Impact of Patient-Specific Aminoglycoside Monitoring for Treatment of Pediatric Cystic Fibrosis Pulmonary Exacerbations

Abstract

OBJECTIVE Aminoglycosides are frequently used for empiric and definitive treatment of cystic fibrosis (CF) pulmonary exacerbations. Various methods have been described for aminoglycoside therapeutic drug monitoring. The objective of this study is to evaluate the effect of patient-specific pharmacokinetic calculations for aminoglycosides used to treat CF pulmonary exacerbations. METHODS Ambidirectional cohort study of patients admitted to a children's hospital from June 1, 2018, through February 28, 2019, and June 1, 2019, through February 8, 2021. The primary outcome was the occurrence of dosing changes after analysis of initial serum concentrations in either group. Secondary outcomes included occurrence of nephrotoxicity, duration of antibiotics, and length of stay. RESULTS Twenty-four patients (75%) in the intervention group versus zero in the control group required dosing adjustments after initial analysis of serum concentrations were completed (p < 0.001). There was not a statistically significant between-group difference for duration of antibiotics in days (median, 14 vs 13.5; Z, 1.07; p = 0.29) or length of stay (median, 11 vs 11; Z, −0.31; p = 0.76). There was also not a statistically significant between-group difference in forced expiratory volume in one second (FEV1) change from admission to discharge (11.4% vs 13.9%; t, 0.61; Degrees of Freedom, 39; p = 0.55). Two patients (6.25%) in the intervention group experienced nephrotoxicity compared with zero patients in the control group (risk difference, 6.25%; 95% CI, −2.14 to 14.64; number needed to harm, 16). CONCLUSIONS Patient-specific pharmacokinetic monitoring led to significantly more dosing changes and was associated with similar patient outcomes as trough-only monitoring. Further studies are needed to identify methods to optimize aminoglycoside dosing and monitoring for these patients with the goal of reducing toxicities while maximizing efficacy.

Optimal Therapeutic Drug Monitoring Strategy for IV Aminoglycosides and IV Vancomycin in People with Cystic Fibrosis: A Systematic Review

“…There was no significant difference between groups for change in ppFEV1, antibiotic duration, length of stay, or nephrotoxicity. 20 In the patient-specific PK group, 75% of participants required dose adjustments after initial measurement of serum concentration, whereas none of those in the trough-only group required dose adjustments (p < 0.001); the majority of adjustments involved a decrease in dose interval to avoid a prolonged drug-free interval. 20…”

“…Of the 4030 records identified in the initial search, 1 study 18 met the inclusion criteria (Figure 1); 2 additional studies were identified in the subsequent search. 19,20 The characteristics of included studies are summarized in Table 1.…”

“…Three of the included studies were deemed to be of "good" quality, [19][20][21] and 1 study was deemed to be of "fair" quality. 18…”

“…19 Exploratory analyses of a retrospective review evaluating the impact of aminoglycoside PK exposure on clinical outcomes in pwCF indicated that AUC and Cmax were not associated with FEV1 recovery, and no optimal threshold for either parameter was identified for this outcome. 22 Concerns have been raised about observed increases in P. aeruginosa MIC with extended-interval dosing, po tentially because of the prolonged drug-free interval 18 ; the majority of dose adjustments in the study by Hemmann and others 20 were in order to shorten the drug-free interval, but this did not result in better clinical outcomes. Moreover, antimicrobial sensitivity testing does not reliably predict clinical outcomes in pwCF.…”