Clinical pharmacology of antifungal agents to overcome drug resistance in pediatric patients

peer reviewedINTRODUCTION: Antifungal resistance is an emerging problem that increases morbidity and mortality in immunosuppressed pediatric patients, who suffer from invasive fungal diseases. Optimal pharmacological management is critical for the successful treatment of invasive fungal infections by resistant strains. AREAS COVERED: This paper reviews the mechanisms of resistance of different classes of antifungal agents and the current understanding of pediatric antifungal pharmacology for overcoming antifungal resistance in children based on laboratory and clinical studies in the English literature. The therapeutic choices against fungal pathogens with intrinsic or acquired resistance are further reviewed. EXPERT OPINION: There is a paucity of data in the pediatric population regarding the epidemiology of the resistant organisms to different antifungal agents. It is also unknown if there are more prevalent molecular mechanisms that promote antifungal resistance. Selection and dosages of the most effective antifungal agent for overcoming the antifungal resistance is crucial. However, there are limited studies guiding the optimal dosage and duration of treatment for management of emergent antifungal resistance. Further studies are warranted to elucidate the optimal pharmacology of the current antifungal agents against resistant organisms and to advance the development of new antifungal agents

A systematic review of randomized controlled trials for the prevention of bronchopulmonary dysplasia in infants

OBJECTIVE: Bronchopulmonary dysplasia (BPD) is the most common cause of pulmonary morbidity in premature infants and is associated with life-long morbidities. Developing drugs for the prevention of BPD would improve public health. We sought to determine characteristics of favorable randomized controlled trials (RCTs) of drugs for BPD prevention. EVIDENCE REVIEW: We searched MEDLINE and EMBASE from 1992–2014 using the MeSH terms “BPD” and “respiratory distress syndrome, newborn.” We included a Cochrane Library search to ensure inclusion of all available RCTs. We identified RCTs with BPD as a primary or secondary outcome and determined the definition of BPD used by the study. We determined whether a phase I or phase II study—to determine drug safety, efficacy, or optimal dose—was performed prior to the RCT. Finally, we searched the Cochrane Library for meta-analyses for each drug and used the results of available meta-analyses to define a favorable versus unfavorable RCT. FINDINGS: We identified 2026 articles; 47 RCTs met our inclusion criteria encompassing 21 drugs; 5 of the drugs reduced the incidence of BPD. We found data from phase I or II studies for 16 of the drugs, but only 1 demonstrated a reduction of BPD. CONCLUSIONS AND RELEVANCE: The majority of the drugs studied in RCTs failed to reduce the incidence of BPD. Performing early-phase studies prior to phase III trials might provide necessary information on drugs and drug doses capable of preventing BPD, thus informing the development of future RCTs

Predictors of mortality in staphylococcus aureus bacteremia

Staphylococcus aureus bacteremia (SAB) is an important infection with an incidence rate ranging from 20 to 50 cases/100,000 population per year. Between 10% and 30% of these patients will die from SAB. Comparatively, this accounts for a greater number of deaths than for AIDS, tuberculosis, and viral hepatitis combined. Multiple factors influence outcomes for SAB patients. The most consistent predictor of mortality is age, with older patients being twice as likely to die. Except for the presence of comorbidities, the impacts of other host factors, including gender, ethnicity, socioeconomic status, and immune status, are unclear. Pathogen-host interactions, especially the presence of shock and the source of SAB, are strong predictors of outcomes. Although antibiotic resistance may be associated with increased mortality, questions remain as to whether this reflects pathogen-specific factors or poorer responses to antibiotic therapy, namely, vancomycin. Optimal management relies on starting appropriate antibiotics in a timely fashion, resulting in improved outcomes for certain patient subgroups. The roles of surgery and infectious disease consultations require further study. Although the rate of mortality from SAB is declining, it remains high. Future international collaborative studies are required to tease out the relative contributions of various factors to mortality, which would enable the optimization of SAB management and patient outcomes