concentration (MIC) for 50% of the drug administration interval (50% fT>MIC) were achieved was determined; 180 middle ear fluid isolates (56 Haemophilus influenzae and 124 Streptococcus pneumoniae) collected during the 2004 Global Respiratory Antimicrobial Surveillance Project (GRASP) were used. The cumulative fraction of response (CFR) was calculated and weighted against the prevalence of organisms causing AOM extrapolated from the literature. The contribution of a ‘Pollyanna phenomenon’ for each organism was also incorporated to estimate clinical effectiveness. Results: Against S. pneumoniae isolates, amoxicillin 30 mg/kg every 8 hours (84.7%) achieved the greatest CFR followed by amoxicillin/clavulanic acid and the other amoxicillin-based regimens. Against H. influenzae isolates, cefpodoxime, ceftibuten, and amoxicillin/clavulanic acid each achieved a CFR of >90%. When weighted by the prevalence of AOM-causing pathogens, CFR was highest for cefpodoxime (87.5%), amoxicillin/clavulanic acid (85.7%), and amoxicillin 30 mg/kg every 8 hours (70.8%). The contribution of a ‘Pollyanna phenomenon’ increased the probability of clinical effectiveness for all agents, with amoxicillin/clavulanic acid (90.2%) and cefpodoxime (90.1%) having the highest weighted CFR. Conclusions: Based on the recent epidemiologic and resistance profiles of S. pneumoniae and H. influenzae, amoxicillin/clavulanic acid (45 mg/kg every 12 hours) and cefpodoxime (5 mg/kg every 12 hours) provide the greatest likelihood of achieving optimal pharmacodynamic exposures empirically in children with AOM.

Tipranavir: a new protease inhibitor for the pediatric population

Highly active antiretroviral therapy can provide sustained viral suppression and a beneficial immunological response in both antiretroviral-naive and -experienced pediatric patients infected with HIV. While there have been many antiretroviral studies in adults infected with HIV, considerably less information is available in similar HIV-infected pediatric or adolescent patients. Tipranavir, a new-generation protease inhibitor approved for use in adults with resistant HIV strains, has recently been studied in HIV-infected children and adolescents. In this article, we summarize available pharmacokinetic, safety, tolerability and efficacy data obtained from children and adolescents treated with a pediatric tipranavir formulation.

Pediatric Antimicrobial Stewardship Programs

The frequent use of antimicrobials in pediatric patients has led to a significant increase in multidrug-resistant bacterial infections among children. Antimicrobial stewardship programs have been created in many hospitals in an effort to curtail and optimize the use of antibiotics. Pediatric-focused programs are necessary because of the differences in antimicrobial need and use among this patient population, unique considerations and dosing, vulnerability for resistance due to a lifetime of antibiotic exposure, and the increased risk of adverse events. This paper serves as a position statement of the Pediatric Pharmacy Advocacy Group (PPAG) who supports the implementation of antimicrobial stewardship programs for all pediatric patients. PPAG also believes that a pediatric pharmacy specialist should be included as part of that program and that services be covered by managed care organizations and government insurance entities. PPAG also recommends that states create legislation similar to that in existence in California and Missouri and that a federal Task Force for Combating Antibiotic-Resistant Bacteria be permanently established. PPAG also supports post-doctoral pharmacy training programs in antibiotic stewardship.

Sharing Antimicrobial Reports for Pediatric Stewardship (SHARPS): A Quality Improvement Collaborative

Background Although many childrens hospitals have established antimicrobial stewardship programs (ASPs), data-driven benchmarks for optimizing antimicrobial use across centers are lacking. We developed a multicenter quality improvement collaborative focused on sharing data reports and benchmarking antimicrobial use to improve antimicrobial prescribing among hospitalized children. Methods A national antimicrobial stewardship collaborative among childrens hospitals, Sharing Antimicrobial Reports for Pediatric Stewardship (SHARPS), was established in 2013. Characteristics of the hospitals and their ASPs were obtained through a standardized survey. Antimicrobial-use data reports were developed on the basis of input from the participating hospitals. Collaborative learning opportunities were provided through monthly webinars and annual meetings. Results Since 2013, 36 US hospitals have participated in the SHARPS collaborative. The median full-time equivalent (pharmacist and physician) dedicated to 30 of these ASPs was 0.75 (interquartile range, 0.45-1.4). To date, the collaborative has developed 26 data reports that include benchmarking reports according to specific antimicrobial agents, indications, and clinical service lines. The collaborative has conducted 27 webinars and 3 in-person meetings to highlight the stewardship work being conducted in the hospitals. The data reports and learning opportunities have resulted in approximately 36 distinct stewardship interventions. Conclusion A pediatric antimicrobial stewardship collaborative has been successful in promoting the development of and innovation among pediatric ASPs. Additional research is needed to determine the impact of these efforts.

A review of clinical experience with newer antifungals in children.

Fungal infections are a significant cause of morbidity and mortality in immunocompromised children. Since the beginning of the 21st century, many new antifungals including the echinocandins (i.e., caspofungin, micafungin, anidulafungin) and the newer generation triazoles (i.e., voriconazole and posaconazole) have received Food and Drug Administration approval. Unfortunately, despite making great strides in the adult arena, these agents are not currently approved in the pediatric population. However, pharmacokinetic data and clinical experiences with these agents in infants, children, and adolescents are mounting. As such, this review will discuss key concepts in pediatric pharmacology and clinical use of these newer antifungal agents.