Abstract
Objectives
To characterize the incidence of and risk factors for a detectable drug level (DDL) in patients that received inhaled aminoglycoside therapy.
Methods
This retrospective, single-centre study included adult patients who received at least one dose of an inhaled aminoglycoside with a drug level during inpatient hospitalization. Patients were excluded if they received an aminoglycoside intravenously within 7 days or if the drug level was not drawn within 4 h of the next dose. A repeated measures logistic regression model evaluated the association between potential risk factors and a DDL.
Results
Among 286 drug levels, 88 (30.8%) drug levels were detectable. In multivariable analysis, cystic fibrosis (CF) (OR: 3.03; 95% CI: 1.10–8.35), chronic kidney disease (CKD) (OR: 4.25; 95% CI: 1.84–9.83), lung transplant recipient (OR: 3.08; 95% CI: 1.09–8.73), mechanical ventilation (OR: 2.99; 95% CI: 1.25–7.15) and tobramycin (OR: 5.26; 95% CI: 2.35–11.78) were associated with higher odds of a DDL. Among those with a DDL, inhaled aminoglycoside type and drug level concentration were not associated with acute kidney injury (P = 0.161).
Conclusions
Among 286 drug levels identified among inpatients receiving inhaled aminoglycoside therapy, 88 (30.8%) unique drug levels were detectable. Based on the results of this study, periodic trough concentrations should be considered for patients receiving inhaled aminoglycoside therapy with CF, CKD, lung transplantation, mechanical ventilation or tobramycin.
Introduction
Inhaled aminoglycosides may be utilized to treat and prevent pulmonary infection in patients with cystic fibrosis (CF), non-cystic fibrosis bronchiectasis, non-tuberculosis mycobacterial infections or nosocomial pneumonia.1–8 As chronic suppressive therapy in patients with CF, inhaled tobramycin decreases pulmonary exacerbation frequency and hospitalization, reduces concomitant antibiotic use and improves pulmonary function tests.2–4 Based on this literature, clinical practice guidelines support the use of inhaled tobramycin in CF for chronic Pseudomonas aeruginosa pulmonary infection in moderate to severe lung disease.1 As adjunctive treatment for ventilator-associated pneumonia, inhaled tobramycin and amikacin have been associated with higher rates of clinical cure.5 Clinical practice guidelines suggest the combined use of inhaled and systemic antibiotics in patients with ventilator-associated pneumonia caused by aminoglycoside- or colistin-susceptible Gram-negative bacilli, or in patients who are not responding to systemic antibiotics alone, regardless of resistance pattern.6
Advantages of aminoglycosides administered via inhalation include achievement of high concentrations in the lung parenchyma, optimization of concentration-dependent bactericidal killing, and minimization of dose-dependent systemic toxicity when compared with intravenous administration.7–9 Systemic accumulation following inhaled antibiotic therapy has been illustrated in the literature although poorly understood. 10–16 Numerous cases of nephrotoxicity, ototoxicity and systemic accumulation defined by detectable drug levels (DDLs), have been reported. The objectives of this study were to describe the incidence of, and risk factors for, a DDL among patients receiving inhaled aminoglycoside therapy.
Methods
This single-centre, retrospective cohort analysis was conducted at a quaternary care academic medical centre. The protocol was reviewed and approved by the Institutional Review Board prior to study conduct. Patients were included if they were 18 years of age or older and received at least one dose of inhaled amikacin or inhaled tobramycin with a drug level during inpatient hospitalization between 1 June 2013 and 1 July 2020. Patients were excluded if an intravenous aminoglycoside was administered within 7 days prior to the drug level or if the drug level was not drawn within 4 h prior to the next dose.
Study patients were administered inhaled aminoglycoside therapy through one of two delivery mechanisms depending on airway status at the time of treatment. Patients without an artificial airway received aerosolized aminoglycoside therapy via small-volume nebulizer. Various commercially available nebulizers were utilized over the study period. Patients requiring mechanical ventilation received aminoglycoside therapy using the Aerogen Vibronic® vibrating mesh nebulizer per departmental protocol. Treatment preparations included tobramycin 300 mg/5 mL (TOBI®) inhalation solution and parenteral amikacin 500 mg/2 mL diluted in 3 mL 0.9% sodium chloride. Aminoglycoside drug levels were drawn at provider or pharmacist discretion.
Patients were identified via query of two data repositories. Individual patient data were collected through retrospective review of the electronic health record including age, gender, race and BMI. Pertinent comorbidities including CF, lung transplant recipient and end-stage renal disease were gathered from the hospital admission history and physical exam note. SOFA score was calculated using the worst value 24 h prior to the drug level.17 Hospital and intensive care unit length of stay (LOS), inpatient duration of inhaled aminoglycoside treatment, aminoglycoside dose, administration times and drug level timing were also collected. Drug delivery method used within 24 h prior to the drug concentration was characterized as nebulization without positive pressure ventilation, nebulization with mechanical ventilation, nebulization via tracheostomy, and nebulization via tracheostomy with mechanical ventilation. Concomitant nephrotoxic medications administered within 5 days before and after the aminoglycoside drug level were also collected (Appendix A).18
Clinical evaluation and definitions
A standard dose was defined as tobramycin 300 mg inhaled twice daily or amikacin 500 mg inhaled twice daily. Doses of lower strength or decreased frequency were characterized as a reduced dose. Baseline serum creatinine (SCr) was defined as the most recent value prior to initiation of inhaled therapy. Baseline estimated glomerular filtration rate (eGFR) was calculated via the electronic health record using the most recent basic metabolic panel prior to initiation of inhaled therapy. Acute kidney injury was based on the respective SCr cutoffs for KDIGO definition Stage 1 (an increase in SCr by 1.5 × baseline or an increase of ≥0.3 mg/dL from baseline), Stage 2 (increase in SCr by 2 × baseline) and Stage 3 [increase in SCr by 3 × baseline or initiation of renal replacement therapy (RRT)], without the inclusion of urine output as these data were not readily available for collection.19 Peak SCr within 7 days preceding drug level was compared with baseline SCr to assess for acute kidney injury (AKI) prior to drug level. Peak SCr within 7 days following a drug level was compared with baseline SCr to assess for AKI following a DDL. Chronic kidney disease (CKD) was defined as an eGFR <60 mL/min.20 Ototoxicity was defined as provider documentation of ototoxicity in the medical record attributed to inhaled aminoglycoside therapy. Screening for hearing impairment was initiated at provider discretion; routine hearing screens were not conducted during the study period.
The primary objective of this study was to describe the incidence of DDL among patients receiving inhaled aminoglycoside therapy. Serum drug levels were considered detectable for tobramycin ≥0.5 mcg/mL or amikacin ≥1.5 mcg/mL. Secondary objectives were to identify risk factors associated with a DDL, compare the incidence of AKI and ototoxicity among patients with and without a DDL, and to determine the impact of aminoglycoside type, amikacin or tobramycin, or DDL concentration on the development of AKI.
Statistical analysis
Patients with a DDL were compared with patients with an undetectable level for patient-level characteristics. Individual drug levels were compared for drug-level characteristics. Patient-level continuous variables were summarized using median with 25th and 75th percentiles [quartile 1 (Q1) to quartile 3 (Q3)] and compared using the Wilcoxon rank-sum test. Categorical variables were summarized using frequencies and percentages and compared using the chi-square test. Drug level characteristics were assessed using repeated measures univariable logistic regression model to account for correlation. ORs and corresponding 95% CIs were reported.
Multivariable logistic regression was used to examine risk factors associated with a DDL. Explanatory variables, selected a priori, included age, BMI, SOFA score, presence of active pulmonary infection, CF, CKD, AKI prior to drug level, lung transplant recipient, mechanical ventilation, tobramycin versus amikacin, duration of therapy (days) and drug level timing in relation to next dose (hours). Backward selection of the main effects occurred first, based on the Akaike information criterion, followed by forward selection of interaction terms of inhaled aminoglycoside and the remaining main effects. Age, SOFA score, CKD and inhaled aminoglycoside were selected as required variables for the model and were ineligible for selection out of the model. Variables in the final model included age, SOFA score, CF, CKD, AKI prior to drug level, lung transplant recipient, mechanical ventilation and inhaled aminoglycoside.
To evaluate the relationship of AKI or ototoxicity with an inhaled aminoglycoside, tobramycin or amikacin, and drug concentration among DDLs, a repeated measures logistic regression model was assessed, with the interaction between these two characteristics as the variable of interest. All analyses were performed with SAS software version 9.4 (SAS Institute, Cary, NC). Statistical significance was set at a P value <0.05 unless otherwise indicated. No adjustments were made for multiple testing as the analysis is hypothesis generating.
Results
A total of 194 unique patients with 286 drug levels were included in the study (Figure 1). Baseline characteristics were similar among patients with and without detectable aminoglycoside drug levels (Table 1). Of the 73 patients with a DDL, 9 (12.3%) patients had two, and 3 (4.1%) patients had three detectable levels. Of DDLs, the median detectable serum concentration was 0.8 mcg/mL (Q1–Q3: 0.6–1.1) for inhaled tobramycin and 2.7 mcg/mL (Q1–Q3: 2–3.1) for inhaled amikacin. The majority of included patients were recipients of a lung transplant (87.1%). Median serum drug level time was 2.3 h (Q1–Q3: 1.6–2.9) prior to the next dose in the total cohort; 2.3 h (Q1–Q3: 1.6–2.8) with a DDL versus 2.2 h (Q1–Q3: 1.7–3) with an undetectable level. In univariable analysis, DDLs were more common among patients with reduced renal function at baseline, AKI prior to drug level, ICU status at the time of the drug level, higher SOFA score, mechanical ventilation or among patients receiving tobramycin (Table 2).
Figure 1.
Drug level selection.
Table 1.
Baseline characteristics at patient level
| Detectable drug level (n = 73) |
Undetectable drug level (n = 121) |
Total (N = 194) |
P value | |
|---|---|---|---|---|
| Age on admission, years | 49 (31–64) | 46 (30–65) | 47.5 (31–64) | 0.741 |
| Female gender | 35 (47.9%) | 54 (44.6%) | 89 (45.9%) | 0.653 |
| Race | 0.562 | |||
| ȃMissing | 0 | 2 | 2 | |
| ȃCaucasian | 64 (87.7%) | 97 (81.5%) | 161 (83.9%) | |
| ȃAfrican American | 7 (9.6%) | 16 (13.4%) | 23 (12.0%) | |
| ȃAsian | 0 (0.0%) | 2 (1.7%) | 2 (1.0%) | |
| ȃOther | 2 (2.7%) | 4 (3.4%) | 6 (3.1%) | |
| BMI on admission, kg/m2 | 19.7 (17.7–24.5) | 21.7 (19.0–24.8) | 21.2 (18.5–24.8) | 0.067 |
| BMI category, kg/m2 | 0.127 | |||
| ȃ<18.5 | 24 (32.9%) | 23 (19.0%) | 47 (24.2%) | |
| ȃ18.5–24.9 | 31 (42.5%) | 68 (56.2%) | 99 (51.0%) | |
| ȃ25–29.9 | 11 (15.1%) | 21 (17.4%) | 32 (16.5%) | |
| ȃ≥30 | 7 (9.6%) | 9 (7.4%) | 16 (8.2%) | |
| Past medical history | ||||
| ȃCystic fibrosis | 34 (46.6%) | 47 (38.8%) | 81 (41.8%) | 0.290 |
| ȃLung transplant | 66 (90.4%) | 103 (85.1%) | 169 (87.1%) | 0.287 |
| ȃEnd-stage renal disease | 0 | 0 | 0 | — |
Data are reported as median (IQR) or n (%).
Table 2.
Baseline characteristics at drug level
| Detectable drug level (n = 88) |
Undetectable drug level (n = 198) |
Total (N = 286) |
P value | |
|---|---|---|---|---|
| Baseline renal function | 0.001 | |||
| ȃGFR ≥60 mL/min | 20 (22.7%) | 95 (48.0%) | 115 (40.2%) | |
| ȃGFR <60 mL/min | 40 (45.5%) | 68 (34.3%) | 108 (37.8%) | |
| ȃRRT | 28 (31.8%) | 35 (17.7%) | 63 (22.0%) | |
| SOFA score | 4 (1.5–7) | 2 (1–4) | 2 (1–5) | <0.001 |
| Active treatment of pneumonia | 55 (62.5%) | 127 (64.1%) | 182 (63.6%) | 0.784 |
| Number of nephrotoxins | 0.653 | |||
| ȃ0 | 8 (9.1%) | 26 (13.1%) | 34 (11.9%) | |
| ȃ1 | 73 (83.0%) | 156 (78.8%) | 229 (80.1%) | |
| ȃ2 | 7 (8.0%) | 16 (8.1%) | 23 (8.0%) | |
| ICU status at time of drug level | 39 (44.3%) | 54 (27.3%) | 93 (32.5%) | 0.007 |
| Inhaled aminoglycoside | <0.001 | |||
| ȃAmikacin | 17 (19.3%) | 95 (48.0%) | 112 (39.2%) | |
| ȃTobramycin | 71 (80.7%) | 103 (52.0%) | 174 (60.8%) | |
| Inhaled aminoglycoside dose | 0.065 | |||
| ȃReduced | 13 (14.8%) | 49 (24.7%) | 62 (21.7%) | |
| ȃStandard | 75 (85.2%) | 149 (75.3%) | 224 (78.3%) | |
| Aminoglycoside delivery | 0.001 | |||
| ȃNebulized | 42 (47.7%) | 132 (66.7%) | 174 (60.8%) | |
| ȃNebulized via ventilator | 15 (17.0%) | 6 (3.0%) | 21 (7.3%) | |
| ȃNebulized via tracheostomy on ventilator | 31 (35.2%) | 60 (30.3%) | 91 (31.8%) | |
| Mechanical ventilation | 46 (52.3%) | 66 (33.3%) | 112 (39.2%) | 0.004 |
| Duration of therapy prior to level, days | 5 (3–18.5) | 9 (4–19) | 9 (3–19) | 0.937 |
| ICU LOS prior to drug level, days | 9 (3–41) | 30 (8–53) | 21 (5–48) | 0.219 |
| AKI prior to drug level | 0.012 | |||
| ȃNo AKI | 26 (29.5%) | 92 (46.5%) | 118 (41.3%) | |
| ȃStage 1 | 25 (28.4%) | 44 (22.2%) | 69 (24.1%) | |
| ȃStage 2 | 7 (8.0%) | 25 (12.6%) | 32 (11.2%) | |
| ȃStage 3 | 30 (34.1%) | 37 (18.7%) | 67 (23.4%) |
Data are reported as median (IQR) or n (%). GFR, glomerular filtration rate.
Among 286 drug levels identified in the study population, 88 (30.8%) unique drug levels were detectable. Patients with a DDL had a longer median hospital LOS compared with patients with an undetectable level (38 days versus 21 days; P = 0.049). Median ICU LOS was not significantly different among patients with a DDL compared with those with an undetectable level (36 days versus 28 days; P = 0.205). In multivariable repeated measures logistic regression analysis, CF (OR: 3.03; 95% CI: 1.10–8.35), CKD (OR: 4.25; 95% CI: 1.84–9.83), lung transplant recipient (OR: 3.08; 95% CI: 1.09–8.73), mechanical ventilation (OR: 2.99; 95% CI: 1.25–7.15) and tobramycin (OR: 5.26; 95% CI: 2.35–11.7) were associated with higher odds of a DDL after controlling for other factors (Figure 2). Whereas AKI prior to drug level overall was associated with a DDL (P = 0.048), the comparisons of no AKI (reference) with Stage 1 (OR: 2.34; 95% CI: 1.04–5.26), Stage 2 (OR: 1.82; 95% CI: 0.52–6.36) and Stage 3 (OR: 0.55; 95% CI: 0.19–1.60) AKI prior to the drug level were not associated with a DDL after adjustment for multiple pairwise comparisons using Dunnett’s post hoc test. Stage 3 AKI prior to drug level consisted primarily of patients receiving renal replacement therapy: 23 (34.3%) patients received intermittent haemodialysis at the time of drug level, and 40 (59.7%) patients received continuous renal replacement therapy (CRRT) at the time of drug level.
Figure 2.
Risk factors associated with a detectable drug level in patients receiving inhaled aminoglycoside therapy. This figure appears in colour in the online version of JAC and in black and white in the print version of JAC.
Among DDLs, the interaction between inhaled aminoglycoside serum drug concentration, as a continuous variable, was not associated with AKI following a drug level (P = 0.161), nor were the individual effects of aminoglycoside type, tobramycin or amikacin (P = 0.157), and drug concentration (P = 0.152). Among drug levels obtained for patients who were not receiving RRT (n = 221), AKI occurred following 103 (46.6%) drug levels: 34 patients (33.0%) with a DDL and 69 (67.0%) with an undetectable level. Ototoxicity occurred across 13 levels (4.5%); 3 (3.4%) with a DDL and 10 (5.1%) with an undetectable level. Analysis of ototoxicity and inhaled aminoglycoside type, tobramycin or amikacin, or drug concentration was not performed due to the low event rate.
Detectable systemic concentrations following inhaled therapy influenced therapeutic modification for 63 (71.6%) DDLs including 51 (81%) frequency reductions, 12 (19%) therapeutic discontinuations and 10 (15.9%) dose reductions. Two patients receiving inhaled amikacin 500 mg twice daily had amikacin serum levels of 15.1 and 5.1 mcg/mL, representing a 10-fold and 3-fold increase, respectively, over the DDL threshold for amikacin. Both patients experienced AKI prior to the DDL and were receiving mechanical ventilation. A third patient receiving inhaled tobramycin 300 mg twice daily on mechanical ventilation and CRRT was found to have a tobramycin level of 5.1 mcg/mL, representing a 10-fold increase above the DDL threshold for tobramycin.
Discussion
In this analysis of inpatients receiving inhaled aminoglycoside therapy, DDLs were common. Cystic fibrosis, CKD, lung transplantation, mechanical ventilation and tobramycin were associated with higher odds of a DDL. Patients with CKD demonstrated 4.25 times higher odds of a DDL compared with patients without CKD. Stage 1 AKI was associated with 2.34 times higher odds of a DDL, further supporting recommendations for therapeutic drug monitoring in the setting of impaired renal function.
Despite limited evidence, a consensus summary suggests routine monitoring of aminoglycoside trough levels to mitigate the risk of adverse drug events during inhaled therapy if systemic accumulation is suspected, particularly in renal dysfunction.1 Although case reports of nephrotoxicity and ototoxicity have been associated with inhaled administration, no clear correlation exists between the severity of toxicity and serum concentration.10–16 Cannella and Wilkinson10 described a patient with irreversible end-stage renal disease potentially due to accumulation of tobramycin with a serum concentration of 0.7 mcg/mL. Patatanian16 reported a case of bilateral profound sensorineural hearing impairment and accumulation of tobramycin with a serum concentration of 12.4 mcg/mL. Both patients received tobramycin 300 mg inhaled twice a day via nebulizer while receiving mechanical ventilation. In this analysis, serum trough concentrations were observed as high as 15.1 mcg/mL. Ototoxicity was documented in 13 patients; however, a lack of routine screening may have contributed to under-reporting. Inhaled aminoglycoside therapy was modified in a large subset of patients (71.6%) with a DDL; yet, neither inhaled aminoglycoside type nor drug concentration of the DDL was associated with AKI.
Lung deposition for inhaled antibiotics is estimated at approximately 30% to 60% of the antibiotic dose deposited in the nebulizer; however, numerous factors may affect deposition, delivery and systemic absorption.21–27 Experimental studies have demonstrated that aerosol delivery is influenced by nebulizer type, mechanical ventilation and heat or humidified inspiratory gas.22 A prospective, open-label study demonstrated negligible systemic absorption, defined as a trough concentration <0.8 mg/L, following inhaled tobramycin 300 mg twice daily via endotracheal or tracheostomy tube in nine hospitalized patients.25 In this study, the odds of a DDL were 2.99 times higher in patients receiving mechanical ventilation. Systemic accumulation of inhaled aminoglycosides may be more likely during mechanical ventilation for several reasons, including alterations in lung physiology, organ dysfunction leading to reduced clearance, a higher severity of illness and more effective aerosol delivery.9,21–24,26 Additionally, vibrating mesh nebulizers, which were utilized during the study period for patients receiving mechanical ventilation, are more efficient in their ability to generate consistent particle size compared with jet nebulizers.8 Additionally, damaged lung tissue may increase the probability of detectable systemic concentrations.21 In animal models representing acute pulmonary infection, lung physiology and stage of infection may affect permeability and absorption.23 In addition to impaired renal function, routine drug monitoring should also be considered in targeted populations including patients receiving mechanical ventilation, CF patients or lung transplant recipients.
Limitations of this study include those inherent to a retrospective single-centre design. Variations in drug delivery including humidity, rate of bias flow, nebulizer type and ventilator compliance could not be accounted for retrospectively. Additionally, drug monitoring was conducted at the discretion of the provider or pharmacist lending to potential selection bias. Strengths of this study include the broad inclusion criteria and pragmatic design, which increase generalizability to current clinical practice. This analysis contributes to the existing literature, comprised primarily of case reports, and lends insight into current therapeutic drug monitoring practices with inhaled aminoglycoside therapy. Future trials with protocolized therapeutic drug monitoring and clinical outcomes associated with dose adjustments are needed for patients receiving inhaled aminoglycoside therapy.
In our analysis, 88 (30.8%) unique drug levels were detectable suggesting systemic accumulation with inhaled aminoglycosides. Based on the results of this study, periodic trough concentrations should be considered for patients receiving inhaled aminoglycoside therapy with CF, CKD, lung transplant recipients, mechanical ventilation or tobramycin, or whenever potential toxicity such as ototoxicity or AKI is suspected.
Contributor Information
Jennifer M Schultheis, Department of Pharmacy, Duke University Hospital, Durham, NC, USA.
Mary E Durham, Department of Pharmacy, Premier Inc., Charlotte, NC, USA.
Shawn J Kram, Department of Pharmacy, Duke University Hospital, Durham, NC, USA.
Michelle Kuhrt, Department of Pharmacy, Duke University Hospital, Durham, NC, USA.
Daniel L Gilstrap, Department of Pulmonary, Allergy, and Critical Care Medicine, Duke University Hospital, Durham, NC, USA.
Alice Parish, Department of Biostatistics & Bioinformatics, Duke University School of Medicine, Durham, NC, USA.
Cynthia L Green, Department of Biostatistics & Bioinformatics, Duke University School of Medicine, Durham, NC, USA.
Bridgette L Kram, Department of Pharmacy, Duke University Hospital, Durham, NC, USA.
Funding
We acknowledge support from the Biostatistics, Epidemiology and Research Design (BERD) Methods Core funded through Grant Award Number UL1TR002553 from the National Center for Advancing Translational Sciences (NCATS), a component of the NIH. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.
Transparency declarations
The authors of this manuscript have nothing to disclose concerning possible financial or personal relationships with commercial entities that may have a direct or indirect interest in the subject matter.
Appendix A
Concomitant nephrotoxic medications within 5 days before and 5 days after drug level
| Cyclosporine | Sulphonamide antibiotics |
| Tacrolimus | Amphotericin B |
| Nonsteroidal anti-inflammatory drugs | Vancomycin |
| Loop diuretics | Aciclovir |
| Tenofovir disoproxil fumarate | Foscarnet |
| Angiotensin receptor blockers | Radiocontrast agents |
| Angiotensin-converting enzyme inhibitors |
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