Pharmacokinetic analysis driven letermovir dosing in pediatric hematopoietic cell transplantation patients with resistant CMV disease.

BACKGROUND: Reactivation of cytomegalovirus (CMV) in CMV-seropositive patients after haploidentical T-cell receptor αß+ /CD19+ depleted hematopoietic cell transplant (HCT) is common. Due to delayed CMV-specific immune reconstitution, patients may require prolonged antiviral therapy, including secondary prophylaxis (SP). We present our clinical experience with the off-label use of letermovir for SP in a severely immunocompromised 2-year-old toddler with refractory pre-B-cell ALL and bilateral retinitis caused by resistant CMV (A594V UL97 mutation) following a haploidentical TCRαß+ /CD19+ depleted HCT. METHODS: The patient underwent measurement of two separate sets of letermovir serum concentrations, drawn at pre-dose, 1 and 4 h (and 8 h during the second therapeutic drug monitoring) post-dose. Pharmacokinetic parameters, including AUC0-24 were calculated, and dose adjustment was performed based on the drug level. RESULTS: While receiving oral letermovir 240 mg once daily without cyclosporine, the observed AUC0-24 was high (75 815 ng h/mL) with a Cmin of 209 ng/mL. The dose was reduced by 25% to 180 mg once daily. Despite the dose reduction, both AUC0-24 and Cmin values further increased to 119 095 ng h/L and 959 ng/mL, respectively. The patient continued oral letermovir 180 mg once daily for about 3 months, with adequate viral suppression (CMV viral load in plasma <150 IU/mL) and no recurrent CMV end-organ disease or adverse events. CONCLUSIONS: Given limited options for anti-CMV therapy in young children with resistant CMV, letermovir could be considered as an alternative antiviral for SP. Further studies are warranted to evaluate the pharmacokinetics of letermovir in pediatric allogeneic HCT recipients.

70% Ethanol for Decontamination of Central Venous Lines Exposed to Calcineurin Inhibitors.

BACKGROUND: Tacrolimus, commonly used for graft versus host disease prophylaxis is usually administered via a dedicated central venous line (CVL) and trough levels drawn from the unexposed lumen. Being an oil-based medication, it may be adsorbed to the inner lumen of the CVL and result in falsely high levels drawn from an inadvertently exposed lumen. There is no treatment for decontamination of such CVLs, and natural decay occurs over months before the CVL can be used to draw reliable trough levels. OBJECTIVE: The primary objective of the study was to estimate the effectiveness of 70% ethanol locks for decontaminating CVLs exposed to tacrolimus. METHODS: We studied the efficacy of 70% ethanol lock in decontaminating CVLs exposed to tacrolimus in patients during transplant. Trough tacrolimus levels were drawn from the exposed and unexposed (control) lumens at 8:00 am, followed by a 2-mL 70% ethanol lock instilled for a 2-hour dwell into the exposed (intervention) lumen. Trough tacrolimus levels were again drawn from both lumens at 8:00 pm and levels compared for efficacy. RESULTS: All 20 sets showed a high 8 am trough level in the exposed intervention arm (median = 30 ng/mL), significantly greater ( P < 0.0001) than that in the control arm (median = 9.05 ng/mL), and were contaminated. After the 2-hour ethanol lock, 65% of the lumens were decontaminated. The difference between the control and intervention arms was no longer found to be statistically significant ( P = 0.0826). CONCLUSION: A 2-hour 70% ethanol lock is effective for decontamination of CVLs exposed to tacrolimus.

Peritoneal and Pleural Drains in Pediatric Hematopoietic Cell Transplant Recipients with Veno-Occlusive Disease are Safe and Do Not Adversely Impact Clinical Outcomes.

There is a lack of data on the safety and efficacy of peritoneal drain (PD) and chest tube (CT) in the management of effusions in stem cell transplant recipients with veno-occlusive disease (VOD). In this retrospective pediatric study, clinical outcomes and health resource utilization (HRU) were compared in 32 patients with VOD who had a PD (PD+) post-HCT versus 27 patients who did not (PD-). Nine patients also had a CT (7 PD+ and 2 PD-). PD + patients were more likely than PD-patients to have received myeloablative conditioning (100% vs. 85.2%; p = 0.04) and have severe or very severe VOD (100% vs. 56% p < 0.01). Mechanical obstruction (38%) and hypotension (38%) were common complications, and 13% developed peritonitis. While the frequencies of cardiac dysfunction and acute kidney injury were comparable between both groups, respiratory support and its median duration were higher in PD + patients. The hospital and intensive care unit length of stay, albumin use, and the duration of defibrotide and albumin therapy was significantly longer in PD + patients. At a median follow-up of 1.04 years (range:0.03-14.6), the 2-year overall survival was similar in both groups (53.8% vs. 51.5%; p = 0.73). Although PD use was similar between 1995 and 2007 vs. 2008-2021; (47% vs. 58%; p = 0.65), day+100 mortality was improved in recent years (53.3% vs. 17.8%; p = 0.01), coinciding with the use of defibrotide (0% vs. 84%; p < 0.01). PD in pediatric patients with VOD post-HCT, although associated with increased HRU, was safe when clinically indicated and did not adversely impact clinical outcomes.

Ibuprofen lysine for the prevention and treatment of patent ductus arteriosus.

Approximately 70-80% of newborns less than 28 weeks' gestational age require pharmacologic and/or surgical intervention to close a hemodynamically significant patent ductus arteriosus (PDA). Indomethacin has been the pharmacologic treatment of choice and has also been used prophylactically in very premature neonates to prevent PDA. The drug, however, is associated with renal and gastrointestinal adverse effects. In July 2006, intravenous ibuprofen lysine became available in the United States for treatment of hemodynamically significant PDA. The mechanism of action for both indomethacin and ibuprofen lysine is through inhibition of prostaglandin synthesis, resulting in ductal constriction. Both drugs appear to be equally efficacious in closing echocardiographically confirmed PDA. Ibuprofen lysine has demonstrated significantly less effects on cerebral, renal, and mesenteric blood flow in premature neonates when compared with indomethacin. A transient but significant increase in serum creatinine concentration, decrease in urine output, and increase in frequency of oliguria were observed with indomethacin when compared with ibuprofen lysine. However, the rate of reopening of the ductus after pharmacologic closure and the need for rescue therapy were not different between the two drugs. In addition, no differences were noted in other outcomes such as frequency of intraventricular hemorrhage, necrotizing enterocolitis, or chronic lung disease, as well as in duration of mechanical ventilation and length of hospital stay. When administered prophylactically, ibuprofen lysine did not prevent intraventricular hemorrhage nor provide any neurodevelopmental benefits. In addition, ibuprofen lysine has not been adequately studied in neonates of 27 weeks' gestational age or younger. Ibuprofen lysine is as efficacious as indomethacin in treating hemodynamically significant PDA in neonates greater than 27 weeks' gestational age.

Efficacy and safety of using L-cysteine as a catheter-clearing agent for nonthrombotic occlusions of central venous catheters in children.

Critically ill pediatric patients, especially in the intensive care unit, receive multiple medications and have a higher risk of central venous catheter (CVC) occlusion. If an occlusion occurs immediately after the administration of multiple medications or incompatible medications, either an acidic solution such as 0.1 N hydrochloric acid (HCl) or a basic solution of 1 mEq/mL sodium bicarbonate or 0.1 N sodium hydroxide can be used. However, compounding and storing of 0.1 N HCl has become more complex due to USP <797> guidelines for sterile compounding, and an alternative is needed. We report a series of cases in which L-cysteine was used instead of HCl to clear CVCs occluded due to administration of multiple medications. L-cysteine is a commercially available, sterile solution with a pH of 1­2.5. CVC occlusion was resolved in 10 of the 16 episodes in 13 patients. Two of the 16 occlusions were phenytoin related and would not have responded. An L-cysteine dose of 50 mg was used during 10 of the 16 episodes, 100 mg during 5 episodes, and 25 mg during 1 episode. A correlation between catheter clearance and dose was not observed. Occlusion resolution due to L-cysteine was not correlated to the prior use of tissue plasminogen activator. Metabolic acidosis, adverse effects, or damage to the catheters due to L-cysteine were not observed. On the basis of this limited experience, we propose L-cysteine as an effective alternative to 0.1 N HCl for clearing CVC occlusions caused by drugs with an acidic pKa.

A technology-enhanced patient case workshop.

OBJECTIVES: To assess the impact of technology-based changes on student learning, skill development, and satisfaction in a patient-case workshop. DESIGN: A new workshop format for a course was adopted over a 3-year period. Students received and completed patient cases and obtained immediate performance feedback in class instead of preparing the case prior to class and waiting for instructors to grade and return their cases. The cases were designed and accessed via an online course management system. ASSESSMENT: Student satisfaction was measured using end-of-course surveys. The impact of the technology-based changes on student learning, problem-solving, and critical-thinking skills was measured and compared between the 2 different course formats by assessing changes in examination responses. Three advantages to the new format were reported: real-life format in terms of time constraint for responses, a team learning environment, and expedient grading and feedback. Students overwhelmingly agreed that the new format should be continued. Students' examination scores improved significantly under the new format. CONCLUSION: The change in delivery of patient-case workshops to an online, real-time system was well accepted and resulted in enhanced learning, critical thinking, and problem-solving skills.

Conjugated heptavalent pneumococcal vaccine.

OBJECTIVE: To review the immunogenicity, efficacy, and safety of the heptavalent conjugated pneumococcal vaccine (PCV7). DATA SOURCES: A MEDLINE search (1993-August 2001) of research limited to humans published in the English language was conducted. STUDY SELECTION: Findings from randomized, controlled, multicenter trials were reviewed. Literature regarding epidemiology, control, and treatment of invasive pneumococcal diseases in different populations and the Advisory Committee on Immunization Practices recommendations were also reviewed. DATA SYNTHESIS: PCV7 administered to infants aged 2, 4, and 6 months, with a booster dose at 12-15 months, has been shown to be immunogenic. It decreases the incidence of invasive pneumococcal disease; individual data on bacteremia and meningitis are unavailable. Findings from clinical trials showed that invasive pneumococcal disease caused by vaccine serotypes was reduced by 87%, 58%, and 62% for children <1 year, <2 years, and <5 years of age, respectively, after introduction of routine vaccine use. The overall incidence of acute otitis media did not decrease significantly. However, culture-confirmed episodes and episodes due to pneumococcal serotypes included in the vaccine were reduced. The vaccine was immunogenic in children with sickle cell disease, but its efficacy in preventing invasive pneumococcal diseases remains unclear. Although immunogenicity and efficacy trials are lacking, the vaccine is recommended for Alaskan Native or American Indian children between 24 and 59 months of age, and for children with underlying conditions such as HIV infection, AIDS, other immunocompromising conditions, and chronic illnesses. At the manufacturer's list price of 58 dollars/dose, PCV7 is not projected to be cost-effective after 4 doses. Postmarketing analysis evaluating immunogenicity and efficacy in the excluded population may favorably change this. CONCLUSIONS: Based on published efficacy and immunogenicity data, pharmacy formularies should include PCV7.