Optimization of Anti-Pseudomonal Antibiotics for Cystic Fibrosis Pulmonary Exacerbations: V. Aminoglycosides

See discussions, stats, and author profiles for this publication at: https://www.researchgate.net/publication/256378431 Optimization of Anti-Pseudomonal Antibiotics for Cystic Fibrosis Pulmonary Exacerbations: V. Aminoglycosides Article in November 2013 Impact Factor: 2.7 DOI: 10.1002/ppul.22813 Source: PubMed CITATIONS 12 READS 143 7 authors, including: Jeffery T Zobell Intermountain Medical Center 23 PUBLICATIONS 132 CITATIONS Chris Stockmann University of Utah 120 PUBLICATIONS 356 CITATIONS SEE PROFILE SEE PROFILE Krow Ampofo University of Utah 110 PUBLICATIONS 1,517 CITATIONS Catherine Mary Turner Sherwin University of Utah 125 PUBLICATIONS 463 CITATIONS SEE PROFILE SEE PROFILE Available from: Jeffery T Zobell Retrieved on: 09 May 2016

Optimization of Anti-Pseudomonal Antibiotics for Cystic Fibrosis Pulmonary Exacerbations: V. Aminoglycosides David C. Young, PharmD, 1,2 * Jeffery T. Zobell, PharmD, 3,4 Chris Stockmann, MSc, 5,6 C. Dustin Waters, PharmD, BCPS, 7 Krow Ampofo, MD, 5 Catherine M.T. Sherwin, PhD, 6 and Michael G. Spigarelli, MD, PhD 6 Summary. Intravenous (IV) anti-pseudomonal aminoglycosides (i.e., amikacin and tobramycin) have been shown to be tolerable and effective in the treatment of acute pulmonary exacerbations (APEs) in both pediatric and adult patients with cystic fibrosis. The aim of this review is to provide an evidence-based summary of pharmacokinetic/pharmacodynamic, tolerability, and efficacy studies utilizing IV amikacin, gentamicin, and tobramycin in the treatment of APE and to highlight areas where further investigation is needed. The Cystic Fibrosis Foundation Pulmonary Guidelines recommend that once-daily administration of aminoglycosides is preferred over three times per day in the treatment of an APE. The literature supports dosing ranges for amikacin and tobramycin of 30 35 and 7 15 mg/kg/day, respectively, given, with subsequent doses determined by therapeutic drug concentration monitoring. The literature does not support the routine use of gentamicin in the treatment of APE due to a lack of studies showing efficacy and evidence indicating an increased risk of nephrotoxicity. Further studies are needed to determine the optimal dosing strategy of amikacin in the treatment of an APE, and to further identify risk factors and determinants that influence the development of P. aeruginosa resistance with once-daily administration of tobramycin. Pediatr Pulmonol. ß 2013 Wiley Periodicals, Inc. Key words: aminoglycoside; amikacin; gentamicin; tobramycin; cystic fibrosis; Pseudomonas aeruginosa; pharmacokinetics; pharmacodynamics. Funding source: none reported INTRODUCTION Cystic fibrosis (CF) is a genetic disorder that leads to dysfunctional CF conductance transmembrane regulator (CFTR) proteins that affect multiple organ systems in the body. 1 Dysfunctional CFTR proteins in the pulmonary system result in thick mucous and recurrent bacterial infection. 1 Subsequent chronic inflammation leads to destruction of the bronchioles and the progressive loss of pulmonary function. 1 The Cystic Fibrosis Foundation (CFF) guidelines recommend treating an acute pulmonary exacerbation (APE) with two intravenous (IV) anti-pseudomonal antibiotics with different mechanisms of action to reduce the chance for the development of resistance and enhance 1 University of Utah College of Pharmacy, Salt Lake City, Utah. 2 Intermountain Cystic Fibrosis Adult Center, Salt Lake City, Utah. 3 Intermountain Primary Children s Medical Center, Salt Lake City, Utah. 4 Intermountain Cystic Fibrosis Pediatric Center, Salt Lake City, Utah. 5 Division of Pediatric Infectious Disease, University of Utah, Salt Lake City, Utah. 6 Division of Clinical Pharmacology and Clinical Trials Office, Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, Utah. 7 Department of Pharmacy, Intermountain McKay-Dee Hospital Center, Ogden, Utah. ß 2013 Wiley Periodicals, Inc. Review Criteria: A systematic review was conducted using Medline. MeSH and free text terms included: Cystic fibrosis, antibiotics, pharmacokinetics, pharmacodynamics, amikacin, gentamicin, tobramycin, aminoglycoside. Search results were restricted to the English language without an age limit. Also, reference lists and conference proceedings were reviewed. Conflict of interest: None. Correspondence to: David C. Young, PharmD, 30 South 2000 East L.S. Skaggs Pharmacy Institute Room 4916, Salt Lake City, UT, 84112. E-mail: david.young@hsc.utah.edu Received 16 November 2012; Revised 31 March 2013; Accepted 3 April 2013. DOI 10.1002/ppul.22813 Published online in Wiley Online Library (wileyonlinelibrary.com).

2 Young et al. antibiotic efficacy. 2 Surveys support the CFF recommendations by showing beta-lactam (98%), ciprofloxacin (1.5%), and aminoglycoside (61 84.3%) utilization in APE. 3 5 On the other hand, a Cochrane review conducted by Elphick et al. demonstrated that the evidence regarding single versus combination antibiotic therapy for the treatment of an APE are conflicting. 6 The authors reported no significant differences in pulmonary function, symptoms scores, adverse effects, and microbiologic outcomes between monotherapy and combination therapy. However, the authors noted a trend towards increased antibiotic resistance in the monotherapy group. In addition, the authors recommended interpreting their results with caution due to significant heterogeneity amongst the trials. As a result, the current CFF recommendation of using a combination of anti-pseudomonal antibiotics with different mechanisms of action is prudent. An aminoglycoside administered plus an anti-pseudomonal beta-lactam antibiotic was the most frequently reported combination utilized by CFF-accredited care centers (95.5%). 5 Consensus regarding optimization of dosing and dosing intervals of anti-pseudomonal antibiotics does not exist when comparing CFF, European Consensus Conference, United Kingdom (UK) CF Trust Working Group, and Food and Drug Administration (FDA) dosing recommendations (Table 1). 7 10 Prior publications in this State-of-the-Art series have examined the optimization of beta-lactams (aztreonam, carbapenems, penicillins, and cephalosporins), fluoroquinolones, and colistimethate sodium for the treatment of an APE in CF patients. 11 14 The optimal aminoglycoside dose, dosing interval, and pharmacokinetic/pharmacodynamic (PK/PD) targets for the treatment of an APE remain uncertain. Currently, the only aminoglycoside approved to be administered by inhalation is tobramycin. 15 Despite the ability to nebulize aminoglycosides such as tobramycin, there is no evidence to support their use during an APE in addition to IV anti-pseudomonal beta-lactam antibiotics. 16 19 The purpose of this review in the series is to summarize the PK/PD, efficacy, and tolerability studies that evaluated the use of aminoglycoside agents (i.e., amikacin, gentamicin, tobramycin) in the treatment of an APE and to highlight areas where further study is warranted. DESCRIPTION OF AMINOGLYCOSIDE AGENTS IV anti-pseudomonal aminoglycosides exhibit a wide range of antimicrobial activity against aerobic grampositive and gram-negative bacteria, including P. aeruginosa, as well as non-tuberculous mycobacteria (i.e., amikacin). Aminoglycosides were derived from different actinomycetes strains from the Streptomyces and Micromonospora families that were found to have activity against various gram-positive and gram-negative bacteria. 20 They were developed from the early 1940s until the 1970s. 20 Aminoglycosides have been shown to cause irreversible ototoxicity and cochlear toxicity, as well as reversible nephrotoxicity, which may be attributed to persistently high plasma concentrations (i.e., elevated trough level). 20 The anti-pseudomonal aminoglycosides include amikacin (Amikin), 21 gentamicin (Garamycin), 22 and tobramycin (Nebcin). 23 Aminoglycoside antibiotics share a common structural hexose nucleus and mechanism of antimicrobial activity (i.e., binding irreversibly to the 30S and/or the 50S ribosomal subunits to inhibit cell wall protein synthesis). 11,21 24 Unlike beta-lactam antibiotics, aminoglycoside antibiotics exhibit concentration-dependent bactericidal activity against susceptible organisms. 11,24,25 Thus, the higher the serum concentration that is achieved, the more rapid the bactericidal activity. 25 Consequently, the ratio of maximum serum concentration (C max ) to the minimum inhibitory concentration (MIC) is an important pharmacokinetic/pharmacodynamic (PK/PD) monitoring parameter for aminoglycoside antibiotics. A high C max /MIC ratio (i.e. 8 10) was strongly correlated with clinical response in hospitalized patients with suspected sepsis, resulting in a sixfold increase in clinical response rates to aminoglycoside therapy. 26 The PK/PD parameter of the ratio of the area under the curve (AUC) to the MIC has also been shown to have importance in the utilization of aminoglycosides in CF. 27,28 PHARMACOKINETICS/PHARMACODYNAMICS (PK/PD) Amikacin Pharmacokinetic studies performed in pediatric CF patients who received amikacin doses ranging from 5 to TABLE 1 Intravenous Aminoglycoside Dosing Recommendations for Patients With Cystic Fibrosis Antibiotic FDA-approved dosing 21 23 CFF recommendations 8 recommendations 7 European UK CF trust recommendation 9 Amikacin 15 mg/kg/day every 8 12 hr 30 mg/kg/day div 6 8 hr 30 mg/kg/day div every 12 hr Gentamicin 3 7.5 mg/kg/day div every 6 8 hr 10 mg/kg/day div every 6 8 hr NA NA Tobramycin 10 mg/kg/day div every 6 hr 10 mg/kg/day div every 6 8 hr 10 mg/kg/day div every 12 hr mg, milligram; kg, kilogram; hr, hours; div, divided. 15 30 mg/kg/day div every 8 12 hr 10 mg/kg/day div every 24 hr

Optimization of Aminoglycosides in CF 3 12.5 mg/kg divided every 6 12 hr were not significantly different from healthy control patients with respect to mean half life ðt 1=2 Þ, volume of distribution (V d ), clearance rates (Cl), or C max (Table 2). 29,30 The mean C max exceeded the MIC in all patients but varied by dose. Between consecutive amikacin infusions, the plasma level was above 4 mcg/ml for 20 30% and 46% of the time after the 5 and 7.5 mg/kg doses (Table 3). 29 Amikacin peak levels in the sputum did not achieve the mean P. aeruginosa MIC of 4 mcg/ml despite 12.5 mg/kg doses divided three to four times daily (Table 3). 30 A number of single daily dose (35 mg/kg/day) studies 31 34 of amikacin in CF patients have been undertaken. Once daily administration of amikacin resulted in longer t 1=2 (1.38 16.57 hr), larger V d (0.40 2.36 L/kg), lower systemic clearance rates (CL s ; 67.5 139 ml/min), higher C max (67 116 mcg/ml), and higher AUC (235 287 [(mg hr)/l]) compared to multiple daily dosing (Table 2). ). Canis et al. 32 found marked inter-patient variability associated with amikacin PK parameters and bronchial diffusion. Age correlated (r ¼ 0.85; P < 0.01) with amikacin total body clearance, and V d. (Table 2) Older patients had an increased total body clearance and lower V d. However, Beringer et al. reported that the wide variability in PK parameters noted by Canis et al, were most likely due to variable assay precision and when corrected for assay error are similar to previously reported estimates (Table 2). 33 Once daily administration of amikacin resulted in sputum concentrations remaining above the MIC to prevent 50% of the organisms to grow (MIC 50 ) for up to 16 hr (Table 3). 31 Gentamicin Although there are many published studies on gentamicin, there is limited PK evidence from clinical trials involving CF patients and gentamicin. Pharmacokinetic studies 35,36 were undertaken to investigate gentamicin dosing in 46 children and young adults with CF. The authors found a significantly increased apparent V d, CL s and decreased t 1=2 for patients with CF compared to control patients (Table 2). Consequently a larger daily gentamicin dose is required to maintain similar levels compared to patients without CF. 35 A gentamicin dose of 8.8 12 mg/kg/day divided every 6 hr is necessary to maintain C max concentrations between 8 and 12 mcg/ml and C min < 2 mcg/ml. 36 38 In an older study, MacDonald et al. 39 investigated gentamicin clearance after single and multiple IV administered doses in 10 non-acutely ill patients with mild to moderate CF. They reported that the mean 1-hr serum concentration, mean V d, and mean CL s of gentamicin were not different in patients without CF and suggested that patients with mild CF should receive standard doses of gentamicin (60 mg/m 2 ). 39 In a more recent study, Campbell et al. 40 suggested that a dose of 120 mg/m 2 should achieve an average 1 hr post-dose peak of 10 mg/l and trough of <1 mg/l, and that patients admitted to an intensive therapy unit might require higher doses due to increased gentamicin clearance rates. 40 There are no published PD studies of gentamicin in CF patients. Tobramycin The PK of tobramycin is seemingly well known and has been described in many studies. 41 43 Most studies have found that patients with CF have a larger V d and greater renal clearance rate (CL r ) for aminoglycosides like tobramycin when compared to those who do not have CF, and therefore require higher doses. 44 47 Dosing in PK studies of tobramycin in patients with CF ranged from 7 to 15 mg/kg/day divided every 6 24 hr (Table 2). 37,47 59 There have been only a limited number of studies that have investigated the use of once-daily aminoglycoside dosing in patients with CF 49 51,53,58 and even fewer studies have been done in children with CF. 51,58 PK studies administering tobramycin in CF patients used doses that ranged from 7 to 15 mg/kg/day and resulted in mean C max concentrations ranging from 22.6 to 42.5 mg/l and minimum serum concentrations (C min ) <1 mg/l (Table 2). 48,50,57,58,60 Touw et al. 56 investigated individualized drug dosage regimens using data from 82 adolescent and adult patients with CF who were treated with IV tobramycin due to an APE. 56 The authors reported higher total body clearance (5.6 L/hr vs. 4.0 L/hr) and creatinine clearance rates (137 ml/min vs. 110 ml/min) in CF patients versus non-cf patients. 56 In a more recent study, Touw et al. 57 found that the mean V d / kg is significantly higher in pediatric compared to adult patients (0.36 L/kg vs. 0.29 L/kg; P <.001) and that children will therefore require a 20% higher mg/kg dose to achieve the same target serum concentrations. 57 In addition, the authors reported that the mean elimination rate, in both pediatric and adult CF patients, was 30% less when tobramycin was administered once versus three times daily. 57 Lastly, the authors emphasized that the optimal C max /MIC ratio was 10 (Table 3). 57 Bates et al. 49 demonstrated that tobramycin (7 15 mg/kg/day) given to pediatric and adult CF patients during an APE resulted in a fivefold increase in the time the serum concentrations remained above an MIC of 1 mcg/ml when compared to tobramycin given as multiple daily doses (Table 3). 49 Roberts et al. 55 performed a nonblinded, randomized, cross-over investigation of the PK interaction between tobramycin and ticarcillin in 18 healthy CF patients with normal renal function. The V d and CL s of tobramycin increased by 14% (P < 0.001) and 13% (P < 0.001), respectively, in the presence of ticarcillin. Beringer et al. 50 reported that dosing of tobramycin (10 mg/kg/day) led to significantly

4 Young et al. TABLE 2 Summary of Pharmacokinetic Studies of Anti-Pseudomonal Aminoglycosides in Cystic Fibrosis Antibiotic Study Patients Age (years) Dose T 1/2 (hr) V d (L/kg) Cl (ml/min) AUC [(mg hr)/l] C max (mg/l i ) C min (mg/l) Amikacin Autret et al. 29 CF 7.6 (3 15) 5 mg/kg every 6 8 hr Healthy controls 7.5 mg/kg every 6 12 hr 12.5 mg/kg every 12 hr 6.3 (1 12) 5 mg/kg every 8 hr Grenier et al. 30 CF 7.6 (3 15) 5 12.5 mg/kg every 6 8 hr Healthy controls 6.3 (1 12) 5 12.5 mg/kg every 6 8 hr Beringer et al. 33 CF 9.8 (1.7 22.2) 35 mg/kg/day Byl et al. 34 CF 19 (10 32) 30 mg/kg/day Canis et al. 32 CF 9.8 (1.7 22.2) 35 mg/kg/day Vicetal. 31 CF 9.6 4.8 (1.8 22) 35 mg/kg/day Gentamicin Kearns et al. 35 CF 12.9 1.4 2.8 0.1 mg/kg every 6 8 hr Healthy controls 11.7 0.9 6.8 0.2 mg/kg/day div every 6 8 hr Bauer et al. 37 CF <18 10.3 3.2 mg/kg/day div every 6 hr Campbell et al. 40 CF Median 20 (14 35) Hendeles et al. 38 CF Pediatric median 9.5 (3 15) Adult median 22 (18 27) 160 300 mg every 8 24 hr Pediatrics: 3.1 0.9 mg/kg every 6 hr Adults: 3.0 0.3 mg/kg every 6 hr MacDonald et al. 39 CF 18.7 (10 29) 60 mg/m 2 /dose (single dose) 60 mg/m 2 every 6 8 hr Mann et al. 36 CF 2 32 8.8 mg/kg/day div every 6 hr 1.1 0.26 0.26 0.06 131 32 NR 18.5 4.2 (9 19.9) 25.6 10.2 (21 44) 31.5 10.8 (21.6 43.8) 1.1 0.6 (0.2 2) 1.9 1.5 1.9 5.5 0.83 0.15 0.26 0.03 157 33 NR 16.8 4.9 NR 0.94 0.25 0.26 0.06 130.7 32.4 NR 19 43.8 NR 0.83 0.15 0.27 0.04 155 17.4 NR 19 43.8 NR 1.38.35 85 NR NR NR 2.6 1.3 0.40 0.16 88.3 23.3 235 110 116 37 (82 192) 3.15 16.57 1.93 1.94 68.3 30 NR 121.4 37.5 (42.7 176) NR 2.24 3.11 (day 1) 2.36 1.67 130 39 ml/hr/kg (day 1) 139 39 ml/hr/kg 287 65 (day 1) 271 71 0.3 0.4 (<0.25 9.2) 0.88 0.62 (0.2 1.9) 73 19 (day 1) 0.8 0.55 (day 1) 67 19 0.74 0.5 1.62 0.15 0.34 0.30 73.8 4.1 NR 7.5 <0.5 1.98 0.27 0.24 0.02 40.6 4.7 NR 7.5 <0.5 1.4 0.4 0.35 0.15 2.79 0.75 ml/min/kg Pediatrics: 1.0 0.2 Adults: 1.1 0.2 NR 7 9 <2 9.2 L/m 2 2.89 L/m 2 NR 10 <1 NR e NR NR Pediatric: 9.6 1.2 Adult: 9.6 1.4 NR e 0.21 0.07 50.4 14.4 NR 5.8 (single dose) 1.1 0.5 0.20 0.06 2.28 0.89 ml/min/kg Tobramycin Aminimanizani CF 29.0 4.6 3.3 mg/kg every 8 hr 3.1 0.38 2.02 ml/min/kg et al. 48 CF 29.0 4.6 10 mg/kg/day 2.7 0.31 1.68 ml/min/kg 8.0 (multiple dose) Pediatric: 1.2 0.4 Adult: 1.2 0.3 <2.5 NR >8 NR 97.3 108 Median 14.0 (11.5 19.3) Median 35.9 (33.2 45.8) Median 0.9 (0.8 1.2) NR

Optimization of Aminoglycosides in CF 5 Table 2 (Continued) Antibiotic Study Patients Age (years) Dose T 1/2 (hr) V d (L/kg) Cl (ml/min) Bates et al. 49 CF 24.6 8.4 (6.6 44.8) 7 15 mg/kg/day Bauer et al. 37 CF <18 11.1 3.9 mg/kg/day div every 6 hr Beringer et al. 50 CF 27 6 10 mg/kg/day Bragonier et al. 51 CF 10 14 8 mg/kg/day CF 10 14 15 mg/kg/day Guglielmo et al. 52 CF NR 10 mg/kg/day CF NR 3.3 mg/kg every 8 hr Kelly et al. 47 CF 3 25 2.5 mg/kg every 6 hr 1.8 0.3 0.27 0.06 1.7 0.4 ml/min/kg AUC [(mg hr)/l] C max (mg/l i ) C min (mg/l) NR 42.4 4.5 (40.1 64.6) 1.2 0.5 0.33 0.20 2.98 0.80 ml/min/kg NR 7 9 <2 2.2 0.8 0.29 1.1 88.3 21.7 NR 110 32.5 29.3 6.9 h 1.1 0.9 f 2.37 0.37 0.43 0.09 3.67 0.82 L/hr 84.6 15.2 21.9 3.0 (16.9 25.9) 0.4 0.7 g 0.0 0.2 h 2.32 0.20 0.45 0.07 3.74 1.24 L/hr 159.9 42.4 40.2 8.1 <1 (32.3 56.6) 1.6 2.2 0.20 0.35 0.06 to 0.13 L/hr/kg NR NR NR 1.8 2.5 0.17 0.34 0.06 to 0.15 L/hr/kg NR NR NR 1.2 0.08 0.37 0.04 180.7 18.1 NR 6 10.5 <1 Massie et al. 53 CF 13.4 (9 20) 12 mg/kg/day 1.82 0.267 1.67 ml/min/kg NR 32.6 (29.3 35.9) Once daily Master et al. 60 CF 16 7 3 mg/kg every 8 hr CF 14 5 9 mg/kg/day Munzenberger CF 13 (6 27) 60 mg/m 2 et al. 54 every 8 hr Roberts et al. 55 CF 14 (4 21) 2.71 0.38 mg/kg every 8 hr 1.92 0.30 0.32 0.01 1.96 0.68 ml/min/kg 95 11.7 2.7 NR 1.71 0.30 0.31 0.07 2.13 0.59 ml/min/kg 104 41.3 11.0 NR 0.95 0.28 to 1.22 0.39 0.26 0.08 to 0.26 0.13 121.9 32.9 to 162.3 79.1 1.6 0.2 0.22 0.03 1.64 0.38 ml/min/kg CF 14 (4 21) With Ticarcillin 1.6 0.2 0.25 0.05 1.86 0.41 ml/min/kg Touw et al. 56 CF 28.1 6.8 3.3 mg/kg every 8 hr and 90 þ 2.14 LBM (kg) Vicetal. 58 CF 10.7 2.9 (7.4 17.9) CF 11.4 4.2 (5.6 19.3) 15 mg/kg/day div every 8 hr 15 mg/kg/day Whitehead et al. 59 CF 21 (16 32) 10 mg/kg/day CF 22 (15 47) 3.3 mg/kg every 8 hr 2.8 6.9 0.25 0.05 <1 NR NR 4.9 25.2 0.2 3.3 NR 10.2 1.2 1.2 0.4 NR 9.0 1.0 1.0 0.4 NR NR NR NR NR 0.54 0.88 3.73 1.37 L/hr/kg 121.5 42 13.2 7.1 (day 1) 12.4 3.9 NR 0.97 0.44 4.73 2.43 L/hr/kg 98.6 32.5 42.5 11.2 (day 1) 39.4 20 1.9 NR NR NR 29.1 (19.5 31.7) 1.1 0.8 (day 1) 0.9 0.5 0.3 0.2 (day 1) 0.4 0.3 2.7 (2.0 3.5)- 6hrlevel 1.9 NR NR NR 10.5 (8.9 12.1) 1.3 (1.1 1.6) mg/kg/day, milligram per kilogram per day; mg/kg/dose, milligram per kilogram per dose; hr, hours; mg/m 2, milligram per meter squared; kg, kilograms; NR, not reported; L/kg, liters per kilogram; ml/min, milliliters per minute; mg hr/l, milligram hours per liter; mg/l, milligram per liter; T 1/2, half-life; V d, volume of distribution; Cl, clearance; AUC, area under the curve; C max,maximumserum

6 Young et al. TABLE 3 Summary of Pharmacodynamic Studies of Anti-Pseudomonal Aminoglycosides in Cystic Fibrosis Antibiotic Study Dose Significant findings Amikacin Autret et al. 29 5 mg/kg every 6 8 hr; 7.5 mg/kg every 6 to 12 hr; 12.5 mg/kg every 12 hr The mean C max always exceeded the MIC but varied by dose; between consecutive doses the plasma level was above the MIC for 21% and 46% of the time after the 5 and 7.5 mg/kg doses, respectively Grenier et al. 30 5 12.5 mg/kg every 6 8 hr Amikacin peak levels in the sputum of children with CF never reached the mean P. aeruginosa MIC of 4 mg/l Vic et al. 31 35 mg/kg/day Sputum concentrations of amikacin were above the MIC 50 for 0.5 16 hr Gentamicin None Tobramycin Aminimanizani et al. 48 3.3 mg/kg every 8 hr; 10 mg/kg/day once daily C max /MIC ratio 10 maximizes pharmacodynamic activity and can be achieved with a dose of 10 mg/kg/day Bates et al. 49 7 15 mg/kg/day Once-daily tobramycin dosing resulted in serum concentrations 8 times above an MIC of 1 mg/l nearly fivefold longer than has been reported divided daily doses Beringer et al. 50 3.4 mg/kg every 8 hr; 5 mg/kg every 12 hr; 10 mg/kg/day Lower C max /MIC but shorter T < MIC were noted with 8 hr vs. 12 hr dosing, 8 hr vs. 24 hr dosing, and 12 hr vs. 24 hr dosing Master et al. 60 3 mg/kg every 8 hr (with ceftazidime); 9 mg/kg/day (monotherapy) Burkhardt et al. 27 3.3 mg/kg every 8 hr; 10 mg/kg/day once daily Both the C max /MIC and AUC/MIC ratios featured a log-linear relationship with FEV 1 % predicted; however, the association with the C max /MIC ratio did not display dependence on the dosing interval Hennig et al. 61 7.5 12 mg/kg/day 10 mg/kg/day most effective at maintaining AUCs 80 125 AUC significantly > vs. every 8 hr (104 vs. 95) despite no difference in Cl r,v d,t 1/2 Mouton et al. 28 3.3 mg/kg every 8 hr The AUC/MIC ratio is the pharmacodynamic index with the strongest correlation with FEV 1 and FVC Touw et al. 57 10 mg/kg/day 20% >mg/kg dose required in pediatric patients due to >V d /kg mg/kg, milligram per kilogram; hr, hours; C max, maximum serum concentration; MIC, minimum inhibitory concentration; CF, cystic fibrosis; mg/l, milligrams per liter; mg/kg/day, milligrams per kilogram per day; MIC 50, minimum inhibitory concentration required to inhibit the growth of 50% of the isolates; C max /MIC, ratio of the maximum serum concentration to the minimum inhibitory concentration; T < MIC, time less than the minimum inhibitory concentration; AUC/MIC, ratio of the area under the curve to the minimum inhibitory concentration; FEV 1 % predicted, forced expiratory volume in 1 sec percent predicted; P. aeruginosa, Pseudomonas aeruginosa; AUC, area under the curve; Cl r, clearance renal; V d, volume of distribution; t 1/2, half-life; FVC, forced vital capacity; FEV 1, forced expiratory volume in 1 sec; V d /kg, volume of distribution per kilogram. (P < 0.001) greater C max /MIC, AUC/MIC, and time below the MIC (T < MIC) ratios than two to three times a day dosing (Table 3). 50 Hennig et al. 61 developed one of the first PK models for (7.5 12 mg/kg/day) IV tobramycin in pediatric CF patients that used target concentration intervention dosing. 61 Inclusion of total body weight reduced between-subject variability in clearance from 50.1% to 11.7% and in volume of the central compartment from 62.2% to 11.6%. 61 The authors concluded that tobramycin dosing needs to be patient specific and that 10 mg/kg/day was the most effective initial regimen that would achieve an AUC between 80 and 125 (Table 3). 61 These results confirmed work in an earlier study by Aminimanizani et al. 48 that concluded that tobramycin (10 mg/kg/day) provides an optimal C max /MIC ratio of 10 in susceptible organisms (MIC <2 mcg/ml) and 24-hr area under the curve (AUC 24 ) of 70 100 (mg hr)/l. 48 Mouton et al. 28 derived quantitative relationships between PD indices and antimicrobial efficacy with tobramycin. 28 The authors found significant relationships between AUC/MIC and C max /MIC to FEV1 (forced expiratory volume in 1 sec; P ¼ 0.002 and 0.013, respectively; Table 3). No correlation was found between age, duration of infection, and the PD indices of both tobramycin and ticarcillin, leading the authors to conclude that these factors did not have a

Optimization of Aminoglycosides in CF 7 significant effect upon the dose-effect relationships found. 28 Similarly, Burkhardt et al. 27 observed that the most significant PK/PD parameter was the C max /MIC ratio. 27 Both C max /MIC and AUC/MIC ratios featured a log-linear relationship with FEV 1 % predicted. 27 In addition, tobramycin dosing with higher C max concentrations led to AUC/MIC ratios that correlated better with FEV 1 compared to every 8-hr dosing (Table 3). 27 EFFICACY/TOLERABILITY Amikacin Amikacin is the second most common aminoglycoside utilized by pediatric CFF centers (42.6%) and its usage amongst adult CFF centers is unknown. 5 Efficacy studies (Tables 4 and 5) administered amikacin in CF patients with doses ranging from 7.5 to 12 mg/kg/dose divided every 8 hr or 35 mg/kg/day. 31,62,63 Lau et al. 62 demonstrated CF patients who were treated with amikacin at 7.5 mg/kg (three patients initially received 10 mg/kg) every 8 hr in combination with carbenicillin (no dosage given) and ampicillin (no dosage given) responded clinically and microbiologically. Adverse effects associated with amikacin (increase in serum creatinine and ototoxicity) were seen in a few patients (Tables 4 and 5). 62 Schaad et al. 63 investigated amikacin 12 mg/kg every 8 hr in combination with aztreonam or ceftazidime (300 mg/ kg/day divided four times daily each) and reported significant clinical and microbiological improvements, and that it was well tolerated (Tables 4 and 5). 63 In the previously mentioned study by Vic et al., 31 all patients treated with amikacin 35 mg/kg/day plus ceftazidime or imipenem (200 mg/kg/day divided three times daily each) had significant improvements in nutritional status, cardiopulmonary function, inflammation, and microbiological outcomes. This amikacin regimen was well tolerated with no evidence of ototoxicity or nephrotoxicity (Tables 4 and 5). 31 Gentamicin Gentamicin is the third most commonly utilized aminoglycoside among CFF-accredited care pediatric centers in the USA (25.8%). 5 Efficacy and tolerability of gentamicin alone or in combination with a beta-lactam antibiotic have been assessed in CF patients (Tables 4 and 5). 64,65 Both studies showed significant clinical improvements (i.e., clinical and radiological scores, and pulmonary function tests) and reported that gentamicin was well tolerated (Tables 4 and 5). 64,65 Parry et al. 64 did show evidence of transient nephrotoxicity in some patients with an elevation in blood urea nitrogen (BUN; 14%) and cylinduria (4%). No evidence of ototoxicity or vestibular toxicity were reported (Table 5). 64 Penketh et al. 65 did not report any changes in BUN from baseline (Table 5). In a study by Martin et al., gentamicin or tobramycin (9 mg/kg/day divided TID) plus carbenicillin (800 mg/kg/day divided every 6 hr) were utilized for the treatment of APE in pediatric CF patients. 66 Both groups experienced significant improvements in clinical and modified X-ray scores (P < 0.001). There were no significant differences found between groups. There were no changes in BUN, electrolytes, or LFT s during the trial (Tables 4 and 5). 66 However, IV gentamicin is not recommended for use in CF patients due to the high potential for inducing renal failure (Table 5). 9,67 69 A small case report by Drew et al. 67 showed that over a 9-month period, three CF patients (ages 4 months to 9 years) developed acute renal failure (ARF) and acute tubular necrosis (ATN) while receiving appropriately dosed gentamicin and ceftazidime. This prompted those authors to survey CF centers in the UK to determine the incidence of ARF in CF patients and to identify possible risk factors. Of the 55 survey responses, 26 cases were further studied and 24 fit the criteria for ARF. Twenty-one cases (88%) of ARF involved an aminoglycoside. Of these cases, 16 (76%) received gentamicin. Seven cases had a renal biopsy performed, and ATN occurred in six (86%) of these. All patients received gentamicin. This led to the conclusion that gentamicin may be a contributing factor in the etiology of ARF in CF patients and further study was needed. 68 In a case control study by Smyth et al. 69 the 24 cases of ARF that were determined by the survey were further analyzed. Control subjects (four per ARF case) were matched to the case subjects for sex and age. The hypothesis of the study was that ARF occurred more frequently in CF patients with recent receipt (within 1 week) or among patients who were concomitantly receiving IV aminoglycosides. The authors examined whether gentamicin was more nephrotoxic than other aminoglycosides, other ARF risk factors (i.e., cysticfibrosis-related diabetes, acute dehydration, and other nephrotoxic drugs, such as non-steroid anti-inflammatory drugs), effects of aminoglycoside dosing regimens (i.e., dose, frequency, cumulative exposure), and effects of a cephalosporin or nebulized antibiotic on increasing the risk of ARF. Twenty-one of 24 cases (88%) received an aminoglycoside within 1 week or were concurrently receiving an aminoglycoside around the episode of ARF versus 3/42 (7%) of controls (OR 81.8, 95% CI 4.7 1,427, P < 0.001). In the year prior to the ARF episode, 19/24 (79%) cases versus 1/42 (2%) controls received gentamicin (P < 0.001). There was no increased risk of ARF in cases versus controls with tobramycin (9/24 vs. 16/42, P ¼ 0.9). A known risk factor for ARF was present in 18/ 24 (75%) cases versus 7/42 (17%) controls (OR 24.0, 95% CI 3.1 186.6, P ¼ 0.002). The authors concluded that aminoglycosides were a risk factor of ARF in CF patients,

8 Young et al. TABLE 4 Summary of Efficacy Studies of Anti-Pseudomonal Aminoglycosides in Cystic Fibrosis Antibiotic Study Mean (SD), age (yrs) Dose Outcomes Amikacin Lau et al. 62 14.1 6.5 7.5 mg/kg every 8 hr; 10 mg/kg every 8 hr " from baseline in clinical response, chest X-rays, spirometry, arterial oxygen Schaad et al. 63 15.4 6.0 12 mg/kg every 8 hr " from baseline in clinical/radiographic score, radiologic score, FEV 1 % predicted, FVC % predicted, O 2 saturation (P < 0.05); from baseline ESR (P < 0.05), WBC, neutrophil counts (P < 0.001) Vicetal. 31 9.6 4.8 35 mg/kg/day " from baseline in weight/height ratio, daily energy intake, prealbumin (P < 0.001); " from baseline FVC% predicted, FEV 1 % predicted, FEF 25 75% % predicted, and nocturnal SaO 2 (P < 0.01); from baseline in HR, WBC, PMNs, and ESR (P < 0.001), RR (P < 0.05) Gentamicin Parry et al. 64 12.9; range: 5 31 Adults: 3 4 mg/kg/day; children: 4 7 mg/kg/day Gentamicin (G) þ tobramycin (T) Penketh et al. 65 Range: 17 29 Dose adjusted to achieve a serum concentration of 8 10 mg/ml 15 min after a bolus injection Martin et al. 66 Range: 3 11 Gentamicin 9 mg/kg/day div TID tobramycin 9 mg/kg/day div TID Tobramycin Burkhardt et al. 27 Range: 19 37 3.3 mg/kg every 8 hr; 10 mg/kg/day once daily Master et al. 60 16 7 3 mg/kg every 8 hr (with ceftazidime; 9 mg/kg/day (monotherapy) Riethmueller et al. 76 11.2; range: 2 18 3.3 mg/kg every 8 hr; 10 mg/kg/day once daily Smyth et al. 77 Range: 5 50 3.3 mg/kg every 8 hr; 10 mg/kg/day once daily 66% of patients " from baseline in Shwachman score (P < 0.01) " from baseline in PEFR, FVC % predicted, and FEV 1 % predicted (P < 0.001) Improvements from baseline in clinical and modified X-ray scores (P < 0.001; both groups) " from baseline in FEV 1 % predicted and IVC % predicted; from baseline in CRP, leukocytes, and IgG " from baseline in FVC, FEV 1, FEV 1, and FEF 25 75% % predicted (P < 0.05) " from baseline in weight, FEV 1 % predicted, FVC % predicted, MEF 25 % predicted; from baseline in P. aeruginosa sputum density, CRP, leukocytes, and IgG " from baseline in FEV 1 % predicted; from baseline in CRP and clinical score Vicetal. 58 10.7 2.9 (7.4 17.9) 15 mg/kg/day div every 8 hr " from baseline in weight/height, prealbumin (P < 0.002), FVC% predicted, FEV 1 % predicted (P < 0.05), FVC 25 75% % predicted (P < 0.02) and nocturnal SaO 2 ; from baseline in HR, RR (P < 0.05), WBC (P < 0.004), and PMNs (P < 0.01) Whitehead et al. 59 21 (16 32) 10 mg/kg/day " from baseline in FVC, FEV 1, and FEF 25 75% % predicted, and BMI (P < 0.02); from baseline in clinical score, WBC, % neutrophils, and CRP (P < 0.001) Wood et al. 78 26.7 (9.5) every 8 hr group; 28.7 (8.4) every 12 hr group Mean dose 7.2 mg/kg every 8 hr; mean dose 6.8 mg/kg every 12 hr No difference in weight, length of hospital stay, days to next exacerbation, or nephrotoxicity yrs, years; mg/kg, milligram per kilogram; hr, hours; ", increased ;, decreased; FEV 1 % predicted, forced expiratory volume in 1 sec percent predicted; FVC % predicted, forced vital capacity percent predicted; mg/kg/day, milligrams per kilogram per day; FEF 25 75%, forced expiratory flow between 25 and 75% of forced vital capacity; SaO 2, transcutaneous oxygen saturation; WBC, white blood cell count; PMNs, polymorphonuclear cells; ESR, erythrocyte sedimentation rate; mg/ml, micrograms per milliliter; PEFR, peak expiratory flow rate; TID, three times daily; IVC % predicted, inspired vital capacity percent predicted; CRP, C-reactive protein; IgG, immunoglobulin G; MEF 25 % predicted, midexpiratory flow rate; BMI, body mass index.

TABLE 5 Summary of Microbiological and Adverse Effects From Studies of Anti-Pseudomonal Aminoglycosides in Cystic Fibrosis Antibiotic Study Microbiological results Adverse effects Amikacin Lau et al. 62 Eradication of PA (11%); no development of amikacin-resistant PA isolates; 33% of patients isolated other aerobic bacteria [E. coli (3); P. mirabilis (2); K. Pneumonia (2); S. aureus (2); H. Influenza (1)] Schaad et al. 63 P. aeruginosa was eradicated in 57 61% of patients " from baseline in S cr (0.8 4.5 mg/dl) 1 patient (patient was concomitantly being treat for cardiovascular collapse); Ototoxicity ( 15 decibels) 2 patients; both patients had history of aminoglycoside exposure No D from baseline in BUN, S cr, CBC; transient thrombocytopenia (11%) in aztreonam/amikacin group.; transient threefold " from baseline in AST, ALT in 14% of the aztreonam/ amikacin and 7% of the ceftazidime/amikacin groups Vic et al. 31 Eradication of PA in 14 patients No reports of ototoxicity or dizziness; no change in proteinuria, lysozymuria, creatinine clearance, or in b 2 microglobulinuria Gentamicin Bertenshaw et al. 68 NR ARF (16/24, 76%) with 6/7 (86%) experiencing ATN Drew et al. 67 NR ARF (3 cases) with 2 patients experiencing ATN Parry et al. 64 NR Transient elevation in BUN (14%); transient cylinduria (4%); no ototoxicity or vestibular toxicity noted Penketh et al. 65 NR No changes in BUN Smyth et al. 69 NR 19/24 (79%) cases of ARF vs. 1/42 (2%) controls received gentamicin (P < 0.001); no " risk of ARF in cases vs. controls with tobramycin (9/24 vs. 16/42, P ¼ 0.9); Gentamicin more nephrotoxic than tobramycin Gentamicin (G) þ Tobramycin (T) Martin et al. 66 G: Eradication achieved in 80% of patients; T: Eradication achieved in 80% of patients Tobramycin Burkhardt et al. 27 Tobramycin-resistant (MIC 16 mg/l) " 29% (D from 1 to 5 patients) in vs. " 19% (D from 2 to 3 patients) in thrice-daily; 8 patients () had " tobramycin MIC vs. 6 patients (thrice daily); mean DMIC from baseline 6.8 mg/l () vs. 0.6 mg/l (thrice daily), P < 0.034; no change in PA susceptibility for meropenem and ceftazidime; no " in isolation of fungi or S. aureus and S. maltophiliaat end of treatment Master et al. 60 " MICs for non-mucoid and mucoid PA in 13.2 to 18.4, P ¼ 0.076 (thrice daily with ceftazidime) vs. 11.5 to 19.4, P ¼ 0.014 ( as monotherapy); # of mucoid PA isolates (MIC 8 mg/l) in thrice daily vs. no change (); # nonmucoid PA isolates (MIC 8 mg/l) no change (thrice daily) vs. " () Optimization of Aminoglycosides in CF 9 No ototoxicity or changes in BUN (both groups) No changes from baseline in LFTs, BUN, S cr ;no ototoxicity reported; no serious adverse events No changes in S cr ; " urinary NAG/creatinine from day 1 to day 10, P < 0.001 (both groups); " median urinary NAG/creatinine 1.94 units/mmol (thrice daily) vs. 1.17 units/mmol (), P < 0.01; 1 patient () had NAG/creatinine at upper limit of normal range (9.6 units/mmol) vs. 6 patients (thrice daily) (9.3 23 units/mmol), P < 0.05; no change in hearing; tinnitus occurred in 2 patients (1 per group) due to rapid tobramycin administration did not recur once rate slowed; no change in S cr or audiology after 12 months (Continued)

10 Young et al. Table 5 (Continued) Antibiotic Study Microbiological results Adverse effects Riethmueller et al. 76 PA sputum density (both groups) No changes in S cr (both groups); " urinary NAG/creatinine in both groups no difference between groups; " a m 1 microglobulin in both groups no difference between groups; no change in hearing Smyth et al. 77 NR S cr 1.5% () vs. "1.7% (thrice daily), P ¼ 0.21 (all patients); 4.5% () vs. "3.7% (thrice daily), P ¼ 0.04 (children); "2.0% () vs. 1.1% (thrice daily), P ¼ 0.14 (adults); " urinary NAG was 33% less in vs. thrice daily in all patients (P ¼ 0.049), and children (P ¼ 0.02); hypomagnesaemia in 7 patients 4 () vs. 3 (thrice daily); no hearing loss; dizziness in 2 patients (1 per group) Vicetal. 58 NR No ototoxicity, dizziness, change in creatinine clearance; no significant " in proteinuria, lysozymuria, and b 2 microglobulinuria Whitehead et al. 59 8 patients (4 per group) developed resistance to PA No changes in serum potassium, magnesium, serum creatinine; no reports of tinnitus, dizziness, or vertigo Wood et al. 78 Neither group completely eradicated PA 7 of 18 (38.9%) patients in every 8 hr tobramycin group had hearing loss 20 db; no patients experienced hearing loss in every 12 hr group. The authors did not report whether prior history of aminoglycoside exposures was equal at baseline PA, Pseudomonas aeruginosa; ", increased; mg/dl, milligrams per deciliter;, decreased; D, change; BUN, blood urea nitrogen; CBC, complete blood count; AST, aspartate transaminase; ALT, alanine transaminase; b 2, beta 2;, greater than or equal to; NR, not reported; ARF, acute renal failure; ATN, acute tubular necrosis; MIC, minimum inhibitory concentration; mg/l, milligrams per liter; DMIC, change in minimum inhibitory concentration; LFTs, liver function tests; NAG, N-acetyl-b-(D)-glucosaminidase; mmol, millimoles; a, alpha; db-decibels. particularly gentamicin, which was shown to be more nephrotoxic than tobramycin. Use of aminoglycosides in patients with known risk factors of renal impairment may require closer monitoring, and routine use of IV gentamicin in the treatment of APE is not recommended. 69 Tobramycin Tobramycin is the most commonly utilized aminoglycoside among CFF-accredited care pediatric centers in the USA (98.5%). 5 Tobramycin can be administered during an APE once, twice, or three times daily. In a 1993 national survey, it was estimated that 6.3% of the US centers that were surveyed utilized extended-interval aminoglycoside dosing. 70 Data from the UK and Australia suggest that aminoglycoside dosing occurs in 17 54% of the centers surveyed. 71,72 Recent surveys of CFF care centers reported that 61 98.5% of the centers surveyed utilize dosing of tobramycin. 4,5 Two Cochrane reviews have been published regarding versus multiple daily dosing of aminoglycosides in patients with CF. 73,74 Both reviews concluded that dosing is equally effective as to three times daily dosing of aminoglycosides to treat an APE with support for less nephrotoxicity in children. 73,74 In addition, a meta-analysis conducted by Barza et al. 75 concluded that once-daily aminoglycosides was as effective as multiple daily dosing with a lower risk of nephrotoxicity in non-cf patients. Current CFF guidelines recommend that dosing of aminoglycosides is preferred to three times daily dosing during the treatment of an APE but dosing recommendations have not been provided. 2 The efficacy and tolerability of tobramycin (10 15 mg/ kg/day) administered in CF patients for the treatment of an APE has been evaluated in six clinical trials (Tables 4 and 5). 27,58 60,76,77 Vicetal. 58 evaluated to bramycin 15 mg/kg/day divided one or three times daily with ceftazidime 200 mg/kg/day divided every 8 hr in 22 patients admitted for APE due to P. aeruginosa for 14 days. 58 The mean C max was 39 and 12 mcg/ml on day 14 in the once versus three times daily tobramycin treatment groups, respectively. 58 Compared to baseline, patients in both groups improved their nutritional status, pulmonaryfunction, heart rate (HR), respiratory rate

Optimization of Aminoglycosides in CF 11 (RR), and inflammatory mediators (Table 4). In addition, the authors assessed tolerance and reported no significant differences between groups (Table 5). 58 Master et al. 60 conducted a study of tobramycin alone (9 mg/ kg/day) or tobramycin (3 mg/kg/dose every 8 hr þ ceftazidime 50 mg/kg/dose every 8 hr) for 10 days. 60 The mean C max was 41 and 12 mcg/ml on day 10 in the once versus three times daily tobramycin treatment groups, respectively. Both groups demonstrated significant improvements in pulmonary function compared to baseline (P < 0.05; Table 4). 60 There were no significant differences between groups with respect to renal function or audiology after 10 days and after 12 months (Table 5). 60 The authors noted a significant increase in the MIC of mucoid and non-mucoid P aeruginosa isolates in the tobramycin monotherapy group (P ¼ 0.014) despite a significantly higher AUC (104 vs. 95; P < 0.05; Table 5). 60 Whitehead et al. 59 conducted a randomized 12-day trial of tobramycin 10 mg/kg/day versus 3.3 mg/kg three times daily in combination with an anti-pseudomonal beta-lactam antibiotic in 60 adolescent and adult patients with CF during an APE. 59 The targeted peak and trough serum concentrations for the three times daily tobramycin group were 10 12 and <2 mg/l, respectively. Target peak and trough serum concentrations for the tobramycin group were not defined. Significant improvements in pulmonary function, nutritional status, clinical score, and inflammatory markers were observed in both treatment groups (Table 4). ). The authors concluded that tobramycin was equivalent to three times daily tobramycin with respect to changes from baseline in forced vital capacity (FVC) % predicted, body mass index (BMI), serum potassium and magnesium, and CRP levels. However, there was insufficient power to determine equivalence of FEV 1 and FEF 25 75%. Eight patients were withdrawn from the study due to development of P. aeruginosa resistance (Table 5). 59 Burkhardt et al. 27 enrolled 33 adult CF patients in a single-center, randomized, controlled, nonblinded trial and evaluated the efficacy of once versus three times daily tobramycin in combination with either meropenem (51.5% of patients) or ceftazidime (48.5% of patients). 27 Seventeen patients received 10 mg/kg of tobramycin delivered and 16 patients received tobramycin 10 mg/kg/day divided three times daily. Target peak and trough serum concentrations were 20 40 and <1 mg/l for versus 5 20 and <2 mg/l for three times daily tobramycin, respectively. Both study group s demonstrated significant improvements from baseline in pulmonary function and inflammatory markers after 14 days of treatment (Table 4). 27 The authors discovered that improvement in FEV 1 correlated with AUC 24 /MIC and C max /MIC ratios. This demonstrated that for equivalent AUC 24 /MIC ratios, once-daily dosing of tobramycin resulted in greater improvements in lung function when compared to three times daily tobramycin dosing. 27 The most important predictor of improvements in lung function in CF patients with chronic P. aeruginosa infections was the C max /MIC ratio. The authors observed a significant increase in the MIC (mean change 6.8 mg/l; P ¼ 0.034) of P. aeruginosa isolates following tobramycin treatment (Table 5). In contrast, there was no change in the MIC (mean change 0.6 mg/l; P > 0.05) following three times daily tobramycin treatment (Table 5). Moreover, there was no change in the susceptibility of P. aeruginosa to meropenem or ceftazidime during the trial. 27 In a 30 patient trial, Riethmueller et al. 76 evaluated tobramycin (10 mg/kg/day) versus three times daily (3.3 mg/kg/dose every 8 hr) in addition to ceftazidime 200 mg/kg/day divided every 8 hr in CF patients who were clinically stable but receive periodic elective antipseudomonal treatment. 76 After 2 weeks of therapy, ceftazidime and tobramycin led to improvements in weight, pulmonary function, reductions in P. aeruginosa sputum density, and inflammatory markers (Tables 4 and 5). The improvements in FEV 1 % predicted and FVC % predicted were maintained 3 weeks after the treatment was completed. There were no significant differences between treatment groups in S cr, N-acetyl-b-D-glucosaminidase (NAG), or audiometry during the 5-week trial (Table 5). 76 Smyth et al. 77 conducted a multi-center, double-blind, randomized, controlled trial comparing once versus three times daily tobramycin in combination with thrice daily ceftazidime in 219 patients (ages 5 50 years) with chronic P. aeruginosa infection treated for an APE for 14 days. 77 Patients were randomly assigned to receive one or three times daily tobramycin with a total daily dose equivalent to that which was received on previous admissions or 10 mg/kg/day if they were tobramycin naïve. Target C max and C min serum concentrations were 20 30 and <1 mg/l for versus 5 12 and <2 mg/l for three times daily tobramycin, respectively. Following 14 days of treatment, the mean change in FEV 1 % predicted was equivalent between the one and three times daily tobramycin groups for both the per-protocol and intention-to-treat analyses (Table 4). In addition, subgroup analyses of pediatric and adult patients revealed no significant differences in FEV 1 % predicted between treatment groups. There were no significant differences detected in the intention-to-treat analyses with respect to serum creatinine (Table 5). However, subgroup analyses revealed that serum creatinine decreased by 5% in the pediatric treatment group whereas it increased by 4% in the three times daily treatment group (P ¼ 0.04; Table 5). Furthermore, increases in NAG concentrations in all patients were 33% higher in the three times daily tobramycin group (P ¼ 0.049; Table 5). Subgroup analyses in children revealed significantly greater increases in NAG concentration after 14 days of

12 Young et al. TABLE 6 Evidence-Based Recommendations of Intravenous Anti-Pseudomonal Aminoglycosides for Pediatric and Adult CF Patients Antibiotic Dose Maximum dose Amikacin 31,32,34 30 35 mg/kg/day every 24 hr C max (peak) range: 80 120 mg/l; C min : <1 mg/l Gentamicin 9,67 69 Not recommended for routine use Not recommended for routine use Tobramycin 27,58,59,77 10 mg/kg/day every 24 hr C max (peak) range: 20 40 mg/l; C min : <1 mg/l mg/kg/day, milligram per kilogram per day; hr, hours; C max, maximum serum concentration; C min, minimum serum concentration. three times versus tobramycin (P ¼ 0.02; Table 5). There were no significant differences among audiograms, clinical scores, or CRP levels between groups (Tables 4 and 5). The authors concluded that ceftazidime administered in combination with tobramycin was equivalent to three times daily tobramycin for an APE. In addition, tobramycin may result in less nephrotoxicity in children. 77 There is currently one published trial regarding the efficacy and tolerability of tobramycin administered twice daily. 78 The authors compared tobramycin (in addition to an anti-pseudomonal penicillin or cephalosporin; no doses reported) divided every 8 hr versus 12 hr with doses that targeted C max concentrations of 10 mg/l and C min concentrations of <2 mg/l. There were no differences noted in weight, length of hospital stay, time to next admission or nephrotoxicity. None (0 out of 8) of the patients in the twice daily group experienced ototoxicity; however, 39% (7 out of 18) experienced ototoxicity in the three times daily group (P < 0.05). There was no reported prior aminoglycoside exposures at baseline, which may affect the interpretation of their findings as the mean age of the study population was 27 years. This finding has not been replicated in the aforementioned tobramycin trials. 27,58 60,76,77 There are currently no efficacy trials published comparing once versus twice daily dosing of tobramycin in CF patients during and APE. EVIDENCE-BASED SUMMARY OF ANTI-PSEUDOMONAL AMINOGLYCOSIDES Studies support an amikacin dosing regimen of 30 35 mg/kg/day IV as a tolerated and effective regimen in pediatric and adult patients for the treatment of APE due to P. aeruginosa (Table 6). 31,32,34 The literature supports targeting amikacin serum C max and C min concentrations of 80 120 and <1 mg/l. 31,32,34 The literature supports targeting a mean AUC of 235 110 [(mg hr)/l]. 34 However, the clinical significance of targeted AUC monitoring for amikacin is unclear and requires further study. There is no literature support for the amikacin dosage regimen of 30 mg/kg/day divided every 6 12 hr, despite the CFF and European recommendations. 7,8 The revised CFF exacerbation guidelines recommend once daily aminoglycoside administration. 2 Larger studies are needed to determine the optimal dosing and PD monitoring strategies of amikacin in treating an APE. There is support for IV tobramycin 10 mg/kg/day given which is better tolerated and as effective as multiple daily dosing regimens (FDA-approved, CFF and European Consensus recommendations) in the treatment of APE due to P. aeruginosa (Table 6). 27,58,59,77 The revised CFF exacerbation guidelines recommend this as the preferred regimen. 2 The literature supports targeting tobramycin serum C max and C min concentrations of 20 40 and <1 mg/l. 27,58,59,77 A targeted mean AUC of 60 120 [(mg hr)/l] has support in the literature. 27,28,48,60 However, the clinical significance of targeted AUC monitoring for tobramycin is unclear and requires further study. Studies have reported that multiple daily dosing of tobramycin have higher rates of side effects, but decreased resistance patterns as compared to tobramycin. 27,58,59,77 Studies to further elucidate the development of resistance are needed. The literature does not support the routine use of gentamicin in the treatment of APE secondary to P. aeruginosa due to the paucity of studies showing efficacy and evidence indicating an increased risk of nephrotoxicity (Tables 5 and 6). 9,67 69 CONCLUSIONS This review has evaluated the PK/PD, efficacy, and tolerability studies of anti-pseudomonal aminoglycosides utilized for the treatment of an APE in CF patients. Following an APE, CF patients often do not return to their baseline lung function and bacteria are becoming increasingly resistance to antibiotics. As a result, it is important to optimize the use of antibiotics in the treatment of an APE. Optimal dosing of aminoglycosides with targeted adjustment to regimens is essential to maximize outcomes and preserve lung function. We have reviewed the literature and provided evidence-based recommendations on the dosing regimens of antipseudomonal aminoglycosides. Importantly, we have also identified areas where further research is necessary to optimize pharmacotherapy for patients with APE.