- Email: [email protected]
Pharmacokinetics of Continuous Infusion Beta-lactams in the Treatment of Acute Pulmonary Exacerbations in Adult Patients With Cystic Fibrosis
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Pharmacokinetics of Continuous Infusion Beta-lactams in the Treatment of Acute Pulmonary Exacerbations in Adult Patients With Cystic Fibrosis
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Lisa T. Hong, PharmD, BCPS; Theodore G. Liou, MD; Rishi Deka, MS; Jordan B. King, PharmD, MS;
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Vanessa Stevens, PhD; and David C. Young, PharmD
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Several clinical trials have shown the efficacy of continuous infusion betalactam (BL) antibiotics in patients with cystic fibrosis (CF); however, little is known about pharmacokinetic changes during the treatment of an acute pulmonary exacerbation (APE). Identifying and understanding these changes may assist in optimizing antibiotic dosing during APE treatment.
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This study was a retrospective cohort study of 162 adult patients with CF admitted to the University of Utah Hospital between January 1, 2008, and May 15, 2014, for treatment of an APE with both a continuous infusion BL and IV tobramycin. We extracted the administered doses of continuous infusion BLs and tobramycin along with serum drug concentrations and calculated medication clearance rates. The primary outcome was change in clearance rates of continuous infusion BLs between day 2 and day 7 of APE treatment.
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The BL clearance rate increased 20.7% (95% CI, 11.42 to 32.49; P < .001), whereas the tobramycin clearance rate decreased 6.3% (95% CI, –12.29 to –4.45; P < .001). The mean percent predicted FEV1 increased between admission and discharge by 12.2% (95% CI, –13.81 to –10.55; P < .001).
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CONCLUSIONS:
BACKGROUND:
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METHODS:
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RESULTS:
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Clinicians should monitor BL levels along with aminoglycoside levels and make dose adjustments to maximize the chance of optimal antibiotic treatment. Continuous infusion BL and tobramycin clearance can change dramatically during the treatment of an APE, which may necessitate significant changes in dosing to achieve optimal antibiotic levels. Clearance rates of these antibiotics may change in opposite directions, requiring specific monitoring of each medication. CHEST 2018; -(-):---
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KEY WORDS:
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antibiotic therapy; cystic fibrosis; pharmacokinetics
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ABBREVIATIONS:
AMG = aminoglycoside; APE = acute pulmonary exacerbation; BL = beta-lactam; CF = cystic fibrosis; CrCL = creatinine clearance; SCr = serum creatinine; T > MIC = time above minimum inhibitory concentration AFFILIATIONS: From the Loma Linda University School of Pharmacy Q2 Q3 (Dr Hong), Loma Linda, CA; University of Utah School of Medicine (Drs Liou and Stevens), Salt Lake City, UT; University of Utah College of Pharmacy (Mr Deka and Dr Young), Salt Lake City, UT; Kaiser Permanente Colorado (Dr King), Aurora, CO; and the University of Utah Health Care (Dr Young), Salt Lake City, UT. Part of this article has been presented at the North American Cystic Fibrosis Conference, October 8-10, 2015, Phoenix, AZ.
101 The authors have reported to CHEST that no Q4 Q5 102 funding was received for this study. 103 CORRESPONDENCE TO: Lisa T. Hong, PharmD, BCPS, Loma Linda 104 University School of Pharmacy, Department of Pharmacy Practice, 24745 Stewart St, Room 205, Loma Linda, CA 92350; e-mail: lhong@ Q6 105 llu.edu 106 Copyright Ó 2018 American College of Chest Physicians. Published by 107 Elsevier Inc. All rights reserved. 108 DOI: https://doi.org/10.1016/j.chest.2018.06.002 109 FUNDING/SUPPORT:
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Cystic fibrosis (CF) is an autosomal recessive disease that affects multiple organ systems, including the lungs, due to the development of thick, viscous secretions.1 Airway secretions allow persistent bacterial infections to develop and lead to progressive decline in lung function punctuated by exacerbations that may require hospitalization for IV antibiotic therapy. Acute pulmonary exacerbations (APEs) are a leading cause of morbidity and mortality in patients with CF.1-4 The most common organisms found during an APE are Staphylococcus aureus and Pseudomonas aeruginosa. S aureus is more common among children, whereas P aeruginosa becomes more predominant in adults.5 Chronic bacterial infections and the multiple courses of antibiotics taken by patients with CF increase the risk for development of multidrug-resistant pathogens.6 In adult patients with CF, current recommendations are to combine an antipseudomonal beta-lactam (BL) and an aminoglycoside (AMG) for the treatment of an APE to target P aeruginosa.1,2,6 Compared with patients without CF, those with CF have differences in pharmacokinetic variables, including a greater volume of distribution and increased total body clearance for most antibiotics, leading to a shorter elimination half-life and higher dose requirements.7-9
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Enhanced clearance rates are seen with both BLs and AMG antibiotics,10-13 but BLs exhibit time-dependent properties with bactericidal activity that increases with time above the minimum inhibitory concentration (T > MIC).14 Therefore, administration of BL antibiotics via continuous infusion maximizes the T > MIC and optimizes bactericidal activity.15 Current guidelines do not recommend continuous infusion BLs2; however, continuous infusion BLs have shown efficacy in small reported series of patients with CF.16-32 Nevertheless, the majority of reports describe few patients with CF and single determinations of clearance.
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The present study examined the clearance rates of continuous infusion BL and AMG antibiotics during the 10- to 14-day treatment of an APE in adult patients with CF. We investigated changes in clearance with continued exposure to antibiotics and explored potential associations between serum creatinine (SCr) and creatinine clearance (CrCl) measurements with clearance rates of AMG and continuous infusion antipseudomonal BLs. We hypothesized an inverse relationship between changes in continuous infusion BL and AMG clearance rates as well as a correlation between changes in antibiotic clearance and renal function.
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Patients and Methods
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Study Setting and Population
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The study included patients at least 18 years of age with CF admitted to the University of Utah Hospital for an APE between January 1, 2008, and May 15, 2014, who were treated with an IV AMG in addition to a continuous infusion antipseudomonal BL. The BLs included aztreonam, ceftazidime, meropenem, piperacillin/tazobactam, and ticarcillin/clavulanate. These patients were included if they had both AMG and BL serum levels drawn on day 2 and day 7 of antibiotic therapy. Repeat antibiotic levels are a consistent practice at our institution, with AMG levels specifically timed at 3 and 10 h postdose. For patients with multiple admissions during the study period, data from the most recent admission were used. Pregnant patients and recipients of dual BL therapy or concurrent vancomycin were excluded. The University of Utah Institutional Review Board approved this study (University of Utah Institutional Review Board 0007667) and deemed it exempt from informed consenting procedures.
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Outcomes
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TABLE 1
] Equations for Clearance Calculations
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We reviewed medical records and collected demographic characteristics, CF genotypes, pulmonary function test results, BL and AMG names, antibiotic dosing, serum antibiotic levels with timing relative to the antibiotic dose administration, SCr level, WBC counts, and temperature. Patients had blood drawn every 3 days during hospitalization for laboratory tests unless otherwise clinically indicated. However, for our study purposes, values upon admission were recorded to describe baseline, along with day 2 and day 7 values, given our interest in changes in antibiotic clearance during that time period. Clinical use of standardized templates for
Cmin ¼ Cmax e–kt
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Continuous Infusion Beta-Lactams
Aminoglycosides ke ¼ [ln(C1/C2)]/t
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The primary outcome was change in clearance rates of the continuous infusion BL from day 2 to day 7 of APE treatment. Secondary outcomes included change in tobramycin clearance rates within the same time period and change in percent predicted FEV1 (FEV1%) between admission and discharge. Equations from the Third
Data Sources
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medication progress notes since 2001 facilitated data collection. Progress notes also contained clearly documented, patient-specific pharmacokinetic parameters, including calculated antibiotic clearance rates based on day 2 and day 7 serum levels. Equations used to calculate clearance rates for both AMGs as well as continuous infusion BLs are displayed in Table 1.33
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CL ¼ R0/Css
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Vd ¼ dose/ke [(1 – e )/ [Cmax – (Cmin e–kt)]
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CL ¼ ke Vd
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CL ¼ clearance; Cmax ¼ maximum concentration; Cmin ¼ minimum concentration; Css ¼ steady state concentration; ke ¼ elimination rate; R0 ¼ rate of infusion; t ¼ time; Vd ¼ volume of distribution. From Q17 Sawchuk et al.33
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National Health and Nutrition Examination Survey were used to normalize FEV1 to FEV1% because these were the values used to make clinical decisions throughout the study period.34 Statistical Analysis A paired samples t test was used to compare day 2 and day 7 BL and tobramycin clearance rates as well as admission and discharge FEV1%. A one-way analysis of variance was conducted to compare the change in clearance rates for all BLs. Given the inclusion of any AMG dosing strategy, a sensitivity analysis was performed in which those who received multiple daily doses of an AMG antibiotic were excluded. Pearson correlation coefficient was used to evaluate associations between change in SCr or CrCL and change in antibiotic clearance rates from day 2 to day 7.
Multivariable linear regression of the change in BL clearance was performed as a function of change in tobramycin clearance rates and CrCL adjusting for age, sex, weight, CF genotype (categorized into mutually exclusive genotype groups), and admission number (number of distinct hospitalizations for each patient during the study period). Adjustments were also made for concurrent nephrotoxic Q8 agents (including angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, diuretics, nonsteroidal antiinflammatory drugs, sulfamethoxazole/trimethoprim, rifampin, and contrast media). All model covariates were chosen a priori based on potential confounding factors. There was no evidence of heteroscedasticity, multicollinearity, or other deviations from linear regression assumptions.
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Results
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All eligible patients were included in the study (N ¼ 162) (Table 2). Table 3 summarizes the antibiotics used along with average initial total daily doses for the selected APE per patient during the study period. Of the BLs, meropenem was used most often (45.7%), followed by piperacillin/tazobactam (19.8%), ticarcillin/ clavulanate (19.1%), ceftazidime (11.1%), and, finally, aztreonam (4.3%).
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Measured serum BL concentrations indicated that the intended target serum level was attained about 65% of the time (e-Fig 1). The mean clearance rate for continuous infusion BLs increased 20.7% from day 2 to day 7 (95% CI, 11.42 to 32.49; P < .001) (Fig 1). There was no difference in the change in clearance rates across BL antibiotics (P ¼ .499) (Table 4). The mean increase in BL clearance of 22.76 66.19 mL/min resulted in a mean dose increase of 19.91% during APE treatment.
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TABLE 2
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Characteristic
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Age, y
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Mean SD or No. (%) 32.29 9.90
Male sex
78 (48.1)
Height, cm
167.54 9.34
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Weight, kg
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Genotype
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Homozygous dF508
66 (40.7)
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Heterozygous dF508
45 (27.8)
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G551D
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Tobramycin clearance rates decreased 6.3% from day 2 to day 7 (95% CI, –12.49 to –4.45; P < .001 (Fig 1). The mean decrease in tobramycin clearance of –7.97 25.28 mL/min lead to a mean dose reduction of 5.36%. Tobramycin dosing was decreased in 83 patients (51.2%), maintained in 37 patients (22.8%), and increased in 42 patients (25.9%). Nineteen patients (11.9%) admitted prior to 2010 received tobramycin dosed every 8 to 12 h. A sensitivity analysis excluding patients dosed more than once daily found a mean change in tobramycin clearance of –6.22 mL/min (P ¼ .004), which was similar in magnitude and statistical significance compared with the original result. Three patients (1.9%) received amikacin rather than tobramycin and had a median reduction in amikacin clearance of 23.8 mL/min (25% decrease) leading to a median dose reduction of 12.1%. Serum AMG levels and
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Serum levels and dose adjustments for each BL are provided in e-Table 1. BL dosing was increased in 81 patients (50%), maintained in 73 patients (45.1%), and decreased in 8 patients (4.9%) (e-Fig 2). More patients who received piperacillin/tazobactam had a dose increase (84.38%) compared with those who received other BLs. Unlike other BL groups, these dose increases led to an increase in serum levels above goal, rather than within goal.
9 (5.6)
Unknown
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Othera
7 (4.3) 44.66 21.41
FEV1%
0.78 0.22
SCr, mg/dL Temperature, C
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WBC count, 10 /L SCr ¼ serum creatinine. a Genotypes not including dF508 or G551D.
TABLE 3
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] Antibiotic Usage
Antibiotic
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Initial Total Daily Dose (Mean SD)
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Aztreonam
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5.71 0.49 g
Ceftazidime
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5.33 1.28 g
Meropenem
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5.33 1.74 g
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Piperacillin/tazobactam
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24.82 7.10 g
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Ticarcillin/clavulanate
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23.30 6.45 g
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0.56 0.11 g
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1.58 0.13 g
Tobramycin Amikacin
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Mean Clearance Rates (mL/min)
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BL
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175.02 ± 94.64
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99.94 ± 28.67
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AMG
Day 2 SCr (mg/dL) CrCL (mL/min)
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0.78 ± 0.22
0.82 ± 0.24
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Figure 1 – Changes in antibiotic clearance rates (mean SD) between day 2 and day 7 or therapy. A statistically significant increase in BL clearance rates occurred (P < .001) while AMG clearance rates decreased (P < .001) despite an increase in mean SCr and a decrease in mean CrCl. AMG ¼ aminoglycoside; BL ¼ beta-lactam; CrCl ¼ creatinine clearance; SCr ¼ serum creatinine.
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subsequent dose adjustments are summarized in eTable 2 and e-Figure 3, respectively. FEV1 increased from a mean of 44.66 21.41% predicted on admission to 56.84 25.13% predicted at discharge (P < .001), with 36 patients (22.2%) achieving their FEV1% goal (defined as achievement of the patient’s highest FEV1% within the past year). Although the remainder of patients did not meet their FEV1% goal, only 10 (6.2%) had a decrease in FEV1% between admission and discharge. Of note, six of these patients did not achieve target antibiotic levels. The change in BL clearance between day 2 and day 7 was evaluated, controlling for several variables identified as possible confounders (Fig 2). Thirtyseven patients (22.8%) received concurrent nephrotoxic agents (sulfamethoxazole/trimethoprim
TABLE 4
or rifampin) during the treatment period, which seemed to have no significant impact on the change in BL clearance (P ¼ .398 and P ¼ .096, respectively). The regression model results revealed a significant impact of “other” genotype (Q493X/1154insT, 1717-1G/A/ 3659delC, E60X/R1158X, R553X/P574H, Q493X/ 3849þ10kbC/T, N1303K/M470V, and S492F/ M470V) on the change in BL clearance (P ¼ .043). This finding indicates that mean changes in BL clearance rates are 53.61 mL/min less for those with “other” genotypes compared with patients with homozygous dF508 genotype. As shown in e-Figure 4, no statistically significant correlation was identified between the change in SCr and the change in antibiotic clearance rates for BL (r ¼ 0.11; P ¼ .143) or AMG (r ¼ 0.06; P ¼ .435). Similarly, no correlation seems to exist between the change in
Antibiotic Aztreonam (n ¼ 7)
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] One-Way ANOVA for Beta-Lactam CL Rates
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432 % Change in CL
P Value
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9.39 12.08
14.51 19.69
.499
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Ceftazidime (n ¼ 18)
12.06 19.18
23.49 38.94
Meropenem (n ¼ 74)
32.07 80.37
20.16 41.06
Piperacillin/tazobactam (n ¼ 31)
10.07 76.19
13.34 49.03
Ticarcillin/clavulanate (n ¼ 31)
22.86 32.59
29.59 43.06
Change in CL (mL/min)
435 436 437 438 439 440
Data are presented as mean SD. See Table 1 for expansion of other abbreviation.
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Parameter estimate (95% CI)
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Male Age Admission Number Day 2 Weight Change in AMG Clearance Change in CrCL Unknown genotype Other genotype G551D genotype Heterozygous dF508 Concurrent rifampin Concurrent SMX/TMP –250
–200
16.77 (–7.38 to 40.93) –0.53 (–1.60 to 0.53) –1.30 (–2.92 to 0.31) –0.34 (–1.30 to 0.61) 0.34 (–0.07 to 0.76) 0.50 (–0.04 to 1.04) 9.88 (–18.55 to 38.33) –53.61 (–105.67 to –1.53) –20.58 (–66.71 to 25.55) 3-9.06 (–35.32 to 17.19) –21.93 (–157.25 to 113.37) 22.57 (–4.07 to 49.22) –150
–100
–50
0
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P value
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.172 .328 .112 .483 .104 .068 .493 .043 .379 .496 .328 .096
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Figure 2 – Multivariable linear regression of factors influencing change in BL clearance rates. The regression model suggests no significant impact of the listed factors on change in BL clearance rates with the exception of “other” genotype (P ¼ .043), which may reduce the change in BL clearance seen during the first 7 days of therapy compared with those with homozygous dF508 genotype. þReference genotype group ¼ homozygous dF508. þþOther genotype ¼ genotypes not including dF508 or G551D. SMX/TMP ¼ sulfamethoxazole/trimethoprim. See Figure 1 legend for expansion of other abbreviations.
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CrCL and the change in antibiotic clearance rates (r ¼ 0.12, P ¼ .122 for BL and r ¼ –0.09, P ¼ .240 for AMG).
Discussion These study data showed that BL clearance rates changed during the period of treatment for a CF APE. Mean BL clearance rates increased > 20% within the first week of treatment, which led to a dose adjustment in about 50% of patients and a mean increase in BL dose by nearly 20%. The dose adjustments made to piperacillin/tazobactam led to more supratherapeutic serum levels and fewer levels achieving goal, which suggests room for improvement in the identification of an optimal dose of this antibiotic. Simultaneously, AMG clearance rates also changed. However, contrary to mean BL clearance rates, mean AMG clearance rates decreased by about 6% during the same time frame and led to a 5% decrease in AMG dose. Monitoring of BL and AMG serum levels and calculation of their corresponding clearance rates are needed to optimize antibiotic dosing. According to our results, changes in antibiotic clearance rates are unrelated to changes in SCr and CrCL levels. Between day 2 and day 7, mean SCr values increased 0.04 mg/dL, leading to a calculated decrease in mean CrCL level of 4.94 mL/min. AMGs are almost entirely eliminated via glomerular filtration,35 which may explain the small decrease in mean AMG clearance rates. However, BL antibiotics undergo glomerular filtration as
well as tubular secretion.36 We hypothesized that this additional mechanism of drug excretion may contribute to the change in BL clearance rates. The mean increase of 12.2% predicted in FEV1 is both statistically and clinically significant and compares favorably with other reports.37,38 Finding this improvement in FEV1% is a promising piece of evidence supporting the use of continuous infusion BL antibiotics during APE treatment. However, we cannot directly compare these results with results from the use of conventionally dosed BLs. Confirmation in a randomized clinical trial is warranted. The finding for “other” genotypes implies a lower change in BL clearance compared with patients with homozygous dF508 genotype. However, this result must be interpreted with caution given the small sample size. The reason for this finding is unclear as it is the combined effect of individual genotypes in the group, none of which was frequent enough to allow for more detailed analyses. To our knowledge, no literature exists Q9 regarding change in CI BL clearance rates in relation to specific genetic mutations. Our study has several strengths. First, we used a wellannotated dataset, including patient genotypes. All patients admitted for the treatment of an APE without contraindications to BL and AMG therapy had the requisite BL and AMG levels because obtaining antibiotic levels on day 2 and day 7 of APE treatment is the standard of practice at our institution.
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Calculation of antibiotic clearance rates was also standardized with the creation of calculators, along with training for any pharmacist taking care of these study patients with CF on how to use these calculators and adjust antibiotic dosing based on drug levels. In terms of data collection, templates for progress notes on patients with CF allowed for consistent documentation of pharmacokinetic information and efficient data collection.
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A limitation to the present study is that we could not include all antipseudomonal BLs because some (eg, imipenem, cefepime) are not routinely used at our institution. Ticarcillin/clavulanate was used in some of the study patients, but it is no longer available.39 Prior to 2010, tobramycin was dosed in every 8- to 12-h intervals; however, sensitivity analyses excluding these patients did not change our results. We are unable to confirm whether there are further changes in antibiotic clearance rates between 7 and 14 days of treatment because levels at the end of therapy have no clinical utility. In addition, we cannot ascertain whether the
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change in antibiotic clearance is an inducible process that occurs with each antibiotic exposure. Our analysis looked at the most recent admission during the given study period and included number of admissions during the study period in the regression analysis; the analysis revealed no statistical significance, suggesting no cumulative effects of repeated antibiotic treatments. However, this adjustment does not account for possible effects from admissions prior to the study period.
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Author contributions: L. T. H. had full access to all of the study data and is the guarantor of the integrity of this study and manuscript. L. T. H., R. D., J. B. K., V. S., and D. C. Y. contributed to study design; data were collected by L. T. H. and were analyzed by L. T. H., R. D., J. B. K., and V. S.; and L. T. H., T. G. L., J. B. K., V. S., and D. C. Y. contributed to the manuscript development.
579 Q12
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587 588
591
Q11 Q13
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Increasing BL clearance rates during APE treatment in patients with CF frequently necessitates important dose increases to maximize efficacy. On the contrary, AMG clearance rates decreased, leading to a mean dose reduction to minimize antibiotic toxicity. Changes in BL and AMG clearance rates occur independent of renal function. Obtaining serum drug levels is essential to determining optimal dosing for individual patients because there is no correlation between antibiotic clearance rates and measures of renal function.
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Acknowledgments
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Conclusions
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Financial/nonfinancial disclosures: The authors have reported to CHEST the following: T. G. L. was supported during the performance of the study by grants from the National Institutes of Health/National Heart, Lung, and Blood Institute [grants R01 HL 125520, R01 HL 072938, R21 HL 084341], the CF Foundation of the United States [grants CC132-16AD, LIOU14Y0, LIOU06A0, LIOU13A0, LIOU14P0, LIOU14Y4, LIOU15Y4], the Ben B. and Iris M. Margolis Family Foundation of Utah, the Claudia Ruth Goodrich Stevens Endowment, and grants for performance of clinical trials from the Foundation for the National Institute of Health, Gilead Sciences, Inc, Nivalis Therapeutics, Inc, Novartis, Savara Pharmaceuticals, Vertex Pharmaceuticals, Inc, the Therapeutics Development Network of the Cystic Fibrosis Foundation, and Cystic Fibrosis Foundation Therapeutics. T. G. L. also discloses membership in the Clinical Research Committee of the Cystic Fibrosis Foundation and membership on the Editorial Board of CHEST. None declared (L. T. H., R. D., J. B. K., V. S., D. C. Y.).
6 Original Research
Other contributions: The authors thank Holly Carveth, MD, and Zubin Bhakta, PharmD, for assisting in caring for the patients with CF during the study period. Additional information: The e-Figures and e-Tables can be found in the Supplemental Materials section of the online article.
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16. Bosso JA, Bonapace CR, Flume PA, White RL. A pilot study of the efficacy of constant-infusion ceftazidime in the
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treatment of endobronchial infections in adults with cystic fibrosis. Pharmacotherapy. 1999;19(5):620-626.
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17. David TJ, Devlin J. Continuous infusion of ceftazidime in cystic fibrosis. Lancet. 1989;1(8652):1454-1455.
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18. Kuzemko J, Crawford C. Continuous infusion of ceftazidime in cystic fibrosis. Lancet. 1989;2(8659):385.
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19. Vinks AA, Touw DJ, Heijerman HG, et al. Pharmacokinetics of ceftazidime in adult cystic fibrosis patients during continuous infusion and ambulatory treatment at home. Ther Drug Monit. 1994;16(4):341-348.
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20. Vinks AA, Brimicombe RW, Heijerman HG, Bakker W. Continuous infusion of ceftazidime in cystic fibrosis patients during home treatment: clinical outcome, microbiology and pharmacokinetics. J Antimicrob Chemother. 1997;40(1):125-133.
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21. Rappaz I, Decosterd LA, Bille J, et al. Continuous infusion of ceftazidime with a portable pump is as effective as thrice-aday bolus in cystic fibrosis children. Eur J Pediatr. 2000;159(12):919-925.
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22. Byl B, Baran D, Jacobs F, et al. Serum pharmacokinetics and sputum penetration of amikacin 30 mg/kg once daily and of ceftazidime 200 mg/kg/day as a continuous infusion in cystic fibrosis patients. J Antimicrob Chemother. 2001;48(2):325-327.
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23. Hubert D, Le Roux E, Lavrut T, et al. Continuous versus intermittent infusions of ceftazidime for treating exacerbation of cystic fibrosis. Antimicrob Agents Chemother. 2009;53(9):3650-3656.
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24. Riethmueller J, Junge S, Schroeter TW, et al. Continuous vs thrice-daily ceftazidime for elective intravenous antipseudomonal therapy in cystic fibrosis. Infection. 2009;37(5):418-423.
25. Prescott WA, Gentile AE, Nagel JL, Pettit RS. Continuous-infusion antipseudomonal beta-lactam therapy in patients with cystic fibrosis. J Pediatr Pharmacol Thera. 2011;36(11):723-763. 26. Baririan N, Chanteux H, Viaene E, et al. Stability and compatibility study of cefepime in comparison with ceftazidime for potential administration by continuous infusion under conditions pertinent to ambulatory treatment of cystic fibrosis patients and to administration in intensive care units. J Antimicrob Chemother. 2003;51(3): 651-658. 27. Han EE, Beringer PM, Falck P, et al. Pilot study of continuous infusion cefepime in adult patients with cystic fibrosis. J Antimicrob Chemother. 2006;57(5): 1017-1019. 28. Munckhof WJ, Carney J, Neilson G, et al. Continuous infusion of ticarcillinclavulanate for home treatment of serious infections: clinical efficacy, safety, pharmacokinetics and pharmacodynamics. Int J Antimicrob Agents. 2005;25(6):514-522. 29. Vinks AA, Den Hollander JG, Overbeek SE, et al. Population pharmacokinetic analysis of nonlinear behavior of piperacillin during intermittent or continuous infusion in patients with cystic fibrosis. Antimicrob Agents Chemother. 2003;47(2):541-547. 30. Bulitta JB, Duffull SB, KinzigSchippers M, et al. Systematic comparison of the population pharmacokinetics and pharmacodynamics of piperacillin in cystic fibrosis patients and healthy volunteers. Antimicrob Agents Chemother. 2007;51(7):2497-2507. 31. Kuti JL, Nightingale CH, Knauft RF, Nicolau DP. Pharmacokinetic properties
and stability of continuous-infusion meropenem in adults with cystic fibrosis. Clin Ther. 2004;26(4):493-501. 32. Hayes D Jr, Kanga JF, Anstead MI, Kuhn RJ. Novel approach to the eradication of Pseudomonas aeruginosa in an infant with CF after outpatient treatment failure. Pediatr Pulmonol. 2008;43(5):511-513. 33. Sawchuk RJ, Zaske DE, Cipolle RJ, Wargin WA, Strate RG. Kinetic model for gentamicin dosing with the use of individual patient parameters. Clin Pharmacol Ther. 1977;21(3):362-369. 34. Hankinson JL, ODencrantz JR, Fedan KB. Spirometric reference values from a sample of the general U.S. population. Am J Respir Crit Care Med. 1999;159(1): 179-187. 35. Product Information: tobramycin IV, IM injection, tobramycin IV, IM injection. Schaumburg, IL: APP Pharmaceuticals, LLC; 2008. 36. Levison ME, Levison JH. Pharmacokinetics and pharmacodynamics of antibacterial agents. Infect Dis Clin North Am. 2009;23(4):791-815. 37. Cazzola M, MacNee W, Martinez FJ, et al. Outcomes for COPD pharmacological trials: from lung function to biomarkers. Eur Respir J. 2008;31(2):416-469. 38. Heltshe SL, Goss CH, Thompson V, Sagel SD, Sanders DB, Marshall BC, Flume PA. Short-term and long-term response to pulmonary exacerbation treatment in cystic fibrosis. Thorax. 2016;71(3):223-229.
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39. Chang DJ. US Medical Affairs. GlaxoSmithKline Safety Advisory. http:// www.fda.gov/downloads/drugs/ drugsafety/drugshortages/ucm433688.pdf; February 9, 2015.
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Pharmacokinetics of Continuous Infusion Beta-lactams in the Treatment of Acute Pulmonary Exacerbations in Adult Patients With Cystic Fibrosis
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Lisa T. Hong, PharmD, BCPS; Theodore G. Liou, MD; Rishi Deka, MS; Jordan B. King, PharmD, MS;
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Vanessa Stevens, PhD; and David C. Young, PharmD
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Several clinical trials have shown the efficacy of continuous infusion betalactam (BL) antibiotics in patients with cystic fibrosis (CF); however, little is known about pharmacokinetic changes during the treatment of an acute pulmonary exacerbation (APE). Identifying and understanding these changes may assist in optimizing antibiotic dosing during APE treatment.
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This study was a retrospective cohort study of 162 adult patients with CF admitted to the University of Utah Hospital between January 1, 2008, and May 15, 2014, for treatment of an APE with both a continuous infusion BL and IV tobramycin. We extracted the administered doses of continuous infusion BLs and tobramycin along with serum drug concentrations and calculated medication clearance rates. The primary outcome was change in clearance rates of continuous infusion BLs between day 2 and day 7 of APE treatment.
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The BL clearance rate increased 20.7% (95% CI, 11.42 to 32.49; P < .001), whereas the tobramycin clearance rate decreased 6.3% (95% CI, –12.29 to –4.45; P < .001). The mean percent predicted FEV1 increased between admission and discharge by 12.2% (95% CI, –13.81 to –10.55; P < .001).
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CONCLUSIONS:
BACKGROUND:
20 21 22 23 24
METHODS:
25 26 27 28 29 30 31
RESULTS:
32 33 34
Clinicians should monitor BL levels along with aminoglycoside levels and make dose adjustments to maximize the chance of optimal antibiotic treatment. Continuous infusion BL and tobramycin clearance can change dramatically during the treatment of an APE, which may necessitate significant changes in dosing to achieve optimal antibiotic levels. Clearance rates of these antibiotics may change in opposite directions, requiring specific monitoring of each medication. CHEST 2018; -(-):---
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KEY WORDS:
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antibiotic therapy; cystic fibrosis; pharmacokinetics
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ABBREVIATIONS:
AMG = aminoglycoside; APE = acute pulmonary exacerbation; BL = beta-lactam; CF = cystic fibrosis; CrCL = creatinine clearance; SCr = serum creatinine; T > MIC = time above minimum inhibitory concentration AFFILIATIONS: From the Loma Linda University School of Pharmacy Q2 Q3 (Dr Hong), Loma Linda, CA; University of Utah School of Medicine (Drs Liou and Stevens), Salt Lake City, UT; University of Utah College of Pharmacy (Mr Deka and Dr Young), Salt Lake City, UT; Kaiser Permanente Colorado (Dr King), Aurora, CO; and the University of Utah Health Care (Dr Young), Salt Lake City, UT. Part of this article has been presented at the North American Cystic Fibrosis Conference, October 8-10, 2015, Phoenix, AZ.
101 The authors have reported to CHEST that no Q4 Q5 102 funding was received for this study. 103 CORRESPONDENCE TO: Lisa T. Hong, PharmD, BCPS, Loma Linda 104 University School of Pharmacy, Department of Pharmacy Practice, 24745 Stewart St, Room 205, Loma Linda, CA 92350; e-mail: lhong@ Q6 105 llu.edu 106 Copyright Ó 2018 American College of Chest Physicians. Published by 107 Elsevier Inc. All rights reserved. 108 DOI: https://doi.org/10.1016/j.chest.2018.06.002 109 FUNDING/SUPPORT:
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Cystic fibrosis (CF) is an autosomal recessive disease that affects multiple organ systems, including the lungs, due to the development of thick, viscous secretions.1 Airway secretions allow persistent bacterial infections to develop and lead to progressive decline in lung function punctuated by exacerbations that may require hospitalization for IV antibiotic therapy. Acute pulmonary exacerbations (APEs) are a leading cause of morbidity and mortality in patients with CF.1-4 The most common organisms found during an APE are Staphylococcus aureus and Pseudomonas aeruginosa. S aureus is more common among children, whereas P aeruginosa becomes more predominant in adults.5 Chronic bacterial infections and the multiple courses of antibiotics taken by patients with CF increase the risk for development of multidrug-resistant pathogens.6 In adult patients with CF, current recommendations are to combine an antipseudomonal beta-lactam (BL) and an aminoglycoside (AMG) for the treatment of an APE to target P aeruginosa.1,2,6 Compared with patients without CF, those with CF have differences in pharmacokinetic variables, including a greater volume of distribution and increased total body clearance for most antibiotics, leading to a shorter elimination half-life and higher dose requirements.7-9
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Enhanced clearance rates are seen with both BLs and AMG antibiotics,10-13 but BLs exhibit time-dependent properties with bactericidal activity that increases with time above the minimum inhibitory concentration (T > MIC).14 Therefore, administration of BL antibiotics via continuous infusion maximizes the T > MIC and optimizes bactericidal activity.15 Current guidelines do not recommend continuous infusion BLs2; however, continuous infusion BLs have shown efficacy in small reported series of patients with CF.16-32 Nevertheless, the majority of reports describe few patients with CF and single determinations of clearance.
167 168 169 170 171 172 173 174 175 176 177 178 179
The present study examined the clearance rates of continuous infusion BL and AMG antibiotics during the 10- to 14-day treatment of an APE in adult patients with CF. We investigated changes in clearance with continued exposure to antibiotics and explored potential associations between serum creatinine (SCr) and creatinine clearance (CrCl) measurements with clearance rates of AMG and continuous infusion antipseudomonal BLs. We hypothesized an inverse relationship between changes in continuous infusion BL and AMG clearance rates as well as a correlation between changes in antibiotic clearance and renal function.
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Patients and Methods
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Study Setting and Population
143 144 145 146 147 148 149 150 151 152 153 154 155
The study included patients at least 18 years of age with CF admitted to the University of Utah Hospital for an APE between January 1, 2008, and May 15, 2014, who were treated with an IV AMG in addition to a continuous infusion antipseudomonal BL. The BLs included aztreonam, ceftazidime, meropenem, piperacillin/tazobactam, and ticarcillin/clavulanate. These patients were included if they had both AMG and BL serum levels drawn on day 2 and day 7 of antibiotic therapy. Repeat antibiotic levels are a consistent practice at our institution, with AMG levels specifically timed at 3 and 10 h postdose. For patients with multiple admissions during the study period, data from the most recent admission were used. Pregnant patients and recipients of dual BL therapy or concurrent vancomycin were excluded. The University of Utah Institutional Review Board approved this study (University of Utah Institutional Review Board 0007667) and deemed it exempt from informed consenting procedures.
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Outcomes
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TABLE 1
] Equations for Clearance Calculations
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We reviewed medical records and collected demographic characteristics, CF genotypes, pulmonary function test results, BL and AMG names, antibiotic dosing, serum antibiotic levels with timing relative to the antibiotic dose administration, SCr level, WBC counts, and temperature. Patients had blood drawn every 3 days during hospitalization for laboratory tests unless otherwise clinically indicated. However, for our study purposes, values upon admission were recorded to describe baseline, along with day 2 and day 7 values, given our interest in changes in antibiotic clearance during that time period. Clinical use of standardized templates for
Cmin ¼ Cmax e–kt
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Continuous Infusion Beta-Lactams
Aminoglycosides ke ¼ [ln(C1/C2)]/t
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The primary outcome was change in clearance rates of the continuous infusion BL from day 2 to day 7 of APE treatment. Secondary outcomes included change in tobramycin clearance rates within the same time period and change in percent predicted FEV1 (FEV1%) between admission and discharge. Equations from the Third
Data Sources
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197 198
201
157 159
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medication progress notes since 2001 facilitated data collection. Progress notes also contained clearly documented, patient-specific pharmacokinetic parameters, including calculated antibiotic clearance rates based on day 2 and day 7 serum levels. Equations used to calculate clearance rates for both AMGs as well as continuous infusion BLs are displayed in Table 1.33
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CL ¼ R0/Css
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–kt
Vd ¼ dose/ke [(1 – e )/ [Cmax – (Cmin e–kt)]
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CL ¼ ke Vd
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CL ¼ clearance; Cmax ¼ maximum concentration; Cmin ¼ minimum concentration; Css ¼ steady state concentration; ke ¼ elimination rate; R0 ¼ rate of infusion; t ¼ time; Vd ¼ volume of distribution. From Q17 Sawchuk et al.33
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National Health and Nutrition Examination Survey were used to normalize FEV1 to FEV1% because these were the values used to make clinical decisions throughout the study period.34 Statistical Analysis A paired samples t test was used to compare day 2 and day 7 BL and tobramycin clearance rates as well as admission and discharge FEV1%. A one-way analysis of variance was conducted to compare the change in clearance rates for all BLs. Given the inclusion of any AMG dosing strategy, a sensitivity analysis was performed in which those who received multiple daily doses of an AMG antibiotic were excluded. Pearson correlation coefficient was used to evaluate associations between change in SCr or CrCL and change in antibiotic clearance rates from day 2 to day 7.
Multivariable linear regression of the change in BL clearance was performed as a function of change in tobramycin clearance rates and CrCL adjusting for age, sex, weight, CF genotype (categorized into mutually exclusive genotype groups), and admission number (number of distinct hospitalizations for each patient during the study period). Adjustments were also made for concurrent nephrotoxic Q8 agents (including angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, diuretics, nonsteroidal antiinflammatory drugs, sulfamethoxazole/trimethoprim, rifampin, and contrast media). All model covariates were chosen a priori based on potential confounding factors. There was no evidence of heteroscedasticity, multicollinearity, or other deviations from linear regression assumptions.
276 277 278 279 280 281 282 283 284 285 286
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Results
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All eligible patients were included in the study (N ¼ 162) (Table 2). Table 3 summarizes the antibiotics used along with average initial total daily doses for the selected APE per patient during the study period. Of the BLs, meropenem was used most often (45.7%), followed by piperacillin/tazobactam (19.8%), ticarcillin/ clavulanate (19.1%), ceftazidime (11.1%), and, finally, aztreonam (4.3%).
236 237 238 239 240 241 242 243 244 245 246 247 248 249 250 251 252 253
Measured serum BL concentrations indicated that the intended target serum level was attained about 65% of the time (e-Fig 1). The mean clearance rate for continuous infusion BLs increased 20.7% from day 2 to day 7 (95% CI, 11.42 to 32.49; P < .001) (Fig 1). There was no difference in the change in clearance rates across BL antibiotics (P ¼ .499) (Table 4). The mean increase in BL clearance of 22.76 66.19 mL/min resulted in a mean dose increase of 19.91% during APE treatment.
254 255 256
TABLE 2
] Baseline Characteristics (N ¼ 162)
257
Characteristic
258
Age, y
259 260
Mean SD or No. (%) 32.29 9.90
Male sex
78 (48.1)
Height, cm
167.54 9.34
262
Weight, kg
59.65 13.08
263
Genotype
261
Homozygous dF508
66 (40.7)
265
Heterozygous dF508
45 (27.8)
266
G551D
268 269 270 271 272 273 274 275
Tobramycin clearance rates decreased 6.3% from day 2 to day 7 (95% CI, –12.49 to –4.45; P < .001 (Fig 1). The mean decrease in tobramycin clearance of –7.97 25.28 mL/min lead to a mean dose reduction of 5.36%. Tobramycin dosing was decreased in 83 patients (51.2%), maintained in 37 patients (22.8%), and increased in 42 patients (25.9%). Nineteen patients (11.9%) admitted prior to 2010 received tobramycin dosed every 8 to 12 h. A sensitivity analysis excluding patients dosed more than once daily found a mean change in tobramycin clearance of –6.22 mL/min (P ¼ .004), which was similar in magnitude and statistical significance compared with the original result. Three patients (1.9%) received amikacin rather than tobramycin and had a median reduction in amikacin clearance of 23.8 mL/min (25% decrease) leading to a median dose reduction of 12.1%. Serum AMG levels and
289 290 291 292 293 294 295 296 297 298 299 300 301 302 303 304 305 306 307 308 309 310 311 312 313 314 315 316 317 318
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Serum levels and dose adjustments for each BL are provided in e-Table 1. BL dosing was increased in 81 patients (50%), maintained in 73 patients (45.1%), and decreased in 8 patients (4.9%) (e-Fig 2). More patients who received piperacillin/tazobactam had a dose increase (84.38%) compared with those who received other BLs. Unlike other BL groups, these dose increases led to an increase in serum levels above goal, rather than within goal.
9 (5.6)
Unknown
35 (21.6)
Othera
7 (4.3) 44.66 21.41
FEV1%
0.78 0.22
SCr, mg/dL Temperature, C
37.10 0.53
9
11.33 4.37
WBC count, 10 /L SCr ¼ serum creatinine. a Genotypes not including dF508 or G551D.
TABLE 3
319
] Antibiotic Usage
Antibiotic
320 No.
Initial Total Daily Dose (Mean SD)
321 322
Aztreonam
7
5.71 0.49 g
Ceftazidime
18
5.33 1.28 g
Meropenem
74
5.33 1.74 g
325
Piperacillin/tazobactam
32
24.82 7.10 g
326
Ticarcillin/clavulanate
31
23.30 6.45 g
159
0.56 0.11 g
3
1.58 0.13 g
Tobramycin Amikacin
323 324
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Mean Clearance Rates (mL/min)
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BL
388 389
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175.02 ± 94.64
393
350 351 352 353
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99.94 ± 28.67
91.97 ± 29.96
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391 392
150
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390
152.26 ± 74.14
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AMG
Day 2 SCr (mg/dL) CrCL (mL/min)
4 5 Day of Therapy
Day 7
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7
398
8
399 400
Change
% Change
P value
401 402
0.78 ± 0.22
0.82 ± 0.24
0.05 ± 0.02
6.66 ± 19.98
.003
403
116.80 ± 36.80
111.86 ± 35.83
–4.94 ± 20.38
–2.57 ± 0.20
.002
404
Figure 1 – Changes in antibiotic clearance rates (mean SD) between day 2 and day 7 or therapy. A statistically significant increase in BL clearance rates occurred (P < .001) while AMG clearance rates decreased (P < .001) despite an increase in mean SCr and a decrease in mean CrCl. AMG ¼ aminoglycoside; BL ¼ beta-lactam; CrCl ¼ creatinine clearance; SCr ¼ serum creatinine.
354 355 356 357 358 359 360 361 362 363 364 365 366 367 368 369 370 371 372 373 374
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subsequent dose adjustments are summarized in eTable 2 and e-Figure 3, respectively. FEV1 increased from a mean of 44.66 21.41% predicted on admission to 56.84 25.13% predicted at discharge (P < .001), with 36 patients (22.2%) achieving their FEV1% goal (defined as achievement of the patient’s highest FEV1% within the past year). Although the remainder of patients did not meet their FEV1% goal, only 10 (6.2%) had a decrease in FEV1% between admission and discharge. Of note, six of these patients did not achieve target antibiotic levels. The change in BL clearance between day 2 and day 7 was evaluated, controlling for several variables identified as possible confounders (Fig 2). Thirtyseven patients (22.8%) received concurrent nephrotoxic agents (sulfamethoxazole/trimethoprim
TABLE 4
or rifampin) during the treatment period, which seemed to have no significant impact on the change in BL clearance (P ¼ .398 and P ¼ .096, respectively). The regression model results revealed a significant impact of “other” genotype (Q493X/1154insT, 1717-1G/A/ 3659delC, E60X/R1158X, R553X/P574H, Q493X/ 3849þ10kbC/T, N1303K/M470V, and S492F/ M470V) on the change in BL clearance (P ¼ .043). This finding indicates that mean changes in BL clearance rates are 53.61 mL/min less for those with “other” genotypes compared with patients with homozygous dF508 genotype. As shown in e-Figure 4, no statistically significant correlation was identified between the change in SCr and the change in antibiotic clearance rates for BL (r ¼ 0.11; P ¼ .143) or AMG (r ¼ 0.06; P ¼ .435). Similarly, no correlation seems to exist between the change in
Antibiotic Aztreonam (n ¼ 7)
382 383 384 385
410 411 412 413 414 415 416 417 418 419 420 421 422 423 424 425 426 427 428 429 431
] One-Way ANOVA for Beta-Lactam CL Rates
379 381
407 408
430
378 380
Q18
406
409
375 376
405 Q21
432 % Change in CL
P Value
433
9.39 12.08
14.51 19.69
.499
434
Ceftazidime (n ¼ 18)
12.06 19.18
23.49 38.94
Meropenem (n ¼ 74)
32.07 80.37
20.16 41.06
Piperacillin/tazobactam (n ¼ 31)
10.07 76.19
13.34 49.03
Ticarcillin/clavulanate (n ¼ 31)
22.86 32.59
29.59 43.06
Change in CL (mL/min)
435 436 437 438 439 440
Data are presented as mean SD. See Table 1 for expansion of other abbreviation.
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Parameter estimate (95% CI)
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Male Age Admission Number Day 2 Weight Change in AMG Clearance Change in CrCL Unknown genotype Other genotype G551D genotype Heterozygous dF508 Concurrent rifampin Concurrent SMX/TMP –250
–200
16.77 (–7.38 to 40.93) –0.53 (–1.60 to 0.53) –1.30 (–2.92 to 0.31) –0.34 (–1.30 to 0.61) 0.34 (–0.07 to 0.76) 0.50 (–0.04 to 1.04) 9.88 (–18.55 to 38.33) –53.61 (–105.67 to –1.53) –20.58 (–66.71 to 25.55) 3-9.06 (–35.32 to 17.19) –21.93 (–157.25 to 113.37) 22.57 (–4.07 to 49.22) –150
–100
–50
0
50
100
150
200
496
P value
497 498
.172 .328 .112 .483 .104 .068 .493 .043 .379 .496 .328 .096
499 500 501 502 503 504 505 506 507 508 509 510
250
Figure 2 – Multivariable linear regression of factors influencing change in BL clearance rates. The regression model suggests no significant impact of the listed factors on change in BL clearance rates with the exception of “other” genotype (P ¼ .043), which may reduce the change in BL clearance seen during the first 7 days of therapy compared with those with homozygous dF508 genotype. þReference genotype group ¼ homozygous dF508. þþOther genotype ¼ genotypes not including dF508 or G551D. SMX/TMP ¼ sulfamethoxazole/trimethoprim. See Figure 1 legend for expansion of other abbreviations.
511 512 513 Q19
461 462 463 464 465 466 467 468 469 470 471 472 473 474 475 476 477 478 479 480 481 482 483 484 485 486 487 488 489 490 491 492 493 494 495
514 515 516
CrCL and the change in antibiotic clearance rates (r ¼ 0.12, P ¼ .122 for BL and r ¼ –0.09, P ¼ .240 for AMG).
Discussion These study data showed that BL clearance rates changed during the period of treatment for a CF APE. Mean BL clearance rates increased > 20% within the first week of treatment, which led to a dose adjustment in about 50% of patients and a mean increase in BL dose by nearly 20%. The dose adjustments made to piperacillin/tazobactam led to more supratherapeutic serum levels and fewer levels achieving goal, which suggests room for improvement in the identification of an optimal dose of this antibiotic. Simultaneously, AMG clearance rates also changed. However, contrary to mean BL clearance rates, mean AMG clearance rates decreased by about 6% during the same time frame and led to a 5% decrease in AMG dose. Monitoring of BL and AMG serum levels and calculation of their corresponding clearance rates are needed to optimize antibiotic dosing. According to our results, changes in antibiotic clearance rates are unrelated to changes in SCr and CrCL levels. Between day 2 and day 7, mean SCr values increased 0.04 mg/dL, leading to a calculated decrease in mean CrCL level of 4.94 mL/min. AMGs are almost entirely eliminated via glomerular filtration,35 which may explain the small decrease in mean AMG clearance rates. However, BL antibiotics undergo glomerular filtration as
well as tubular secretion.36 We hypothesized that this additional mechanism of drug excretion may contribute to the change in BL clearance rates. The mean increase of 12.2% predicted in FEV1 is both statistically and clinically significant and compares favorably with other reports.37,38 Finding this improvement in FEV1% is a promising piece of evidence supporting the use of continuous infusion BL antibiotics during APE treatment. However, we cannot directly compare these results with results from the use of conventionally dosed BLs. Confirmation in a randomized clinical trial is warranted. The finding for “other” genotypes implies a lower change in BL clearance compared with patients with homozygous dF508 genotype. However, this result must be interpreted with caution given the small sample size. The reason for this finding is unclear as it is the combined effect of individual genotypes in the group, none of which was frequent enough to allow for more detailed analyses. To our knowledge, no literature exists Q9 regarding change in CI BL clearance rates in relation to specific genetic mutations. Our study has several strengths. First, we used a wellannotated dataset, including patient genotypes. All patients admitted for the treatment of an APE without contraindications to BL and AMG therapy had the requisite BL and AMG levels because obtaining antibiotic levels on day 2 and day 7 of APE treatment is the standard of practice at our institution.
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Calculation of antibiotic clearance rates was also standardized with the creation of calculators, along with training for any pharmacist taking care of these study patients with CF on how to use these calculators and adjust antibiotic dosing based on drug levels. In terms of data collection, templates for progress notes on patients with CF allowed for consistent documentation of pharmacokinetic information and efficient data collection.
552 553 554 555 556 557 558 559 560 561
A limitation to the present study is that we could not include all antipseudomonal BLs because some (eg, imipenem, cefepime) are not routinely used at our institution. Ticarcillin/clavulanate was used in some of the study patients, but it is no longer available.39 Prior to 2010, tobramycin was dosed in every 8- to 12-h intervals; however, sensitivity analyses excluding these patients did not change our results. We are unable to confirm whether there are further changes in antibiotic clearance rates between 7 and 14 days of treatment because levels at the end of therapy have no clinical utility. In addition, we cannot ascertain whether the
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change in antibiotic clearance is an inducible process that occurs with each antibiotic exposure. Our analysis looked at the most recent admission during the given study period and included number of admissions during the study period in the regression analysis; the analysis revealed no statistical significance, suggesting no cumulative effects of repeated antibiotic treatments. However, this adjustment does not account for possible effects from admissions prior to the study period.
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Author contributions: L. T. H. had full access to all of the study data and is the guarantor of the integrity of this study and manuscript. L. T. H., R. D., J. B. K., V. S., and D. C. Y. contributed to study design; data were collected by L. T. H. and were analyzed by L. T. H., R. D., J. B. K., and V. S.; and L. T. H., T. G. L., J. B. K., V. S., and D. C. Y. contributed to the manuscript development.
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Increasing BL clearance rates during APE treatment in patients with CF frequently necessitates important dose increases to maximize efficacy. On the contrary, AMG clearance rates decreased, leading to a mean dose reduction to minimize antibiotic toxicity. Changes in BL and AMG clearance rates occur independent of renal function. Obtaining serum drug levels is essential to determining optimal dosing for individual patients because there is no correlation between antibiotic clearance rates and measures of renal function.
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Acknowledgments
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Conclusions
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Financial/nonfinancial disclosures: The authors have reported to CHEST the following: T. G. L. was supported during the performance of the study by grants from the National Institutes of Health/National Heart, Lung, and Blood Institute [grants R01 HL 125520, R01 HL 072938, R21 HL 084341], the CF Foundation of the United States [grants CC132-16AD, LIOU14Y0, LIOU06A0, LIOU13A0, LIOU14P0, LIOU14Y4, LIOU15Y4], the Ben B. and Iris M. Margolis Family Foundation of Utah, the Claudia Ruth Goodrich Stevens Endowment, and grants for performance of clinical trials from the Foundation for the National Institute of Health, Gilead Sciences, Inc, Nivalis Therapeutics, Inc, Novartis, Savara Pharmaceuticals, Vertex Pharmaceuticals, Inc, the Therapeutics Development Network of the Cystic Fibrosis Foundation, and Cystic Fibrosis Foundation Therapeutics. T. G. L. also discloses membership in the Clinical Research Committee of the Cystic Fibrosis Foundation and membership on the Editorial Board of CHEST. None declared (L. T. H., R. D., J. B. K., V. S., D. C. Y.).
6 Original Research
Other contributions: The authors thank Holly Carveth, MD, and Zubin Bhakta, PharmD, for assisting in caring for the patients with CF during the study period. Additional information: The e-Figures and e-Tables can be found in the Supplemental Materials section of the online article.
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