Pipeline of Novel Antifungals for Invasive Fungal Disease in Transplant Recipients: A Pediatric Perspective.

Invasive fungal disease (IFD) remains a significant cause of morbidity and mortality in children undergoing transplantation. There is a growing armamentarium of novel antifungal agents recently approved for use or in late stages of clinical development. The overarching goal of this review is to discuss the mechanisms of action, spectrum of activity, stage of development, and pediatric-specific data for the following agents: encochleated amphotericin B deoxycholate, fosmanogepix, ibrexafungerp, isavuconazole, olorofim, opelconazole, oteseconazole, and rezafungin. Additionally, key drug attributes of these novel agents and their potential future therapeutic roles in pediatric transplant recipients are discussed.

Impact of an Antibiotic Stewardship Program on the Incidence of Vancomycin-Associated Acute Kidney Injury in Hospitalized Children.

OBJECTIVE: Vancomycin causes considerable acute kidney injury (AKI) in children, particularly in the setting of troughs of 15 to 20 mg/L. We sought to determine whether the addition of prospective audit and feedback to a preauthorization and therapeutic drug monitoring (TDM) program further reduces the incidence of AKI. METHODS: We conducted a quasiexperimental study of children admitted to The Johns Hopkins Hospital receiving vancomycin for ≥48 hours. The incidence of AKI was compared between the preintervention and intervention periods. Additional risk factors for vancomycin-associated AKI were also explored. RESULTS: A total of 386 courses of vancomycin therapy met eligibility criteria (200 in the preintervention vs 186 in the intervention period). The incidence of vancomycin-associated AKI did not differ between the preintervention and intervention periods, 8% vs 9%, respectively. On multivariable analysis, the number of concurrent nephrotoxins was found to be an independent predictor of vancomycin-associated AKI, with each additional nephrotoxin increasing the risk of AKI by 40% (adjusted OR, 1.40; 95% CI, 1.06-1.85; p = 0.019). Specific nephrotoxins that increased the risk of vancomycin-associated AKI included piperacillin/tazobactam, liposomal amphotericin B, and ibuprofen. CONCLUSION: The addition of prospective audit and feedback to a preauthorization and TDM program did not result in further AKI reduction. Prospective audit and feedback is a resource-intensive intervention. If preauthorization restrictions and TDM are already in place, our findings suggest stewardship efforts may be more effective if redirected to focus on other modifiable risk factors for vancomycin-associated AKI, such as minimizing additional nephrotoxins.

Extensively drug-resistant tuberculosis in a young child after travel to India.

Extensively drug-resistant (XDR) tuberculosis is becoming increasingly prevalent worldwide, but little is known about XDR tuberculosis in young children. In this Grand Round we describe a 2-year-old child from the USA who developed pneumonia after a 3 month visit to India. Symptoms resolved with empirical first-line tuberculosis treatment; however, a XDR strain of Mycobacterium tuberculosis grew in culture. In the absence of clinical or microbiological markers, low-radiation exposure pulmonary CT imaging was used to monitor treatment response, and guide an individualised drug regimen. Management was complicated by delays in diagnosis, uncertainties about drug selection, and a scarcity of child-friendly formulations. Treatment has been successful so far, and the child is in remission. This report of XDR tuberculosis in a young child in the USA highlights the risks of acquiring drug-resistant tuberculosis overseas, and the unique challenges in management of tuberculosis in this susceptible population.

Autoinduction of voriconazole metabolism in a child with invasive pulmonary aspergillosis.

Inter- and intra-patient variability in voriconazole pharmacokinetics has been described in children as the result of age-specific differences in hepatic metabolism, saturable nonlinear pharmacokinetics, CYP450 2C19 polymorphisms, decreased bioavailability compared with adults, and drug-drug interactions. We introduce dose-dependent autoinduction of metabolism as another cause for altered voriconazole pharmacokinetics in children and summarize previously published literature on this phenomenon. A 10-year-old girl with severe aplastic anemia developed invasive pulmonary aspergillosis after high-dose cyclophosphamide therapy and required high doses of voriconazole for longer than 2 months. She initially achieved a therapeutic trough of 1.4 µg/ml on voriconazole 11 mg/kg/dose orally every 12 hours but required dose escalations to 9.3 mg/kg/dose orally every 8 hours to maintain a trough above 1 µg/ml. Because there were no changes in concomitant medications, route of administration, adherence, or oral intake, we conclude that the only plausible explanation for the precipitous drop in voriconazole troughs was autoinduction of metabolism, a phenomenon previously reported in adults receiving higher than usual doses or prolonged courses (longer than 2 months). These data highlight the need for continued therapeutic drug monitoring of voriconazole after initial therapeutic troughs are achieved because autoinduction of metabolism can lead to significant declines in subsequent voriconazole troughs, potentially leading to treatment failure.

Severe prolonged sedation associated with coadministration of protease inhibitors and intravenous midazolam during bronchoscopy.

STUDY OBJECTIVE: To determine whether human immunodeficiency virus (HIV)-positive patients who received intravenous midazolam during an inpatient bronchoscopy procedure were more likely to experience severe prolonged sedation if they were taking antiretroviral therapy that included a protease inhibitor versus those who were not taking any antiretroviral therapy. DESIGN: Retrospective cohort study. SETTING: Tertiary care academic medical center. PATIENTS: Two hundred forty-one HIV-positive adults who received intravenous midazolam while undergoing bronchoscopy between January 1, 2003, and December 31, 2006, were analyzed; 51 patients were taking an antiretroviral regimen that included a protease inhibitor (exposed group), whereas 190 patients were not taking any antiretroviral agents (nonexposed group). MEASUREMENTS AND MAIN RESULTS: Patient demographics, medication administration records, and bronchoscopy data were collected from electronic databases and patient medical records. The exposed and nonexposed groups had similar demographic characteristics except that patients in the exposed group had lower HIV viral loads and were less likely to have altered mental status or respiratory distress before bronchoscopy. In addition, the exposed group had a higher proportion of males and patients with hepatitis B or C virus coinfection. The incidence of severe prolonged sedation was 9.80% in the exposed group versus 1.58% in the nonexposed group (relative risk [RR] 6.21, 95% confidence interval [CI] 1.53-25.12). Specific protease inhibitors associated with severe prolonged sedation were atazanavir-ritonavir and lopinavir-ritonavir. Length of hospital stay was approximately 3 days longer in the exposed group compared with the nonexposed group. CONCLUSION: Although the interaction between intravenous midazolam and protease inhibitors is well known, this study was the first systematic evaluation, to our knowledge, of the risk of severe prolonged sedation in a cohort of hospitalized HIV-positive patients. Coadministration of protease inhibitors with intravenous midazolam was associated with severe prolonged sedation as well as increased length of hospital stay. Therefore, concomitant use of these drugs should be closely monitored, or alternative sedatives for procedural sedation should be considered.