First name
Kevin
Middle name
J
Last name
Downes

Title

Pharmacokinetics of Antimicrobials in Children with Emphasis on Challenges Faced by Low and Middle Income Countries, a Clinical Review.

Year of Publication

2022

Date Published

12/2022

ISSN Number

2079-6382

Abstract

Effective antimicrobial exposure is essential to treat infections and prevent antimicrobial resistance, both being major public health problems in low and middle income countries (LMIC). Delivery of drug concentrations to the target site is governed by dose and pharmacokinetic processes (absorption, distribution, metabolism and excretion). However, specific data on the pharmacokinetics of antimicrobials in children living in LMIC settings are scarce. Additionally, there are significant logistical constraints to therapeutic drug monitoring that further emphasize the importance of understanding pharmacokinetics and dosing in LMIC. Both malnutrition and diarrheal disease reduce the extent of enteral absorption. Multiple antiretrovirals and antimycobacterial agents, commonly used by children in low resource settings, have potential interactions with other antimicrobials. Hypoalbuminemia, which may be the result of malnutrition, nephrotic syndrome or liver failure, increases the unbound concentrations of protein bound drugs that may therefore be eliminated faster. Kidney function develops rapidly during the first years of life and different inflammatory processes commonly augment renal clearance in febrile children, potentially resulting in subtherapeutic drug concentrations if doses are not adapted. Using a narrative review approach, we outline the effects of growth, maturation and comorbidities on maturational and disease specific effects on pharmacokinetics in children in LMIC.

DOI

10.3390/antibiotics12010017

Alternate Title

Antibiotics (Basel)

PMID

36671218

Title

Clinical Pharmacokinetics and Pharmacodynamics of Cefepime.

Year of Publication

2022

Number of Pages

929-953

Date Published

06/2022

ISSN Number

1179-1926

Abstract

Cefepime is a broad-spectrum fourth-generation cephalosporin with activity against Gram-positive and Gram-negative pathogens. It is generally administered as an infusion over 30-60 min or as a prolonged infusion with infusion times from 3 h to continuous administration. Cefepime is widely distributed in biological fluids and tissues with an average volume of distribution of ~ 0.2 L/kg in healthy adults with normal renal function. Protein binding is relatively low (20%), and elimination is mainly renal. About 85% of the dose is excreted unchanged in the urine, with an elimination half-life of 2-2.3 h. The pharmacokinetics of cefepime is altered under certain pathophysiological conditions, resulting in high inter-individual variability in cefepime volume of distribution and clearance, which poses challenges for population dosing approaches. Consequently, therapeutic drug monitoring of cefepime may be beneficial in certain patients including those who are critically ill, have life-threatening infections, or are infected with more resistant pathogens. Cefepime is generally safe and efficacious, with a goal exposure target of 70% time of the free drug concentration over the minimum inhibitory concentration for clinical efficacy. In recent years, reports of neurotoxicity have increased, specifically in patients with impaired renal function. This review summarizes the pharmacokinetics, pharmacodynamics, and toxicodynamics of cefepime contemporarily in the setting of increasing cefepime exposures. We explore the potential benefits of extended or continuous infusions and therapeutic drug monitoring in special populations.

DOI

10.1007/s40262-022-01137-y

Alternate Title

Clin Pharmacokinet

PMID

35764774

Title

Antiviral Toxicities in Pediatric Solid Organ Transplant Recipients.

Year of Publication

2022

Date Published

08/2022

ISSN Number

1600-6143

Abstract

Prophylaxis with valganciclovir (VGCV) is used routinely to prevent cytomegalovirus (CMV) infections in at-risk pediatric solid organ transplant (SOT) recipients. However, the rate and factors associated with toxicities in this population are not well-described. We conducted a retrospective cohort study of children undergoing SOT at our hospital from January 2012 - June 2018. We evaluated the frequency of hematologic and renal toxicities from day 15 through 1-year post-SOT in relation to antiviral exposures, focused on VGCV prophylaxis. Marginal rate models were used to determine the risk of kidney injury and neutropenia in relation to VGCV prophylaxis. Among 281 SOTs, VGCV prophylaxis was administered on 20.1% of all follow-up days. The incidence rates of kidney injury, leukopenia, and neutropenia were significantly higher during VGCV prophylaxis compared to when no antiviral agents were given. Using multivariable marginal rate models, receipt of VGCV prophylaxis was associated with development of kidney injury (rate ratio [RR] 1.79, 95% confidence interval [CI]: 1.22-2.65) and neutropenia (RR 4.82, 95% CI: 3.08-7.55). VGCV dosing did not impact the development of kidney injury or neutropenia. Toxicities are common with VGCV prophylaxis in pediatric SOT recipients.

DOI

10.1111/ajt.17171

Alternate Title

Am J Transplant

PMID

35971847

Title

A Pharmacokinetic Analysis of Tobramycin in Patients Less than Five Years of Age with Cystic Fibrosis: Assessment of Target Attainment with Extended-Interval Dosing through Simulation.

Year of Publication

2022

Number of Pages

e0237721

Date Published

2022 Apr 28

ISSN Number

1098-6596

Abstract

<p>Extended interval dosing of tobramycin is recommended for treatment of pulmonary exacerbations in adults and older children with cystic fibrosis (CF), but data are limited in patients less than 5 years of age. We performed a retrospective population pharmacokinetic (PK) analysis of hospitalized children with CF &lt;5 years of age prescribed intravenous tobramycin for a pulmonary exacerbation from March 2011 to September 2018 at our hospital. Children with normal renal function who had ≥1 tobramycin concentration available were included. Nonlinear mixed effects population PK modeling was performed using NONMEM using data from the first 48 h of tobramycin treatment. Monte Carlo simulations were implemented to determine the fraction of simulated patients that met published therapeutic targets with regimens of 10-15 mg/kg/day once-daily dosing. Fifty-eight patients received 111 tobramycin courses (range 1-9/patient). A two-compartment model best described the data. Age, glomerular filtration rate, and vancomycin coadministration were significant covariates on tobramycin clearance. The typical values of clearance and central volume of distribution were 0.252 L/hr/kg^0.75 and 0.308 L/kg, respectively. No once-daily regimens achieved all pre-specified targets simultaneously in &gt;75% of simulated subjects. A dosage of 13 mg/kg/dose best met the predefined targets of C &gt;25 mg/L and AUC of 80-120 mg·h/L. Based on our population PK analysis and simulations, once-daily dosing of tobramycin would not achieve all therapeutic goals in young patients with CF. However, extended-interval dosing regimens may attain therapeutic targets in the majority of young patients.</p>

DOI

10.1128/aac.02377-21

Alternate Title

Antimicrob Agents Chemother

PMID

35481751

Title

CMV infection and management among pediatric solid organ transplant recipients.

Year of Publication

2022

Number of Pages

e14220

Date Published

2022 Jan 06

ISSN Number

1399-3046

Abstract

<p><strong>BACKGROUND: </strong>Cytomegalovirus (CMV) is an important cause of morbidity and mortality in pediatric solid organ transplant (SOT) recipients. However, the impact of asymptomatic CMV infections (ie, DNAemia) on clinical outcomes is not well established.</p>

<p><strong>METHODS: </strong>We performed a retrospective cohort study of children undergoing first SOT at our institution from January 2012 to June 2018. We evaluated the epidemiology of CMV infections and performed multivariable Cox regression to assess the association between CMV DNAemia without disease or CMV disease (syndrome or end-organ disease) on negative outcomes (death, re-transplantation, or moderate/severe rejection) within the first year after SOT.</p>

<p><strong>RESULTS: </strong>Among 271 individuals, 43 (15.9%) developed ≥1 CMV infection during the first year after SOT. There were 56 unique CMV infections including 14 episodes of CMV disease. In 167 patients offered CMV prophylaxis, only 8 (4.8%) developed their first CMV DNAemia episode while on prophylaxis 32 developed CMV DNAemia after prophylaxis completion; only 1 episode of CMV disease occurred while on antiviral prophylaxis. When accounting for receipt of ATG, oral steroids, and number of immunosuppressives on a given day, CMV disease was more strongly associated with negative outcomes (Hazard Ratio (HR): 3.28, 95% CI: 0.73-14.64; p&nbsp;=&nbsp;.12) than CMV DNAemia without disease (HR 1.42, 95% CI: 0.19- 10.79; p&nbsp;=&nbsp;.74), although not to a statistically significant degree.</p>

<p><strong>CONCLUSIONS: </strong>Most CMV infections occurred after completion of antiviral prophylaxis. CMV disease was more strongly associated with negative outcomes than asymptomatic CMV DNAemia and should be the focus of CMV prevention practices.</p>

DOI

10.1111/petr.14220

Alternate Title

Pediatr Transplant

PMID

34994041

Title

Live Virus Vaccination Following Pediatric Liver Transplantation: Outcomes from Two Academic Children's Hospital.

Year of Publication

2021

Date Published

2021 Dec 29

ISSN Number

1600-6143

Abstract

<p>Pediatric liver transplant recipients are often transplanted at a young age, precluding them from receiving live virus vaccinations (LVV) such as varicella (VZV) vaccine and measles, mumps and rubella (MMR). This places them at profound risk for vaccine preventable illness. We sought to detail safety of vaccination. This was a retrospective cohort study of pediatric liver transplant recipients at two children's hospitals.&nbsp;Among 204 liver transplant recipients included in the study, 97 received at least one LVV after liver transplant. Six patients who did not receive LVV after transplant had evidence of vaccine-preventable infection following vaccination (1 disseminated VZV disease, 5 VZV-related rash), while one patient who received LVV after transplant developed a diffuse VZV-related rash. Rejection rates were the same between those that did and did not receive a live virus vaccine post-transplant. There were no serious adverse events caused by vaccination post-transplant.&nbsp;Live virus vaccination following liver transplant was safe at our two institutions, although there exist limitations in our study due to its retrospective study design. Larger scale studies should be performed to evaluate the effectiveness of LVV in relation to immunosuppression.</p>

DOI

10.1111/ajt.16937

Alternate Title

Am J Transplant

PMID

34967134

Title

Return to School and COVID-19 Vaccination for Pediatric Solid Organ Transplant Recipients in the United States: Expert Opinion for 2021-2022.

Year of Publication

2021

Date Published

2021 Nov 03

ISSN Number

2048-7207

Abstract

<p>The COVID-19 pandemic continues to generate challenges for pediatric solid organ transplant (SOT) recipients and their families. As rates of COVID-19 fluctuate, new SARS-CoV-2 variants emerge, and adherence to and implementation of mitigation strategies vary from community to community, questions remain about the best and safest practices to prevent COVID-19 in vulnerable patients. Notably, decisions about returning to school remain difficult. We assembled a team of specialists in pediatric infectious diseases, transplant infectious diseases, public health, transplant psychology, and infection prevention and control to re-address concerns about school re-entry, as well as COVID-19 vaccines, for pediatric SOT recipients in the United States in 2021. Based on available literature and guidance from national organizations, we generated expert statements specific to pediatric SOT recipients focused on school attendance in 2021.</p>

DOI

10.1093/jpids/piab098

Alternate Title

J Pediatric Infect Dis Soc

PMID

34734268

Title

Procalcitonin in Pediatric Sepsis: What Is It Good for?

Year of Publication

2021

Author

Date Published

2021 Jul 30

ISSN Number

2048-7207

DOI

10.1093/jpids/piab066

Alternate Title

J Pediatric Infect Dis Soc

PMID

34329449

Title

American College of Rheumatology Guidance for the Management of Pediatric Rheumatic Disease During the COVID-19 Pandemic: Version 2.

Year of Publication

2021

Date Published

2021 Jun 10

ISSN Number

2326-5205

Abstract

<p><strong>OBJECTIVE: </strong>To provide clinical guidance to rheumatology providers who treat children with pediatric rheumatic disease (PRD) in the context of the coronavirus disease 2019 (COVID-19) pandemic.</p>

<p><strong>METHODS: </strong>The task force, consisting of 7 pediatric rheumatologists, 2 pediatric infectious disease physicians, 1 adult rheumatologist, and 1 pediatric nurse practitioner, was convened on May 21, 2020. Clinical questions and subsequent guidance statements were drafted based on a review of the queries posed by the patients as well as the families and healthcare providers of children with PRD. An evidence report was generated and disseminated to task force members to assist with 3 rounds of asynchronous, anonymous voting by email using a modified Delphi approach. Voting was completed using a 9-point numeric scoring system with predefined levels of agreement (categorized as disagreement, uncertainty, or agreement, with median scores of 1-3, 4-6, and 7-9, respectively) and consensus (categorized as low, moderate, or high). To be approved as a guidance statement, median vote ratings were required to fall into the highest tertile for agreement, with either moderate or high levels of consensus.</p>

<p><strong>RESULTS: </strong>To date, 39 guidance statements have been approved by the task force. Those with similar recommendations were combined to form a total of 33 final guidance statements, all of which received median vote ratings within the highest tertile of agreement and were associated with either moderate consensus (n&nbsp;=&nbsp;5) or high consensus (n&nbsp;=&nbsp;28).</p>

<p><strong>CONCLUSION: </strong>These guidance statements have been generated based on review of the available literature, indicating that children with PRD do not appear to be at increased risk for susceptibility to SARS-CoV-2 infection. This guidance is presented as a "living document," recognizing that the literature on COVID-19 is rapidly evolving, with future updates anticipated.</p>

DOI

10.1002/art.41772

Alternate Title

Arthritis Rheumatol

PMID

34114365

Title

Precision dosing of vancomycin: in defence of AUC-guided therapy in children.

Year of Publication

2021

Date Published

2021 Jun 07

ISSN Number

1460-2091

Abstract

<p>In 2020, new vancomycin guidelines were released, recommending the transition from trough-based to AUC24 monitoring for adult and paediatric patients. Given the resources required to achieve this transition, there has been debate about the costs and benefits of AUC24-based monitoring. A recent narrative review of vancomycin therapeutic drug monitoring in paediatrics claims to have uncovered the methodological weaknesses of the data that informed the guidelines and advises against premature adoption of AUC24-guided monitoring. In this article, we present supporting arguments for AUC24-guided monitoring in children, which include that: (i) troughs alone are inadequate surrogates for AUC24; (ii) vancomycin-associated nephrotoxicity has significant consequences that warrant optimization of dosing; (iii) a substantial portion of children receiving vancomycin are at high risk for poor outcomes and deserve targeted monitoring; and (iv) limited efficacy data in support of AUC24 is not a justification to revert to a less supported monitoring approach.</p>

DOI

10.1093/jac/dkab194

Alternate Title

J Antimicrob Chemother

PMID

34096598

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