Pharmacokinetics and safety of coformulated bictegravir, emtricitabine, and tenofovir alafenamide in children aged 2 years and older with virologically suppressed HIV: a phase 2/3, open-label, single-arm study.

BACKGROUND: Coformulated bictegravir, emtricitabine, and tenofovir alafenamide is a single-tablet regimen and was efficacious and well tolerated in children and adolescents with HIV (aged 6 years to <18 years) in a 48-week phase 2/3 trial. In this study, we report data from children aged at least 2 years and weighing 14 kg to less than 25 kg. METHODS: We conducted this open-label, multicentre, multicohort, single-arm study in South Africa, Thailand, Uganda, and the USA. Participants were virologically suppressed children with HIV, aged at least 2 years, weighing 14 kg to less than 25 kg. Participants received bictegravir (30 mg), emtricitabine (120 mg), and tenofovir alafenamide (15 mg) once daily, switching to bictegravir (50 mg), emtricitabine (200 mg), and tenofovir alafenamide (25 mg) upon attaining a bodyweight of at least 25 kg. The study included pharmacokinetic evaluation at week 2 to confirm the dose of coformulated bictegravir, emtricitabine, and tenofovir alafenamide for this weight band by comparing with previous adult data. Primary outcomes were bictegravir area under the curve over the dosing interval (AUCtau) and concentration at the end of the dosing interval (Ctau) at week 2, and incidence of treatment-emergent adverse events and laboratory abnormalities until the end of week 24 in all participants who received at least one dose of bictegravir, emtricitabine, and tenofovir alafenamide. This study is registered with ClinicalTrials.gov, NCT02881320. FINDINGS: Overall, 22 participants were screened (from Nov 14, 2018, to Jan 11, 2020), completed treatment with bictegravir, emtricitabine, and tenofovir alafenamide (until week 48), and entered an extension phase. The geometric least squares mean (GLSM) ratio for AUCtau for bictegravir was 7·6% higher than adults (GLSM ratio 107·6%, 90% CI 96·7-119·7); Ctau was 34·6% lower than adults (65·4%, 49·1-87·2). Both parameters were within the target exposure range previously found in adults, children, or both". Grade 3-4 laboratory abnormalities occurred in four (18%) participants by the end week 24 and six (27%) by the end of week 48. Drug-related adverse events occurred in three participants (14%) by the end of week 24 and week 48; none were severe. No Grade 3-4 adverse events, serious adverse events, or adverse events leading to discontinuation occurred by the end of week 24 and week 48. INTERPRETATION: Data support the use of single-tablet coformulated bictegravir (30 mg), emtricitabine (120 mg), and tenofovir alafenamide (15 mg) for treatment of HIV in children aged at least 2 years and weighing 14 kg to less than 25 kg. FUNDING: Gilead Sciences.

A tale of two intensive care units (ICUs): Baseline Staphylococcus aureus colonization and mupirocin susceptibility in neonatal and pediatric patients requiring intensive care.

OBJECTIVE: To assess the incidence rate of S. aureus colonization at baseline along with the mupirocin susceptibility (or resistance) rate in patients in a neonatal intensive care unit (NICU) and a pediatric intensive care unit (PICU) in conjunction with the implementation of universal decolonization as the standard of care. DESIGN: Prospective cohort study. SETTING: Children's Hospital of Michigan (CHM) inpatient intensive care units (ICUs). PARTICIPANTS: Newly admitted pediatric patients to the CHM NICU or PICU aged between 1 day and ≤21 years. INTERVENTIONS: Baseline and follow-up S. aureus screening cultures were obtained before patients underwent universal decolonization with mupirocin 2% antibiotic ointment (intranasal and umbilical) and chlorhexidine baths as standard of care to reduce CLABSI rates. RESULTS: Baseline S. aureus colonization rates of new admissions to the CHM NICU and PICU were high at 32% and 29%, respectively. Baseline mupirocin susceptibility to any S. aureus growth was 98.4%. All baseline culture isolates whether positive for MRSA or MSSA, with one exception, had minimum inhibitory concentrations (MICs) of ≤0.19 µg/mL. All follow-up study cultures after universal decolonization at 7 days or beyond with any S. aureus growth had mupirocin MICs of ≤0.125 µg/mL. CONCLUSIONS: Baseline S. aureus colonization rates of new admissions to the CHM ICUs were high as was baseline mupirocin susceptibility. Follow-up cultures, albeit limited in number, did not detect increasing mupirocin MICs over 1 year, despite broad mupirocin exposure due to the implementation of universal decolonization.

Fixed-dose combination bictegravir, emtricitabine, and tenofovir alafenamide in adolescents and children with HIV: week 48 results of a single-arm, open-label, multicentre, phase 2/3 trial.

BACKGROUND: Bictegravir is a potent integrase strand-transfer inhibitor (INSTI) with a high genetic barrier to resistance. Bictegravir, coformulated with emtricitabine and tenofovir alafenamide, is recommended by key European and US HIV treatment guidelines as the preferred single-tablet regimen for adults and adolescents. The aim of this study was to assess the pharmacokinetics, safety, and efficacy of switching to this regimen in virologically suppressed children and adolescents with HIV. METHODS: In this single-arm, open-label trial, we enrolled virologically suppressed children and adolescents (aged 6 to <18 years) with HIV at 22 hospital clinics in South Africa, Thailand, Uganda, and the USA. Eligible participants had a bodyweight of at least 25 kg, were virologically suppressed (HIV-1 RNA <50 copies per mL) on a stable ART regimen for at least 6 months before screening, had a CD4 count of at least 200 cells per µL, and an estimated glomerular filtration rate of at least 90 mL/min per 1·73 m2 by the Schwartz formula at screening. All participants received the fixed-dose regimen of coformulated bictegravir 50 mg, emtricitabine 200 mg, and tenofovir alafenamide 25 mg once daily. Pharmacokinetic analysis was used for dosing confirmation, and results compared with adult values. The primary outcomes were area under the curve at the end of the dosing interval (AUCtau) and concentration at the end of the dosing interval (Ctau) of bictegravir, and incidence of treatment-emergent adverse events and laboratory abnormalities at week 24. Efficacy and safety analyses included all participants who received at least one dose of study drug. We report the 48-week results. This study is registered with ClinicalTrials.gov, NCT02881320. FINDINGS: Between Sept 29, 2016 and Feb 16, 2018, we enrolled 102 participants. 100 participants received bictegravir, emtricitabine, and tenofovir alafenamide (cohort 1 [adolescents aged 12 to <18 years], n=50; cohort 2 [children aged 6 to <12 years], n=50). The mean bictegravir AUCtau was 89 100 ng × h/mL (coefficient of variation 31·0%) in adolescents (cohort 1) and 128 000 ng × h/mL (27·8%) in children (cohort 2). Compared with adults, bictegravir Ctau was 35% lower in adolescents and 11% lower in children. The 90% CIs of both parameters were within the predefined pharmacokinetic equivalence boundary and within overall range of exposures observed in adults and deemed to be safe and efficacious (geometric least-squares mean ratio [GLSM] 86·3% [90% CI 80·0-93·0] for AUCtau and 65·4% [58·3-73·3] for Ctau in adolescents; GLSM 125% [90% CI 117-134] for AUCtau and 88·9% [80·6-98·0] for Ctau for children). Bictegravir, emtricitabine, and tenofovir alafenamide was well tolerated; most adverse events were grade 2 or less in severity and no study drug-related serious adverse events were reported. One participant discontinued study drug due to adverse events (grade 2 insomnia and anxiety). Virological suppression (HIV-1 RNA <50 copies per mL) was maintained by all 100 participants at week 24 and by 98 (98%) of 100 at week 48; no participants had treatment-emergent resistance. INTERPRETATION: In adolescents and children with HIV, the bictegravir, emtricitabine, and tenofovir alafenamide single-tablet regimen was well tolerated and maintained virological suppression. Our data support the treatment of HIV in adolescents and children with this single-tablet regimen. At present, the single-tablet regimen is recommended as first-line treatment in the USA for adolescents and as an alternative regimen in children and has the potential to represent an important regimen in the paediatric population. FUNDING: Gilead Sciences.

SARS-CoV-2-associated multisystem inflammatory syndrome in children: clinical manifestations and the role of infliximab treatment.

This study was conducted to assess the clinical spectrum, management, and outcome of SARS-CoV-2-related multisystem inflammatory syndrome in children (MIS-C). We reviewed medical records of children with MIS-C diagnosis seen at the Children's Hospital of Michigan in Detroit between April and June 2020. Thirty-three children were identified including 22 who required critical care (group 1) and 11 with less intense inflammation (group 2). Children in group 1 were older (median 7.0 years) than those in group 2 (median 2.0 years). Abdominal pain was present in 68% of patients in group 1. Hypotension or shock was present in 17/22 patients in group 1. Thirteen (39.4%) had Kawasaki disease (KD)-like manifestations. Five developed coronary artery dilatation; All resolved on follow-up. Intravenous immunoglobulin (IVIG) was given to all patients in group 1 and 7/11 in group 2. Second-line therapy was needed in 13/22 (group 1) for persisting inflammation or myocardial dysfunction; 12 received infliximab. All patients recovered.Conclusion: MIS-C clinical manifestations may overlap with KD; however, MIS-C is likely a distinct inflammatory process characterized by reversible myocardial dysfunction and rarely coronary artery dilatation. Supportive care, IVIG, and second-line therapy with infliximab were associated with a favorable outcome. What is Known: • Multisystem inflammatory syndrome in children (MIS-C) manifestations include fever, gastrointestinal symptoms, shock, and occasional features of Kawasaki disease (KD). • Treatment includes immunomodulatory agents, most commonly IVIG and corticosteroids. What is New: • Spectrum of MIS-C varies from mild to severe inflammation and coronary artery dilatation occurred in 5/22 (23%) critically ill patients. • IVIG and infliximab therapy were associated with a favorable outcome including resolution of coronary dilatation; only 2/33 received corticosteroids.

Limited granulomatosis with polyangiitis in an adolescent with Crohn's disease on infliximab therapy: cause or coincidence?

Pulmonary involvement in Crohn's disease (CD) may precede the development of intestinal inflammation, but in most cases occurs during the course of treatment, either as an extra-intestinal manifestation, because of secondary infections, or as a side effect of the therapy itself. This case highlights the differential diagnosis and work up for multiple pulmonary nodules that developed in a patient with CD who had been in remission on infliximab therapy. Even though infectious causes, such as Mycobacteria and Fungi, account for majority of these cases, the possibility of non-infectious conditions such as autoimmune disorders should also be considered.

The impact of ethanol lock therapy on length of stay and catheter salvage in pediatric catheter-associated bloodstream infection.

BACKGROUND: Ethanol lock therapy (ELT) with systemic antimicrobial therapy (SAT) is a treatment for catheter-associated bloodstream infections (CABSI). However, its impact on hospital length of stay (LOS) is unknown. OBJECTIVES: Assess the impact of ELT on LOS, LOS attributable to CABSI (ALOS), and catheter salvage in pediatric hematology, oncology, stem cell transplant (HOSCT) CABSI. METHODS: Retrospective review of HOSCT CABSI from January 2009 to July 2011. RESULTS: A total of 124 CABSI episodes were reviewed in 66 patients. Mean LOS with ELT after 1 positive blood culture (BC) was 7.1 versus 12.3 days after ≥2 positive BC (P = .014). Mean ALOS was 1.6 days with ELT versus 2.9 days without ELT (P = .018). Mean ALOS with ELT after 1 positive BC was 3.75 days versus 5.8 days after ≥2 positive BC (P = .022). Catheter salvage rate: 41 of 48 (85%) with ELT versus 49 of 68 (72%) without ELT (P = .169). CONCLUSION: Earlier initiation of ELT may decrease ALOS.

Pentavalent rotavirus vaccine in infants with surgical gastrointestinal disease.

OBJECTIVES: Pentavalent rotavirus vaccine (RV5) has been shown to be well-tolerated and efficacious in preventing rotavirus gastroenteritis in healthy infants. Safety and immunogenicity of RV5 in infants with surgical gastrointestinal disease have not been studied. The aim of the present study was to evaluate the safety and immunogenicity of RV5 in infants with a history of congenital or acquired intestinal disease requiring resection compared with healthy infants. METHODS: Infants with intestinal resection were matched by gestational age and chronological age to healthy infants (controls). Dose 1 of RV5 was given at 10 to 12 weeks of chronological age. Doses 2 and 3 were given at intervals of 4 to 10 weeks, with all 3 doses given by 32 weeks. All infants were monitored for adverse events (AEs) by telephone calls, clinic visits, and parental written reports during the first 42 days after each dose and monthly thereafter by telephone for 12 months. Serum anti-rotavirus immunoglobulin A (IgA) titers were measured prevaccination and 2 weeks after dose 3. RESULTS: A total of 5 infants with surgical gastrointestinal disease and 3 control subjects were enrolled. All participants (100%) mounted a 3-fold increase in serum anti-rotavirus IgA geometric mean titer postvaccination. RV5 administration to surgical infants was well tolerated with a majority of AEs being attributed to the underlying medical condition. CONCLUSIONS: Postvaccination serum anti-rotavirus IgA levels indicate that RV5 is immunogenic in infants with a history of bowel resection, despite varying lengths of residual bowel. RV5 was well tolerated with few vaccine-related AEs.

Detection of respiratory coinfections in pediatric patients using a small volume polymerase chain reaction array respiratory panel: more evidence for combined droplet and contact isolation.

BACKGROUND: In fall 2009, Children's Hospital of Michigan (CHM) instituted combined isolation precautions (contact and droplet isolation) for pediatric inpatients with upper respiratory infection (URI) symptoms to prevent health care-associated infection. METHODS: Pediatric patients with symptoms of URI had nasopharyngeal (NP) swab samples obtained prospectively between January and April and September and December 2010 for small volume polymerase chain reaction (SVPCR) array respiratory panel (RP) multiplex nucleic acid testing. NP swabs or nasal washes were obtained for viral culture and rapid antigen testing (RAT). RESULTS: Of 499 evaluable SVPCR array RP samples, 344 (69%) tested positive for at least 1 of the 21 tested organisms. The most commonly identified pathogen was rhinovirus/enterovirus (181/344 [53%]) for which no RAT exists at CHM. Of 344 positive specimens, 57 (17%) had at least 2 identified pathogens; 8 (2%) of these had 3. In 11% of patients, molecular testing detected pathogens or pathogen combinations requiring both contact and droplet precautions. CONCLUSION: SVPCR array RP testing detected respiratory pathogens in pediatric patients with URI at rates higher than that of RAT and viral culture. Because of the pathogens and pathogen combinations detected, the study findings suggest that combined contact and droplet isolation precautions may be warranted to prevent health care-associated infection in pediatric inpatients with URI. Further studies will be needed to confirm these results.

Short-dwell ethanol lock therapy in children is associated with increased clearance of central line-associated bloodstream infections.

BACKGROUND: Central line-associated bloodstream infection (CLABSI) is a known complication of central line use. Salvage of infected central lines with ethanol lock therapy (ELT) with systemic antimicrobials may be an alternative treatment option in children. METHODS: Retrospective review was performed in children with CLASBI who underwent short-dwell ELT (70% ethanol, 4- to 25-hour dwell times ≤3 days) with systemic antimicrobials from January 1, 2007 to July 15, 2009. RESULTS: A total of 59 patients, aged 2 months to 19 years (mean ± SD = 6.3 ± 6.1 years) with 80 episodes of CLABSI were included. The CLABSI eradication rate was 86% (69/80 episodes; 95% confidence interval [CI] 78%, 94%), significantly greater than 50% (Z = 2.35, P < .05), the estimated clearance rate of CLABSI eradication using systemic antimicrobials alone. Overall central line retention was 78% (60/77 episodes, 95% CI 69%, 87%). ELT was well tolerated. CONCLUSIONS: These findings suggest the potential benefit of short-dwell ELT combined with systemic antimicrobials in CLABSI treatment. Randomized controlled trials are needed.

Nosocomial infections and multidrug-resistant bacterial organisms in the pediatric intensive care unit.

Nosocomial infections in Pediatric Intensive Care Units (PICUs) caused by multidrug-resistant bacterial organisms are increasing. This review attempts to report on significant findings in the current literature related to nosocomial infections in PICU settings with an international perspective. The types of nosocomial infections are addressed, including catheter-related bloodstream infections, ventilator-associated pneumonia, urinary tract infections, gastrointestinal infections and post-surgical wound infections. A review of emerging resistant bacterial pathogens includes methicillin-resistant Staphylococcus aureus, vancomycin-resistant Enterococcus sp., Clostridium difficile, extended-spectrum ß-lactamase producing Gram-negative organisms, Klebsiella pneumoniae carbapenemase-producing strains and multi-drug resistant Acinetobacter baumannii. Basic and enhanced infection control methods for the management and control of multidrug-resistant organisms are also summarized with an emphasis on prevention.

An outbreak of carbapenem-resistant Acinetobacter baumannii infection in a neonatal intensive care unit: investigation and control.

OBJECTIVE: To investigate the mode of transmission of and assess control measures for an outbreak of carbapenem-resistant (multidrug-resistant) Acinetobacter baumannii infection involving 6 premature infants. DESIGN: An outbreak investigation based on medical record review was performed for each neonate during the outbreak (from November 2008 through January 2009) in conjunction with an infection control investigation. SETTING: A 36-bed, level 3 neonatal intensive care unit in a university-affiliated teaching hospital in Detroit, Michigan. INTERVENTIONS: Specimens were obtained for surveillance cultures from all infants in the unit. In addition, geographic cohorting of affected infants and their nursing staff, contact isolation, re-emphasis of adherence to infection control practices, environmental cleaning, and use of educational modules were implemented to control the outbreak. RESULTS: Six infants (age, 10-197 days) with multidrug-resistant A. baumannii infection were identified. All 6 infants were premature (gestational age, 23-30 weeks) and had extremely low birth weights (birth weight, 1000 g or less). Conditions included conjunctivitis (2 infants), pneumonia (4 infants), and bacteremia (1 infant). One infant died of causes not attributed to infection with the organism; the remaining 5 infants were discharged home. All surveillance cultures of unaffected infants yielded negative results. CONCLUSIONS: The spread of multidrug-resistant A. baumannii infection was suspected to be due to staff members who spread the pathogen through close contact with infants. Clinical staff recognition of the importance of multidrug-resistant A. baumannii recovery from neonatal intensive care unit patients, geographic cohorting of infected patients, enhanced infection control practices, and staff education resulted in control of the spread of the organism.

Staphylococcal scalded skin syndrome in a preterm newborn presenting within first 24 h of life.

A preterm neonate was noted to have diffuse blanching erythema around the mouth followed by appearance of bullous lesions on the upper back, lower neck and right scapular areas at 23 h of life. The bullae subsequently ruptured leaving an extremely tender, erythematous, denuded area of the skin, which extended over next few hours to involve most of the upper back and right shoulder regions. Nikolsky sign was positive. Clinical diagnosis of staphylococcal scalded skin syndrome was made. The throat, blood, urine and cerebrospinal fluid cultures did not yield any growth, but wound culture was positive for Staphylococcus aureus. Treatment included administration of intravenous fluids and vancomycin for 10 days. The wound area was covered with vaseline and sterile gauge dressings. On day 5 of life, epithelialisation began and was complete on the seventh day of life. She was discharged home with intact skin, without scars, on day 12 of life.