A comparison of aminoglycoside antibiotic serum... : Pediatric Pulmonology (2025)

CBC: complete blood countCF: cystic fibrosisCI: confidence intervalCVC: central venous catheterFEV1: forced expiratory volume in 1 sHPLC: high performance liquid chromatographyPICC: peripherally inserted central catheterPV: peripheral venipuncturePwCF: people with cystic fibrosisSD: standard deviation

1 INTRODUCTION

People with cystic fibrosis (PwCF) frequently require hospitalization for treatment of a pulmonary exacerbation. In 2021, 19% of people in the CF patient registry were treated with intravenous antibiotics for a pulmonary exacerbation. Pulmonary exacerbations have greatly decreased due the innovation of CFTR modulators such as elexacaftor‐tezacaftor‐ivacaftor in 2019. The isolation precautions put in place during the SARS‐CoV‐2 pandemic also likely decreased the spread of respiratory pathogens and decreased the rate of exacerbation further. Although the latest innovations have decreased rates of exacerbations, there are many individuals who continue to have frequent exacerbations and hospitalizations. This could be due to multiple factors, such as genetic ineligibility to take a modulator, modulator intolerance, or severe lung disease., Ongoing efforts to reduce discomfort are needed to improve quality of life for these individuals.

In PwCF, the most common pathogen identified in the airways is Pseudomonas aeruginosa. United States Cystic Fibrosis Foundation (CFF) Pulmonary Guidelines recommend treatment of a pulmonary exacerbation due to Pseudomonas aeruginosa with two or more intravenous anti‐pseudomonal antibiotics. Over 94% of CFF‐Accredited Care Centers report use of aminoglycosides in their anti‐pseudomonal regimen based on recent surveys. Therapeutic drug monitoring (TDM) optimizes the safety and efficacy of anti‐pseudomonal antibiotics in PwCF treated for a pulmonary exacerbation. A common standard of practice across United States institutions is to collect serum intravenous aminoglycoside levels by peripheral venipuncture (PV). Some centers use a peripherally inserted central catheter (PICC) for therapy administration and non‐TDM laboratory monitoring such as blood chemistry. However, there are concerns that intravenous antipseudomonal antibiotic serum levels may be falsely elevated when collected directly through a PICC., Recent studies have demonstrated substantial agreement in intravenous anti‐pseudomonal antibiotic serum levels when collected by PV vs PICC in pediatric PwCF, suggesting that TDM by PICC may be acceptable., , Serum levels obtained by PV can cause pain, and patient dissatisfaction in both children and adults., , , In addition, many patients are difficult to access peripherally. The accuracy of intravenous anti‐pseudomonal antibiotic serum levels collected by PICC has not been documented in adult PwCF.

The University of Utah Adult Cystic Fibrosis Center serves approximately 420 patients throughout a five‐state region and admitted 150 PwCF yearly before 2019 for CF pulmonary exacerbation treatment. Two years after elexacaftor‐tezacaftor‐ivacaftor became available and during the height of the SARS‐CoV‐2 pandemic, the number of patients admitted at least once in 2022 dropped to 72, with 56 of these patients requiring at least one additional admission. Each hospital admission had an average length of stay of 14 days. Tobramycin continues to be used as an agent in approximately 60% of the therapy plans. Our institution uses high dose, extended interval dosing which requires TDM. During the average length of stay of 14 days, PwCF complete TDM on day 2 and day 7 of admission.

Institutional standard of care is to collect serum intravenous anti‐pseudomonal antibiotic concentrations by peripheral venipuncture (PV). The primary objective of this study was to evaluate the difference between intravenous tobramycin steady‐state serum levels collected by PV vs PICC in adult PwCF admitted to University of Utah Health for the treatment of a pulmonary exacerbation.

2 METHODS

All procedures were approved and conducted in accordance with the ethical standards of the University of Utah Institutional Review Board. The authors considered PwCF for enrollment who were admitted to University of Utah Adult Cystic Fibrosis Center for a pulmonary exacerbation between January 12, 2018 and January 7, 2019. Patient characteristics and clinical outcomes were collected by manual chart review. The authors included patients who were 18 years or older, had a functional single lumen PICC, and were prescribed tobramycin as part of their antipseudomonal inpatient exacerbation treatment regimen. Patients who received a double lumen PICC were excluded from the study due to the infrequency of use at our center. Many frequently admitted patients have difficulty with PV access, therefore the authors excluded patients who would not be able to provide a sample by PV. The authors did not allow patients to re‐enroll in the study if they were readmitted during the study period time in an effort to reduce bias and increase diversity of the patient characteristics included. See Table 1 for a list of all study exclusions. A study investigator or coinvestigator screened all PwCF admitted for pulmonary exacerbation. Patients meeting inclusion criteria were approached for enrollment and informed consent was obtained before Day 7 of admission.

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The standard of care for TDM monitoring at this institution requires one tobramycin peak and one random tobramycin level be collected by PV on Days 2 and 7 of admission. To enable study of matched serum samples obtained via PV and PICC, one tobramycin steady‐state serum sample was collected by PV while another sample was collected simultaneously by PICC on Day 7 of admission. Day 7 was selected for comparison rather than Day 2 to allow more time for study enrollment. Nurses collected PV samples at the same time as PICC samples according to a specific flush volume‐based flush and waste protocol (Table 2). No more than 5 min were allowed between the two types of samples. Tobramycin peak levels were collected 3 h after the start of tobramycin infusion, and random levels were collected 8 h after the start of tobramycin infusion. The authors trained nurses assigned to enrolled patients regarding the study procedures. The specific intra‐assay variability of the tobramycin assay used at University of Utah is <10% or 0.1 mcg/mL.

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2.1 Statistical analysis

Before starting enrollment, a power calculation was completed using the results from the prospective study by Green and colleagues, modified by local clinical expertize. Based on sample size calculations, the authors estimated that matched samples from 16 patients would provide the study with 80% power to detect a difference between PV versus PICC concentration at an alpha of 0.01, assuming a standard deviation of 10. The author aimed to enroll a total of 25 patients to allow for attrition. Statistical significance was set at p < .01.

Descriptive statistics were used to report the study sample's baseline demographic and clinical characteristics including mean (plus standard deviation) and median (plus interquartile range. A Wilcoxon signed‐rank test for paired samples was used to compare the tobramycin peak and random levels collected by PV and PICC. A correlation coefficient was calculated to measure association between PV and PICC samples. The authors conducted a sensitivity analysis to exclude the effect of the one patient without a size 3 French PICC. Data were analyzed in SAS v9.4 (SAS Institute), Stata 16 (StataCorp), and R Studio v1.2.5033 (RStudio, Inc.).

3 RESULTS

The authors screened and enrolled a total of 25 patients in this study. Screening was completed after an independent decision was made that the patient had a pulmonary exacerbation requiring hospital admission. The authors included samples from 19 patients (76%) in the final analysis. Four patients were excluded due to sample loss during handling; one patient was excluded due to deviation in the protocol when the TDM assays were ordered incorrectly; and one patient was excluded due to erroneous results caused by laboratory error.

Baseline characteristics are outlined in Table 3. Of those included in the final analysis, the median age (IQR) was 29 years (11.5), the majority were male (57.9%), and all patients were Non‐Hispanic and white. The admission forced expiratory volume in 1 s (FEV1) (percent predicted) ranged from 28% to 105%. The majority of patients received concomitant anti‐pseudomonal beta‐lactam therapy with either meropenem (36.8%) or ceftazidime (36.8%). All but one patient received a size 3 French PICC. The mean tobramycin peak collected by PV (27.2 mcg/mL ± 6.1) was similar to the mean peak collected by PICC (26.9 mcg/mL ± 5.9, p = .94 [see Table 4]). The correlation coefficient was 0.88 (95% CI = 0.85–0.91, p < .001). Figures 1 and 2 illustrate the relationship between PICC and PV values collected. When the patient without a size 3 French PICC was excluded, there was no change in the absence of a statistically significant difference between the groups.

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4 DISCUSSION

The authors found similar intravenous tobramycin serum levels collected simultaneously by PV and PICC in adult PwCF. The findings of this study disagree with previously published literature suggesting that serum levels collected by PICC in PwCF may be falsely elevated.

There are limited previous studies examining the relationship between aminoglycoside levels collected by PV and levels collected by PICC or single lumen port. Boodhan and colleagues compared gentamicin levels collected by PV and single lumen port in pediatric patients and found significant disagreement. However, the study did not define what volume was used for a saline flush, and the levels were collected by a port as opposed to a PICC. Mcbeth and colleagues compared tobramycin levels drawn by PV or central venous catheter (CVC) in pediatric PwCF and found significant disagreement. Notably, only 10 (12%) of paired samples in the CVC analysis were collected by a PICC, with the remaining collected by port or other. Neither of these studies addressed the question of PICC vs PV agreement in adults, was designed to analyze PICC vs PV samples specifically, or outlined a reproducible flush and waste protocol.

Green and colleagues found a statistically but not clinically significant difference in PV versus PICC levels in pediatric patients receiving IV tobramycin. The mean PV tobramycin peak level was noted to be 28.4 mcg/mL, which was higher than the mean PICC tobramycin peak level at 24.9 mcg/mL (p < .001). The authors report that the differences found between PV and PICC levels would not have resulted in alternate dosing. As a result of their findings, the institution changed standard of care from PV to PICC collection for tobramycin levels.

To address previous study limitations, we followed a specific reproducible volume‐based flush and waste protocol for levels collected by PICC and focused on samples collected exclusively by PICC to prevent the inclusion of other CVC modalities, thus ensuring methodological consistency and minimizing the risk of bias. These key elements of the study design address the limitations noted in prior works. Our results suggest that collection of tobramycin serum levels by PICC may be equivalent to PV. Additional multicenter studies are needed to confirm these results and demonstrate that the alternative method is comparable in safety regarding tobramycin related adverse events.

The implication of data studying the methodology of drawing serum drug concentrations directly impacts patient comfort. Distress from peripheral venipuncture is a public health issue that seldom receives attention in the adult population. A systematic review and meta‐analysis found that 20% to 30% of young adults experience needle fear. In a general practice survey by Wright and colleagues, the authors found that 20.5% of patients reporting needle phobia avoided medical care as a result. The need for multiple venipunctures throughout life increases the chance for associated traumatic experiences. This cycle of negative conditioning is hypothesized to result in generalized, associated fear for healthcare settings and procedures overtime. Therefore, minimization of unnecessary venipunctures should be prioritized for patients with high frequency of healthcare exposure such as PwCF. Our study suggests that collecting tobramycin levels by PICC rather than peripheral venipuncture may be one way to improve the healthcare experience for these patients.

This study adds to the body of literature supporting potential use of serum samples collected by PICC rather than PV when coupled with a specific flush and waste protocol. The authors found similar tobramycin levels collected by PV vs PICC. The results support further need for larger studies to evaluate PICC rather than PV sampling for tobramycin to avoid harm by systematically reducing venipunctures.

There are limitations to this study. First, the authors met thesample size goal of at least 16 with a total of 19 study participants, but the attrition from initial enrollment was large suggesting that tobramycin level measurements timed to facilitate pharmacokinetics remain challenging. Based on the baseline characteristics of our cohort, the authors believe that the patients included in this study are representative of other patients cared for at our center, however, a multi‐center approach would increase generalizability of this study. A bootstrapping analysis based on the data obtained in this study concluded that a much larger sample size (over 200 patients) would be needed to show a significant difference between the collection methods. However, the clinical significance of such a study, namely, whether dosing adjusted by one method or the other is superior in terms of treatment outcomes or adverse reactions, cannot be predicted with confidence. Second, measurement error inherent in the High Performance Liquid Chromatography tobramycin assay that the authors used in this study is <10% or 0.1 mcg/mL. Variation with different methods or within different laboratories could affect the ability to detect meaningful differences between PV and PICC levels and modify the portability of our findings. Nevertheless, measurement error should not change because of sample origins as long as there is sufficient care taken with the pre‐sample flushing protocol. Another limitation of the study is the additional blood loss required for PICC collection due to the sample waste procedure. The authors recognize that the required waste of blood equal to 5 mL may not be reasonable in certain patient populations. Lastly, the findings of this study are limited to tobramycin. There is no clear basis that allows extrapolation of these findings to amikacin or other anti‐pseudomonal antibiotics due to the inter‐assay variability and pharmacokinetic differences between antibiotics.

5 CONCLUSION

In this study comparing PV vs PICC samples of tobramycin steady state levels, there was similarity in the samples between collection modalities. This finding adds to existing literature to support the use of PICC for lab sampling. However, this study is limited by the small sample size. An additional, multi‐center study with a larger sample size will help to reinforce the results that this study found and allow for increased generalizability.

AUTHOR CONTRIBUTIONS

Sabrina J. Sherwood: Conceptualization; investigation; writing–original draft; methodology; writing–review and editing; project administration. Casey Tak: Methodology; software; formal analysis; data curation; writing–review and editing; validation; conceptualization. Zubin N. Bhakta: Investigation; writing–review and editing; conceptualization; methodology. Kristyn Packer: Writing–review and editing; investigation; conceptualization; funding acquisition; methodology; project administration. Hollyann Jacobs: Conceptualization; investigation; methodology; writing–review and editing; writing–original draft. Theodore G. Liou: Writing–original draft; conceptualization; writing–review and editing; investigation; funding acquisition; methodology; validation; visualization; formal analysis; project administration; supervision; data curation. David C. Young: Conceptualization; investigation; writing–original draft; funding acquisition; methodology; validation; visualization; writing–review and editing; formal analysis; supervision; data curation; project administration; resources.

CONFLICT OF INTEREST STATEMENT

The authors declare no conflicts of interest.

ETHICS STATEMENT

All procedures were approved and conducted in accordance with the ethical standards of the University of Utah Institutional Review Board.

ACKNOWLEDGMENTS

Sabrina Sherwood performed this study as an employee of University of Utah Health during the study period. This study was supported in part by the CF Foundation (CC132‐16AD), the Ben B and Iris M Margolis Foundation of Utah and the Claudia Ruth Goodrich Stevens Endowment Fund. Theodore G Liou received other support from the CF Foundation (LIOU13A0, LIOU14Y4, Liou 14Y0, Liou 14P0), the National Heart Lung and Blood Institute (NHLBI) of the National Institutes of Health (NIH) (R01 HL125520) and received support during the current study for performing clinical trials from Abbvie, Calithera Biosciences, Corbus Pharmaceuticals, Gilead Sciences, Laurent Pharmaceuticals, Nivalis Therapeutics, Novartis, Proteostasis, Savara Pharmaceuticals, Translate Bio and Vertex Pharmaceuticals.

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