Dosing of antibacterial agents in obese adults: does one size fit all?

Expert Review of Anti-infective Therapy Downloaded from informahealthcare.com by Chinese University of Hong Kong on 02/23/15 For personal use only.

Review

Dosing of antibacterial agents in obese adults: does one size fit all? Expert Rev. Anti Infect. Ther. 12(7), 829–854 (2014)

Kenna D Payne1 and Ronald G Hall II*1,2 1 Texas Tech University Health Sciences Center, 1300 S. Coulter, Rm 323, Amarillo, TX 79106, USA 2 Dose Optimization and Outcomes Research (DOOR) Program, 5920 Forest Park Rd, Suite 400, Dallas, TX 75235, USA *Author for correspondence: Tel.: +1 214 654 9404 Fax: +1 214 654 9707 [email protected]

Obesity is a global pandemic affecting 33% of adults in the United States. Obese persons receiving cefazolin or fluconazole have been shown to have worse outcomes with suboptimal dosing. Studies evaluating the safety of colistin, daptomycin, and vancomycin have shown increased weight or obesity may potentially increase toxicity. Many antimicrobials lack pharmacokinetic data to support dose individuation in obese persons, due in part to the lack of obese patients in drug development studies. A one size fits all approach to dose optimization for obese patients is not likely. Current expert opinion suggests some antimicrobials (i.e. vancomycin) be dosed according to total body weight, whereas others (i.e. aminoglycosides) require adjusted body weight for dose calculations. Yet other antimicrobials are reported to need no dose adjustment, largely based on studies using body mass index groups. Therefore, each drug should be individually evaluated to determine the proper dose for obese persons. KEYWORDS: antibacterial • BMI • body weight • dose adjustment • obesity • pharmacokinetics

The WHO defines overweight and obesity as abnormal or excessive fat accumulation that may impair health and uses BMI to classify adults in weight categories. Recent estimates state that 1.4 billion adults are overweight [1]. Out of these adults, approximately 500 million are obese. Prevalence rates for obesity in the USA are now greater than 33% and combined overweight with obesity is now above 68%, both of which increased from the previous decades [2,3]. Even with recent legislation regarding diet and exercise in school settings, as well as widely accessible recommendations on maintaining a healthy weight as an adult, it does not appear as if this pandemic will be resolved any time soon [3]. Therefore, healthcare providers must be educated on the differences in treating patients who are overweight and obese. Obese persons are not mandated to be included in all stages of drug development by the US FDA, even though obese patients may have altered pharmacokinetics and/or outcomes. Dose optimization for obese patients has been shown to be associated with improved outcomes for some antimicrobials. A one-size-

informahealthcare.com

10.1586/14787210.2014.912942

fits-all dosing approach cannot be applied to all antibacterials due to potential safety issues. Therefore, specific data guiding the dose optimization of each antibacterial are needed in order to maximize the efficacy and safety of these agents in obese patients. This review will discuss the available literature TABLE 1 for antibacterial agents in obese adults. Pharmacokinetic & pharmacodynamic evaluation

There is much conflict in this field on what alterations are prevalent in the obese. One of the largest areas of debate is the optimal method to estimate glomerular filtration rate (GFR) [4]. Obesity is associated with increased GFR and kidney size. Doubling of total weight leads to an increase of 64% in kidney mass. Note that this is not a 1:1 linear increase, but closer to the 3/4 law [5,6]. Currently, the Cockcroft–Gault equation is the preferred method to calculate renal clearance (Cl) for drug therapy because dosing adjustments for renal dysfunction in FDA prescribing information are based on this formula. However, significant controversy exists over

2014 Informa UK Ltd

ISSN 1478-7210

829

Review

Payne & Hall II


Table 1. Literature results summary for antibacterial agents in obesity. Study (year)

Drug

Patients

Study dose

Weight

BMI

Cheatham et al. (2013)

Pipercillin/ tazobactam

14 hospitalized patients (12 morbidly obese, 2 obese)

4.5 g iv. Q8h (4 pts) 6.75 g iv. Q8h (10 pts) Given over 4 h

Mean: 161 kg

Range: 34.4–72.9 kg/m2 Mean: 52.3 kg/m2

Sturm et al. (2013)

Pipercillin/ tazobactam

9 patients

4.5g iv. Q6h

Mean: 164 kg

57 kg/m2

Forse et al. (1989)

Cefazolin

Gastric bypass patients = 40 Normal weight controls = 8

Bypass patients: 1 g im. = 10 1 g sc. = 9 1 g iv. = 11 2 g iv. = 10 NW = 1 g iv.

1 g im.: 123.2 kg 1 g sc.: 127.7 kg 1 g iv.: 127.3 kg 2 g iv.: 127.3 kg NW: 64.5 kg

1 g im.: 46 kg/m2 1 g sc.: 47 kg/m2 1 g iv.: 47 kg/m2 2 g iv.: 47 kg/m2 NW: 22 kg/m2

Edmiston et al. (2004)

Cefazolin

38 morbidly obese patients undergoing gastric bypass Group A (BMI 40–49) n = 17 Group B (BMI 50–59) n = 11 Group C (BMI ‡60) n = 10

2 g iv. before incision and 2 g iv. at 3 h during operation

Group A: 128.5 kg Group B: 145.7 kg Group C: 191.9 kg

Group A: 47 kg/m2 Group B: 53.9 kg/m2 Group C: 69.2 kg/m2

van Kralingen et al. (2011)

Cefazolin

20 patients with BMI >35 kg/m2 undergoing laparoscopic gastric banding or gastric bypass surgery

2 g iv. before incision

Mean: 151 kg Range: 112–260 kg

Mean: 51 kg/m2 Range: 38–79 kg/m2

Barbour et al. (2009)

Cefuroxime

6 morbidly obese female patients undergoing abdominal surgery

1.5 g iv. 30–60 min before surgery

Range: 109–140 kg

Range: 44–53 kg/m2

Toma et al. (2011)

Cefoxitin

14 obese and 2 normal weight patients undergoing elective abdominal or pelvic surgery and 11 healthy normal weight patients

Normal weight: 1 g iv. Obese: 2 g iv

Normal weight: 60 kg Obese: 26 kg

Normal weight: 20 kg/m2 Obese: 43 kg/m2

Itani et al. (2008)

Cefotetan

Post hoc analysis of 321 patients (93 obese and 231 normal/overweight)

NR

Normal weight: 13.7–29.8 kg/m2 Obese: 30–63.6 kg/m2

2 g iv. single dose

IBW(kg): male = 50 + 2.3 (height per inch over 60 inches); female = 45.5 + 2.3 (height per inch over 60 inches). ABW = IBW + 0.4 (TBW – IBW). § LBW2005(kg): male = (9270 TBW)/(6680 + 216 BMI); female = (9270 TBW)/(8780 + 244 BMI). { CKD-EPI(ml/min/1.73 m2): male (Scr £0.9) = 141 (Scr/0.9)-0.411 (0.993)age; male (Scr >0.9) = 144 (Scr/0.9)-1.209 (0.993)age; female (Scr £ 0.7) = 144 (Scr/0.7)-0.329 %T>MIC: Percent that the plasma drug concentration exceeds the minimum inhibitory concentration; ABW: Adjusted body weight; AUC: Area under the curve; Cmax/Cpeak: Maximum plasma drug concentration administration; Cmin/Ctr: Minimal plasma drug concentration following administration; cSSTI: Complicated skin and soft tissue IE: Infective endocarditis; im.: Intramuscular; iv.: Intravenous; Ke: Drug elimination rate constant; LBW: Lean body weight; MIC: Minimum inhibitory concentration; NR: Not reported; † ‡

830

Expert Rev. Anti Infect. Ther. 12(7), (2014)


Dosing of antibacterial agents in obese adults

Review

Volume of distribution

Serum clearance

Half-life

Notes

Ref.

33.4 l

13.7 l/h

1.9 h

Extended interval infusion

[14]

31.0 l

6.0 l/h

3.7 h

30 min infusion. %T > MIC was 100% for all study patients at MIC = 16 mg/l

[13]

NR

NR

NR

Plasma drug concentrations higher for obese patients receiving 2 g iv. vs 1 g im. or sc., 65.2 mcg/ml vs 29.5 and 26.1 mcg/ml respectively Adipose tissue concentrations also higher after 2 g in obese vs 1 g doses at 4 mcg/g vs 1.7 and 0.96 mcg/g Plasma and tissue concentrations after 2 g dose in obese was similar to normal weight controls after 1 g. Use of 2 g iv. in obese patients reduced SSI rate from 16.5 to 5.6% for obese patients in 4 months

[16]

NR

NR

NR

Lower serum, skin, adipose, and omentum drug concentrations were noted for increasing BMI. 10% of BMI >60 kg/m2 had tissue concentrations >8 mcg/ml Tissue concentrations were subinhibitory for 80% of staphylococcal and 39% of gram-negative pathogens recovered from institution’s surgical site infections Over 90% of serum samples exhibited cefazolin concentrations ‡8 mcg/ml, but cefazolin tissue concentrations were subtherapeutic

[17]

13.0 l

4.2 l/h

NR

Strong correlation between Vd and TBW (r = 0.781). No correlation noted between Cl and TBW Overall protein binding reported for cefazolin was 79%, and suggested saturable protein binding

[18]

25.3 l

8.39 l/h

2.37 h

Cmax of 66.8 mcg/ml in plasma, 60.1 mcg/ml in skeletal muscle, and 39.2 mcg/ml in adipose tissue Concentrations in adipose tissue fell below MIC of 8 mcg/ml, whereas plasma and skeletal muscle levels remain higher than those levels for the 6 h period All levels remained above 2 mcg/ml during the 6 h period

[19]

Normal weight: 11 l Obese: 18 l

Normal weight: 240 ml/min Obese: 197 ml/min

NR

Normal weight: Cmax 240 mcg/ml (normalized to dose 242 mcg/ml). Cmax in subcutaneous tissue per microdialysis 22 mcg/ml. Obese: Cmax 258 mcg/ml (normalized to dose 129 mcg/ml), Cmax in subcutaneous tissue per microdialysis 11 mcg/ml Tissue concentration from samples in obese patients at incision 7.8 mcg/ml, and closure 2.7 mcg/ml

[20]

NR

NR

NR

Surgical site infection rate among normal weight patients 26.4% and all obese 41.9%

[21]

(0.993)age; female (Scr >0.7) = 144 (Scr/0.7)-1.209 (0.993)age. AUC/MIC: Area under the curve to minimum inhibitory concentration; CF: Correction factor; cIAI: Complicated intra-abdominal infection; Cl: Total body clearance; infection; CVVHDF: Continuous venovenous hemofiltration; IBW: Ideal body weight; ICU: Intensive care unit; IDSA: Infectious Diseases Society of America; sc.: Subcutaneous; SSI: Surgical site infection; t1/2: Half-life; TB: Tuberculosis; TBW: Total body weight; TDD: Total daily dose; Vd: Volume of distribution.


831

Review

Payne & Hall II


Table 1. Literature results summary for antibacterial agents in obesity (cont.). Study (year)

Drug

Patients

Study dose

Weight

BMI

Yost et al. (1986)

Cefotaxime

23 subjects (12 normal weight and 11 obese)

1 g iv. single dose

Normal weight was within +/10% IBW† and obese 190–210% IBW

NR

Itani et al. (2008)

Ertapenem

Post hoc analysis of 326 patients (105 obese and 221 normal/overweight)

1 g iv. single dose

NR

Normal weight: 13.7–29.8 kg/m2 Obese: 30–63.6 kg/m2

Chen et al. (2006)

Ertapenem

30 healthy patient (10 normal weight, 10 class I/II obese, 10 class III obese)

1 g iv. single dose

Normal weight: 66.7 kg Class I/II obese: 96 kg Class III obese: 127.2 kg

Normal weight: 22.5 kg/m2 Class I/II obese: 33.4 kg/m2 Class III obese: 43.4 kg/m2

De Werra et al. (2013)

Ertapenem

63 obese patients undergoing general or bariatric surgery (32 patients received ertapenem, 31 patients received either ampicillin/ sulbactam or ceftriaxone)

Single dose intravenously prior to surgery. Dosage not stated.

Case group: Mean: 136.69 kg Range: 89–207 kg Control group: Mean: 130.98 kg Range: 64–159 kg

Case group: Mean: 47.82 kg/m2 Range: 36.11–67.3 kg/m2 Control group: Mean: 45.76 kg/m2 Range: 30.45–59.12 kg/m2

Bearden et al. (2005)

Meropenem

9 morbidly obese females undergoing bariatric surgery

1 g iv. over 30 min single dose

154.6 kg

56.9 kg/m2

Cheatham et al. (2013)

Meropenem

9 ICU patients with BMI ‡40 kg/m2 (4 male, 5 female)

500 mg or 1 g iv. Q6h (dose chosen at discretion of physician)

152.3 kg

Mean: 54.7 kg/m2 Range: 40.7–63.8 kg/m2

Kays et al. (2014)

Meropenem

20 hospitalized patients with a BMI ‡40 kg/m2 or ‡100 pounds over IBW (10 meropenem patients and 10 doripenem patients)

Doripenem 500 mg iv. Q8h infused over 1 h or meropenem 1 g Q8h infused over 0.5 h

200.4 kg

65.5 kg/m2

Nandy et al. (2010)

Doripenem

285 subjects (176 healthy volunteers and109 patients)

500 and 1000 mg given at various time intervals (6, 8 or 12 h)

Mean: 72.1 Range: 45–142 kg

NR

IBW(kg): male = 50 + 2.3 (height per inch over 60 inches); female = 45.5 + 2.3 (height per inch over 60 inches). ABW = IBW + 0.4 (TBW – IBW). LBW2005(kg): male = (9270 TBW)/(6680 + 216 BMI); female = (9270 TBW)/(8780 + 244 BMI). { CKD-EPI(ml/min/1.73 m2): male (Scr £0.9) = 141 (Scr/0.9)-0.411 (0.993)age; male (Scr >0.9) = 144 (Scr/0.9)-1.209 (0.993)age; female (Scr £ 0.7) = 144 (Scr/0.7)-0.329 %T>MIC: Percent that the plasma drug concentration exceeds the minimum inhibitory concentration; ABW: Adjusted body weight; AUC: Area under the curve; Cmax/Cpeak: Maximum plasma drug concentration administration; Cmin/Ctr: Minimal plasma drug concentration following administration; cSSTI: Complicated skin and soft tissue IE: Infective endocarditis; im.: Intramuscular; iv.: Intravenous; Ke: Drug elimination rate constant; LBW: Lean body weight; MIC: Minimum inhibitory concentration; NR: Not reported; † ‡ §

832




Review


Serum clearance

Half-life

Notes

Ref.

Normal weight Male: 22.3 l Female: 31.6 l Obese Male: 19.8 l Female: 31.1 l

Normal weight Male: 360.7 ml/ min Female: 411.7 ml/ min Obese Male: 264.8 ml/min Female: 352.4 ml/min

NR

Elimination rate decreased 20% and Vd increased approximately 50% in the obese group compared to the normal weight groups. Cl slightly increased in the obese group vs normal weight group

[22]

NR

NR

NR

Surgical site infection rate among normal weight patients 26.4% and all obese 41.9%

[21]

Normal weight: 5.15 l Class I/II obese: 6.04 l Class III obese: 7.18 l

Normal weight: 1.58 l/h/1.73 m2 Class I/II obese: 1.5 l/h/1.73 m2 Class III obese: 1.38 l/h/1.73 m2

NR

Normal weight: >90% probability of target attainment (%T>MIC = 20%) for MICs = 0.25 mcg/ml and 65% for MICs = 1 mcg/ml Class I/II obese: >90% probability of target attainment (%T>MIC = 20%) for MICs = 0.25 mcg/ml and 53% for MICs = 1 mcg/ml Class III obese: >90% probability of target attainment (%T>MIC = 20%) for MICs = 0.25 mcg/ml and 42% for MICs = 1 mcg/ml

[23]

NR

NR

NR

Wound infection rates: bariatric surgery 15% vs nonbariatric surgery 16% 1 patient in the case group developed a surgical site infection, 6 patients in the control group developed surgical site infections Serum active against most bacteria tested, with the exception of those bacteria with carbapenemases

[25]

28.8 l

20.8 l/h

1.16 h

Cmax and AUC values were 58 and 66% of those reported for normal weight patients, respectively For MICs of 1 mcg/ml or 4 mcg/ml, the %T>MIC were 78.6 and 49.6% of an 8 h interval, respectively

[26]

37.4 l

10.2 l/h

3.1 h

Obese: Vd 0.25 l/kg Normal weight (previous study): 0.28–0.38 l/kg

[27]

25.1 l

8.1 l/h

2.8 h

Cmax = 62.6 mg/l, Cmin = 4.9 mg/l, AUC = 138.3 mg h/l

[30]

Vc 11.5 l Vp 5.8 l

13.6 l/h

NR

Strong positive correlation found for increasing body weight and central and peripheral Vd

[28]



833

Review

Payne & Hall II



Drug

Patients

Study dose

Weight

BMI

Roberts et al. (2013)

Doripenem

31 critically ill patients with nosocomial pneumonia

250 or 500 mg iv.

83 kg

27.8 kg/m2

Kays et al. (2014)

Doripenem

20 hospitalized patients with a BMI ‡40 kg/m2 or ‡100 pounds over IBW (10 meropenem patients and 10 doripenem patients)

Doripenem 500 mg iv. Q8h infused over 1 h or meropenem 1 g Q8h infused over 0.5 h

180.2 kg

65.1 kg/m2

Blouin et al. (1982)

Vancomycin

10 healthy subjects (6 morbidly obese and 4 normal weight)

1 g iv. over 40 min

Normal weight: 65.9–89.1 kg Obese: 111.4– 226.4 kg

NR

Vance-Bryan et al. (1993)

Vancomycin

230 patients (107 obese and 123 normal weight)

10–15 mg/kg iv. over 60 min for multiple doses

>10% below LBW = 9, £10% below LBW = 47, £10% above LBW = 39, £20% above LBW = 28, >20% above LBW = 107

NR

Bauer et al. (1998)

Vancomycin

48 patients (24 morbidly obese and 24 normal weight)

Doses and intervals adjusted to goal Cmax of 35 mcg/ml and Cmin of 5–10 mcg/ml


NR

Hall et al. (2008)

Vancomycin

421 patients (67 underweight, 100 normal weight, 99 overweight, and 155 obese based on WHO criteria)

Mostly 1 g iv. twice daily; the study objective was to determine the % of patients getting ‡10 mg/kg/dose

NR

NR

Leong et al. (2011)

Vancomycin

48 obese patients in Phase I and 96 obese patients in Phase II

Not reported

Mean: Phase 1 = 104.6 kg Phase II = 102.9 kg

NR

Hall et al. (2012)

Vancomycin

337 patients (289 survivors and 47 nonsurvivors) with MRSA bacteremia

Survivors: 24.9 mg/ kg/day Nonsurvivors: 21 mg/kg/day

Survivors: 78.1 kg Nonsurvivors: 80 kg

NR

Hall et al. (2013)

Vancomycin

337 patients (289 survivors and 47 nonsurvivors) with MRSA bacteremia

Survivors: 24.9 mg/ kg/day nonsurvivors: 21 mg/kg/day

Survivors: 78.1 kg Nonsurvivors: 80 kg

NR


834




Review


Serum clearance

Half-life

Notes

Ref.

NR

NR

NR

Nonlinear mixed-effects modeling and Monte Carlo simulation in order to simulate effects Simulations support the use of extended infusions in obese patients

[29]

32.2 l

11.7 l/h

2.8 h

Cmax = 21.0 mg/l, Cmin = 1.6 mg/l, AUC = 47.6 mg h/l Vd significantly related to TBW and BMI (r2 = 0.719 and 0.502, respectively)

[30]

Normal: 28.9 l Obese: 43 l

Normal: 80.8 ml/ minObese: 187.5 ml/min

Normal: 4.8 h Obese: 3.2 h

Strong correlation coefficients (r = 0.943) between Vd and TBW, and Cl (r = 0.981) and TBW TDD should be based on TBW, and should be dosed more frequently in obesity

[32]

NR

NR

NR

9 groups studied, divided based on % differences between TBW and LBW Increased TBW associated with increased Vd and decreased Cl per kg of body weight Increase in TBW by 10 kg estimated to result in an 8.1 l increase in Vd, and a decrease of Cl by 0.09 ml/min/kg

[33]

Normal weight: 46 l Obese: 52 l

Normal weight: 77 ml/min (1.1 ml/ min/kg TBW) Obese: 197ml/min (1.2 ml/min/kg TBW)

Normal weight: 7.2 hObese: 3.3 h

Correlation of TBW to Cl was strong (r = 0.948) and moderate for TBW to Vd (r = 0.490) Correlation of IBW to Cl was poor (r = 0.204), and no correlation of IBW to Vd was found

[34]

NR

NR

NR

27.7% of obese patients received initial doses ‡10 mg/kg/doses. Only 43.4% of class I, 16.3% of class II, and 0% of class III obesity achieved the recommended initial dosing 97% underweight, 46% normal weight, 1% overweight and 0.6% obese received IDSA recommended doses of ‡15 mg/kg/dose

[38]

NR

NR

NR

In Phase I, precision and bias analysis found adjusted body weight to be a more precise and less biased predictor of vancomycin clearance than IBW or TBW In Phase II, the modified Leonard and Boro method was more precise in predicting serum vancomycin concentrations than Rushing and Ambrose method

[35]

NR

NR

NR

Guideline-recommended empiric doses in 33% of survivors and 38% of nonsurvivors No statistically significant relationship between empiric guidelinerecommended weight-based vancomycin dosing and in-hospital mortality

[40]

NR

NR

NR

No statistically significant relationship between guidelinerecommended weight-based dosing of vancomycin and development of nephrotoxicity

[41]



835

Review

Payne & Hall II



Drug

Patients

Study dose

Weight

BMI

Dvorchik et al. (2005)

Daptomycin

25 subjects (6 moderately obese [BMI = 25–39.9 kg/m2], 7 morbidly obese [BMI ‡40 kg/m2], 12 normal weight [BMI = 18.5–24.9 kg/m2])

4 mg/kg single dose based on TBW

Normal weight: 56–78 kg Moderately obese: 76–101 kg Morbidly obese: 98–147 kg;

Normal weight: 24.3 kg/m2 Moderately obese: 33.2 kg/m2 Morbidly obese: 46.2 kg/m2

Pai et al. (2007)

Daptomycin

14 subjects (7 morbidly obese and 7 normal weight)

4 mg/kg single dose based on TBW

Normal weight: 58.8 kg Morbidly obese: 114.3 kg

Normal weight: 21.8 kg/m2 Morbidly obese: 46.2 kg/m2

Bhavnani et al. (2010)

Daptomycin

108 patients

6 mg/kg iv. Q24h for 10–42 days

52–129 kg

NR

Brookstaver et al. (2013)

Daptomycin

126 hospitalized obese patients

Class I obese: 6.49 mg/kg/dose Class II obese: 6.51 mg/kg/dose Class III obese: 5.83 mg/kg/dose

Class I obese: 103.5 kg Class II obese: 113.9 kg Class III obese: 140.4 kg

NR

Meagher et al. (2003)

Linezolid

318 patients (95 obese patients)

600 mg p.o./iv. Q12h pts 35 kg/m2 receiving Roux-en-Y gastric bypass surgery

600 mg iv. 1, then 600 mg p.o. 1 after a 7-day washout period. Before and 3 months after surgery

Presurgery: Median: 128.2 kg Range: 105.9– 135.5 kg Postsurgery: Median: 92.3 kg Range: 83.2–98.6 kg

Presurgery: Median: 42.6 kg/m2 Range: 38.5–58.1 kg/m2 Postsurgery: Median: 30.9 kg/m2 Range: 28.7–44.6 kg/m2


836




Review


Serum clearance

Half-life

Notes

Ref.

Normal weight: 6.35 l Moderately obese: 7.9 l Morbidly obese: 10.68 l

Normal weight: 723.8 ml/h Moderately obese: 855.8 ml/h Morbidly obese: 1015.83 ml/h

Normal weight: 6.83 h Moderately obese: 7.34 h Morbidly obese: 8.12 h

Normal weight: Cmax = 46.28 mcg/ml, AUC = 322.37 mcg h/ml Moderately obese: Cmax = 57.75 mcg/ml, AUC = 420.53 mcg h/ml Morbidly obese: Cmax = 67 mcg/ml AUC=547.78 mcg h/ml; values of Cl and Vd best correlated with BMI (r2 = 0.475 and 0.666) and IBW (r2 = 0.386 and 0.728)

[44]

Normal weight: 7.69 l Morbidly obese: 10.04 l

Normal weight: 0.73 l/h Morbidly obese: 0.82 l/h

Normal weight: 7.72 h Morbidly obese: 8.68 h

Normal: Cmax = 42.3 mcg/ml, AUC = 346mg h/l Morbid: Cmax = 67.3 mg/l, AUC = 581 mg h/l Cl and Vd were best correlated to TBW (r2 = 0.30 and 0.66) and BMI (r2 = 0.24 and 0.52)

[45]

6.56 l

0.957 l/h

NR

6/108 patients developed CPK elevations, 4/6 classified as obese with TBW 111-121 kg Cmin ‡24.3 mg/l found to be associated with increased risk of CPK elevations Probabilities for CPK elevation: 4 mg/kg = 3.73%, 6 mg/kg = 6.92%, 8 mg/kg = 10.7%, 10 mg/kg = 15.3%, and 12 mg/kg = 19.5%

[46]

NR

NR

NR

CPK elevations >1000 units/l occurred in 1 (3.6%) BMI class I patient, 3 (10.3%) BMI class II patients, and 4 (10.5%) BMI class III patients 8 patients (6.3%) discontinued daptomycin due to adverse drug events, with no significant difference among BMI classes BMI demonstrated no significant effect on clinical effectiveness

[47]

Obese: 69.7 l/65 kg

Obese: 7.27 l/h/65 kg

43.5 l/h/65 kg

Obese: AUC = 210 mcg/ml/24h Volunteers (prior study): Vd = 50.7 l/65 kg, Cl = 4.23 l/h/65 kg, AUC = 283 mcg/ml/24 h

[49]

NR

NR

6.5 h

AUC = 92 mcg h/ml, Cmax = 12.3 mcg/ml Clinical cure in all 7 patients

[51]

181.1 l 1.05 l/kg

10.2 l/h

8.8 h

Probability of target attainment (PTA) >90% for doses ‡1800 mg/day at MICs £1 mcg/ml At MIC of 2 mcg/ml, a dose of 3600 mg/day needed to achieve PTA >90%

[50]

Class I/II obese: 44.1 l Class III obese: 62.2 l

Class I/II obese: 7.83 l/h Class III obese: 7.39 l/h

NR

No difference in pharmacokinetic parameters or AUC exposures. Observed a significant positive relationship between weight and Vd

[55]

NR

Presurgery: 15.5 l/ hPostsurgery: 9.97 l/h

NR

Presurgery: iv. Cmax = 7.33 mg/l, p.o. Cmax = 6.74 mg/l Postsurgery: iv. Cmax = 9.24 mg/l, p.o. Cmax = 8.69 mg/l Cl significantly associated with TBW (r2 = 0.58)

[56]



837

Review

Payne & Hall II



Drug

Patients

Study dose

Weight

BMI

Van Wart et al. (2006)

Tigecycline

Phase 2: 146 patients with cSSTI or cIAI Phase 3: 24 patients with cSSTI Phase 3: 155 patients with cIAI

100 mg iv., then 50 mg iv. Q12h up to 14 days

Phase 2: Mean: 84.3 kg Range: 47–227 kg Phase 3 cSSTI: Mean: 83.7 kg Range: 21–78 kg Phase 3 cIAI: Mean: 73.9 kg Range: 18–85 kg

NR

Bhavnani et al. (2010)

Tigecycline

123 patients with cIAI

100 mg iv. bolus, then 50 mg iv. Q12h for 5–14 days


NR

Pai et al. (2014)

Tigecycline

12 healthy patients (8 class III obese and 4 normal weight

100 mg iv. single dose

Normal weight: 65.3 kg Class III obese: 135 kg

NR

Allard et al. (1993)

Ciprofloxacin

28 volunteers (17 obese and 11 normal weight)

400 mg iv. over 1 h single dose

Normal weight: 71.8 kg Obese: 110.7 kg

Normal weight: 23.3 kg/m2 Obese: 36.4 kg/m2

Hollenstein et al. (2001)

Ciprofloxacin


2.85 mg/kg iv. over 20 min single dose


Normal weight: 19.8 kg/m2 Obese: 41 kg/m2

Kees et al. (2011)

Moxifloxacin

12 morbidly obese patients undergoing gastric bypass

400 mg p.o. Qday for 3 days, then 400 mg iv. on day 4 (surgery day)


Mean: 48.9 kg/m2 Range 43–58.2 kg/m2

Cook et al. (2011)

Levofloxacin

15 obese subjects (12 hospitalized and 3 ambulatory volunteers)

750 mg iv. over 90 min single dose

Hospitalized: 161.9 kg Ambulatory: 113.3 kg

Hospitalized: 54.8 kg/m2 Ambulatory: 37.4 kg/m2

Schwartz et al. (1978)

Gentamicin


Gentamicin1 mg/kg iv. over 20 min (max 120 mg) single dose

Normal weight: 55.3 kg Obese: 103.6 kg (76% overweight)

NR


838




Review


Serum clearance

Half-life

Notes

Ref.

115 l

15.7 l/h

NR

Weight was found to be a significant covariate for Cl of tigecycline Increasing weight was associated with linear increases in Cl

[57]

NR

16.1 l/h

NR

AUC = 6.19 mg h/l Probabilities of clinical success by weight: for 3.1 found to be most important factor and predictor of clinical success: AUC/MIC 3.1 89% (p = 0.029). Predicted probability of success with TBW ‡ 94 kg and AUC/MIC 0.7) = 144 (Scr/0.7)-1.209 (0.993)age. AUC/MIC: Area under the curve to minimum inhibitory concentration; CF: Correction factor; cIAI: Complicated intra-abdominal infection; Cl: Total body clearance; infection; CVVHDF: Continuous venovenous hemofiltration; IBW: Ideal body weight; ICU: Intensive care unit; IDSA: Infectious Diseases Society of America; sc.: Subcutaneous; SSI: Surgical site infection; t1/2: Half-life; TB: Tuberculosis; TBW: Total body weight; TDD: Total daily dose; Vd: Volume of distribution.


839

Review

Payne & Hall II



Drug

Patients

Study dose

Weight

BMI

Korsager et al. (1980)

Gentamicin

27 patients (17 obese and 10 normal weight)

0.8–1.3 mg/kg iv. over 3–5 min (max 120 mg) single dose

Normal weight: Mean: 62.8 kg Range: 53–72 kg Obese: Mean: 106.9 kg Range: 91–140 kg

NR

Sketris et al. (1981)

Gentamicin

60 female obstetric and gynecologic patients (30 obese and 30 normal weight)

No initial dose listed

Normal weight: 54.1 kg Obese: 87.7 kg (51.4% overweight)

NR

Bauer et al. (1983)

Gentamicin


No initial dose listed; goal Cpk and Ctr were 5–8 mcg/ ml and 0.9) = 144 (Scr/0.9)-1.209 (0.993)age; female (Scr £ 0.7) = 144 (Scr/0.7)-0.329 %T>MIC: Percent that the plasma drug concentration exceeds the minimum inhibitory concentration; ABW: Adjusted body weight; AUC: Area under the curve; Cmax/Cpeak: Maximum plasma drug concentration administration; Cmin/Ctr: Minimal plasma drug concentration following administration; cSSTI: Complicated skin and soft tissue IE: Infective endocarditis; im.: Intramuscular; iv.: Intravenous; Ke: Drug elimination rate constant; LBW: Lean body weight; MIC: Minimum inhibitory concentration; NR: Not reported; † ‡ §

840




Review


Serum clearance

Half-life

Notes

Ref.

NR

NR

NR

Apparent Vd of 12.5–23.5 l for the obese and 10.8–20.5 l for the normal weight groups Use of adjudged (adjusted) weight = (TBW-IBW) 43.7% + IBW, to be used in calculating initial doses in severe obesity

[70]

Normal weight: 10 l Obese: 13.3 l

NR

NR

Normal weight: Ke = 0.55 h-1, Vd/TBW = 0.19 l/kg, Vd/IBW = 0.19 l/kg, Vd/LBW = 0.19l/kg Obese: Ke = 0.52 h-1, Vd/TBW = 0.15 l/kg, Vd/IBW = 0.23 l/kg, Vd/LBW = 0.24 l/kg 30% excess weight added to IBW to predict gentamicin Vd

[71]


Normal weight: 95.9 ml/min Morbidly obese: 135.8 ml/min

Normal weight: 2.2 hMorbidly obese: 2.2 h

Normal weight: Vd/TBW = 0.25 l/kg, Vd/IBW = 0.26 l/kg Morbidly obese: Vd/TBW = 0.17;/kg, Vd/IBW = 0.41 l/kg. Correction factor of 0.45. Positive correlation between TBW and Vd (r = 0.751)

[72]

Normal weight: 16.7 l Obese: 18.2 l

Normal weight: 66.9 ml/min Obese: 77.2 ml/min

Normal weight: 3.27 h Obese: 3.15 h

Normal weight: Ke = 0.26 h-1 Obese: Ke = 0.26 h-1 Use of dosage weight method best predicted Vd, Ke, and Cl in the obese group, did not differ significantly from actual values, and was the least biased and most precise predictor Found a CF of 0.55 for gentamicin, but not significantly different from 0.4

[73]

Underweight: 20.8 l Normal weight: 24.3 l Overweight: 26.8 l

Underweight: 71.2 ml/min/1.73 m2 Normal weight: 75.9 ml/min/1.73 m2 Overweight: 73.4 ml/min/1.73 m2

NR

Underweight: by BMI; Vd = 20.8 l, Cl = 71.2 ml/min/1.73 m2, CF of 1.11 TBW, and by TBW/IBW; Vd = 17.9 l, Cl = 66.1 ml/min/ 1.73 m2, CF of 1.13 TBW Normal weight: by BMI; Vd = 24.3 l, Cl = 75.9 ml/min/1.73 m2, and by TBW/IBW; Vd = 22.6 l, 73.9 ml/min/1.73 m2 Overweight: by BMI; Vd = 26.8 l, Cl = 73.4 ml/min/1.73 m2, CF of 0.37(TBW-IBW) + IBW, and by TBW/IBW; Vd = 25.4 l, Cl = 72.7 ml/min/1.73 m2, CF of 0.43 (TBW-IBW) + IBW

[74]

Underweight: 18.9 l Normal weight: 21.7 l Overweight: 24.8 l Obese: 27.3 l

NR

NR

Use of LBW2005§ was shown to be better predictor of Vd then IBW or TBW CKD-EPI4{ equation found most precise to estimate clearance in underweight to obese patients

[75]

Normal: 17 l Obese: 19.21 l

NR

Normal: 1.85 h Obese: 1.8 h

Normal: serum concentration at 60 min = 2.3 mcg/ml, Vd/TBW = 0.295 l/kg, Vd/ABW = 0.295 l/kg Obese: serum concentration at 60 min = 2.9 mcg/ml, Vd/TBW = 0.232 l/kg, Vd/ABW = 0.297 l/kg ABW = normalized body weight + 40% excess weight

[67]

Vd = 24.5 l

Cl = 106.3 ml/min/ 1.73 m2

NR

AUC = 14.92 mcg h/ml Data suggest an equation for Vd = 0.26 l/kg (IBW + 0.58 [TBW-IBW]) for initial dosing

[68]



841

Review

Payne & Hall II



Drug

Patients

Study dose

Weight

BMI

Bauer et al. (1983)

Tobramycin


No initial dose listed; goal Cpk and Ctr were 5–8 mcg/ ml and MIC: Percent that the plasma drug concentration exceeds the minimum inhibitory concentration; ABW: Adjusted body weight; AUC: Area under the curve; Cmax/Cpeak: Maximum plasma drug concentration administration; Cmin/Ctr: Minimal plasma drug concentration following administration; cSSTI: Complicated skin and soft tissue IE: Infective endocarditis; im.: Intramuscular; iv.: Intravenous; Ke: Drug elimination rate constant; LBW: Lean body weight; MIC: Minimum inhibitory concentration; NR: Not reported; † ‡ §

842




Review


Serum clearance

Half-life

Notes

Ref.

Normal weight 18.31 l Morbidly obese: 29.01 l

Normal weight 101.3 ml/min Morbidly obese: 162.4 ml/min

Normal weight 2.1 h Morbidly obese: 1.9 h

Normal weight: Vd/TBW = 0.26 l/kg, Vd/IBW = 0.26 l/kg. Morbidly obese: Vd/TBW = 0.19 l/kg, Vd/IBW = 0.45 l/kg CF of 0.37. Positive correlation between TBW and Vd (r = 0.751)

[69]

Underweight: 20.8 l Normal weight: 24.3 l Overweight: 26.8 l

Underweight: 71.2 ml/min/1.73 m2 Normal weight: 75.9 ml/min/1.73 m2 Overweight: 73.4 ml/min/1.73 m2

NR

Underweight: by BMI; Vd = 20.8 l, Cl = 71.2 ml/min/1.73 m2, CF of 1.11 TBW, and by TBW/IBW; Vd = 17.9 l, Cl = 66.1 ml/min/ 1.73 m2, CF of 1.13 TBW Normal weight: by BMI; Vd = 24.3 l, Cl = 75.9 ml/min/1.73 m2, and by TBW/IBW; Vd = 22.6 l, 73.9 ml/min/1.73 m2 Overweight: by BMI; Vd = 26.8 l, Cl = 73.4 ml/min/1.73 m2, CF of 0.37(TBW-IBW) + IBW, and by TBW/IBW; Vd = 25.4 l, Cl = 72.7 ml/min/1.73 m2, CF of 0.43(TBW-IBW) + IBW

[74]

Underweight: 18.8 l Normal weight: 22.2 l Overweight: 25.2 l Obese: 27.2 l

NR

NR

Use of LBW2005 was shown to be better predictor of Vd then IBW or TBW CKD-EPI equation found most precise to estimate clearance in underweight to obese patients

[75]

27.4 l

110.3 ml/min/1.73 m2

NR

AUC = 151.7 mcg h/ml, and CF of 0.38 (range of 0.14–0.59), using equation Vd = 0.26 l/kg (IBW + CF[TBW-IBW]), best correlated with actual values of Vd

[69]


Normal weight: 99.2 ml/min Morbidly obese: 157.3 ml/min

Normal weight: 2.2 hMorbidly obese: 2 h

Normal weight: Vd/TBW = 0.26 l/kg, Vd/IBW = 0.26 l/kg Morbidly obese: Vd/TBW = 0.18 l/kg, Vd/IBW = 0.44 l/kg CF of 0.42. Positive correlation between TBW and Vd (r = 0.751)

[72]

NR

NR

600 mg group: 2.2 h 450 mg group: 1.9 h

Weight was found to correlate with the AUC of rifampin, pyrazinamide, and ethambutol; Pearson’s correlation coefficient of –0.371 and –0.445 in higher and lower-dose groups, respectively Body weight was an independent predictor of rifampin AUC, increasing weight results in decreased AUC

[83]

NR

NR

NR

Weight found to have significant effect on Cl, central and peripheral Vd For every 1 kg increase in TBW above 74 kg, corresponding average 1.14% increase in Cl and 1.45% increase in Vd

[79]

NR

NR

NR

BMI 37.3 kg/m2: dose per TBW = 18.3 mg/kg, dose per IBW = 31.3 mg/kg BMI 30.6 kg/m2: dose per TBW = 18.8 mg/kg, dose per IBW = 33.3 mg/kg

[77]



843

Review

Payne & Hall II



Drug

Patients

Study dose

Weight

BMI

Hall et al. (2012)

Ethambutol

18 volunteers (6 normal weight, 6 overweight and class I/II obese, 6 class III obese)

1600 mg orally as a single fasting dose

Median: 90.8 kg Range: 45.6–160.4 kg

NR

Wilkins et al. (2006)

Pyrazinamide

227 active TB patients

1000–2000 mg/day p.o

Median: 51.5 kg

Median: 19.4 kg/m2

Pasipanodya et al. (2010)

Pyrazinamide

Meta-analysis of 29 controlled trials

Multiple dosing strategies

NR

NR


which weight should be used in order to most accurately estimate Cl. Cockcroft and Gault derived their equation from a predominately male patient population with a mean total body weight (TBW) of 72 kg [7]. The authors recommended that ideal body weight (IBW) be utilized in overweight patients, but this statement was not supported by presented data or cited literature. Winters and colleagues evaluated the effect of weight on the accuracy of creatinine Cl in a retrospective analysis of 3678 patients [8]. The least-biased weights were TBW in underweight patients, IBW in normal weight patients and adjusted body weight with a correction factor of 0.4 in overweight, obese and morbidly obese patients. Other methods for predicting GFR are better correlating with measured Cl or GFR values. The modification of diet in renal disease and CKD-EPI equations more accurately estimate GFR [9], but the modification of diet in renal disease and Cockcroft–Gault equations are recommended by the National Kidney Disease Education Program for calculating renal dose adjustments in medications [10]. However, these methods may not be practical for routine clinical use due to complex equations requiring the input of multiple variables. Many investigators have sought to determine the best covariate to use as a dosing adjustment for antimicrobials affected by weight changes. The candidates that have been investigated include BMI, body surface area, TBW, IBW, adjusted body weight, lean body weight or fat-free weight. The achievement of a pharmacokinetic–pharmacodynamic target has been associated with improved microbial killing and clinical success. Free drug concentrations are best to determine the amount of drug that is not bound to plasma proteins and able to bind to receptor sites on bacteria. However, total drug concentrations are much more frequently reported in the literature and used for therapeutic drug monitoring in clinical practice. There is also inter- and intra-individual variability in the percentage of protein binding for a given drug, and therefore, a single ‘correction factor’ can be misleading. The 844

pharmacodynamics of antibacterials are generally classified according to either the ratio of the peak concentration to MIC (Cmax/MIC), ratio of the area under the concentration–time curve to the MIC (AUC/MIC) or the percentage of the dosing interval above minimum inhibitory concentration (%T>MIC). Alterations in volume of distribution (Vd) have a more pronounced effect on Cmax/MIC drugs, while Cl has a greater influence on %T>MIC or AUC/MIC antimicrobials. What is the available data evaluating antibacterial therapy in the obese population? b-Lactams Penicillins

Penicillins are the oldest group of b-lactams and have the least data in obese persons. To our knowledge, no studies have been conducted with penicillin, aminopenicillins or ticarcillin. The data for antistaphylococcal penicillins are limited to a single case report. Yuk et al. found a nearly doubled Vd for nafcillin in a morbidly obese patient with endocarditis compared with data in normal weight volunteers [11]. A moderate increase in nafcillin Cl was observed, which could lead to lower pharmacokinetic–pharmacodynamic target attainment rates in obese patients. We recommend using the maximum FDA-approved dosing regimen (2 g intravenous (iv.) Q4h) in obese patients. Data for piperacillin/tazobactam are also limited. A single case report in a morbidly obese patient also had increases in Vd and Cl compared with normal weight volunteers (see literature results summary table for specific pharmacokinetic values) [12]. One study evaluating piperacillin/tazobactam in nine morbidly obese critically ill patients found an increase in Vd but did not demonstrate increased Cl, likely due to the population’s decreased renal function [13]. Cheatham and colleagues evaluated the pharmacokinetics and pharmacodynamics of highdose prolonged infusion piperacillin/tazobactam (6.75 g iv. Q8h) in 14 hospitalized patients [14]. They reported that in Expert Rev. Anti Infect. Ther. 12(7), (2014)



Review


Serum clearance

Half-life

Notes

Ref.

491 l

80.8 l/h

NR

Weight, but not BMI, was found to be a significant covariate of ethambutol clearance

[78]

29.2 l

NR

NR

Weight was found to increase both oral Cl and Vd Oral Cl was increased by an average 0.545 l/h and Vd by 4.33 l, each for every 10 kg over 48 kg

[80]

NR

NR

NR

No significant increase in hepatotoxicity frequency with high dose pyrazinamide: 0.042 for 30 mg/kg, 0.055 for 40 mg/kg and 0.098 for 60 mg/kg

[81]


order to attain similar pharmacokinetic profiles to nonobese patients, obese patients would need a 50% increase in dose for a 100% increase in BMI. Probability of target attainment (PTA) ‡90% was achieved for MICs £16 mg/L with the dosing regimens of 4.5 g iv. Q8h infused over 4 h and higher. Maximizing piperacillin/tazobactam dosing regimens (4.5 g iv. Q8h infused over 4 h) is advisable given the remaining questions due to the current data. If an institution is only utilizing traditional infusion, the suggested dosing regimen would be 3.375 g iv. Q4h or 4.5 g iv. Q6h infused over 30 min. Cephalosporins

Most of the data concerning dose optimization of cephalosporins come from their use in surgical prophylaxis to prevent surgical site infections. Obesity remains an independent risk factor for development of surgical site infections despite use of antimicrobial prophylaxis [15]. While other factors are responsible for some of the additional risk of surgical site infection results in obese patients, dose optimization has decreased surgical site infection rates. Forse and colleagues determined that in morbidly obese patients undergoing gastroplasty, 1 g iv. cefazolin did not provide adequate tissue and plasma concentrations compared with normal weight patients undergoing elective gastric operations [16]. Morbidly obese patients had adequate tissue and serum concentrations only when given 2 g iv. cefazolin prophylaxis. After standardization of cefazolin 2 g iv. for prophylaxis in morbidly obese surgical patients at their institution, postoperative wound infection rates dropped from 16.5 to 5.6%. Cefazolin was further studied in morbidly obese gastric bypass patients divided into the following BMI cohorts: 40– 49.9 kg/m2, 50–59.9 kg/m2 and ‡60 kg/m2 [17]. Investigators demonstrated an inverse relationship regarding BMI and tissue penetration. Only 10% of patients with a BMI >60 kg/m2 achieved an appropriate tissue concentration after receiving a 2 g dose. There was a poor correlation between tissue and informahealthcare.com

plasma concentrations, indicating that plasma concentrations alone may not be a reliable predictor of clinical outcomes. Van Kralingen and colleagues observed that the Vd for cefazolin was correlated to both TBW and lean body weight [18]. This resulted in an inverse correlation between weight and plasma concentrations (free and total). The investigators deemed that a single 2 g cefazolin dose was sufficient for the methicillinsusceptible Staphylococcus aureus susceptibility breakpoint of 1 mg/l. They also stated that higher doses or more frequent administration may be necessary for treating pathogens demonstrating intermediate resistance. Obese patients should receive cefazolin 2 g iv. Q6h when requiring multiple doses. Class III patients, especially those with a BMI ‡60 kg/m2, may need increased and/or more frequent dosing that has yet to be evaluated. Data evaluating the effect of obesity on oral firstgeneration cephalosporins are needed. Obese patients receiving cefuroxime 1.5 g prior to gastric bypass, colectomy or gastric banding had an elevated half-life and an increased Vd [19]. Tissue free drug concentrations were collected via microdialysis for both skeletal muscle and adipose tissue throughout the surgery. Therefore, the authors were able to determine whether cefuroxime concentrations would exceed the MICs of various potential pathogens in the tissue for the duration of the surgery. This pilot study found insufficient cefuroxime tissue concentrations to maintain therapeutic T > MIC in obese individuals for proper eradication of enteric gram-negative organisms with an MIC breakpoint of 8 mg/l, despite adequate tissue concentrations for eradication of methicillin-susceptible S. aureus. Obese patients receiving a 2 g dose of cefoxitin had a lower drug tissue penetration than normal weight patients receiving a 1 g dose when dose normalization occurred [20]. The study also showed an increased Vd in obese patients. We recommend administering a second dose of cefoxitin 2–3 h after the initial prophylaxis to obese patients undergoing prolonged surgeries. 845


Review

Payne & Hall II

Obese patients receiving cefotetan 2 g for surgical prophylaxis had a higher risk for surgical site infections compared with nonobese patients (>40 vs 26.4%) [21]. Higher doses and/or more frequent dosing of cefotetan may be warranted for obese patients. Administering higher doses of cefotetan would require further study since 2 g is the current maximum recommended dose by the FDA. More frequent dosing would likely be more practical given the short half-lives of b-lactams. To our knowledge, the only data regarding the effect of obesity on third, fourth or advanced generation cephalosporins is with cefotaxime. Cefotaxime had a decreased rate of elimination and increased Vd and Cl in obese patients compared with normal weight patients [22]. Despite these pharmacokinetic changes, the plasma concentration profiles were similar between the two groups. Therefore, we recommend using standard dosing of cefotaxime in adults (1–2 g iv. Q6-12H). Carbapenems

Ertapenem pharmacokinetics were evaluated in 30 healthy volunteers, 10 each in BMI groups ranging from normal weight, class I–II obesity and class III obesity [23]. Each patient was given a 1 g dose, and serum concentrations were evaluated during the following 24 h. Investigators observed that obesity increased the Vd and decreased renal elimination of ertapenem. A 1 g dose appeared effective for all BMI categories when the MIC was 0.25 mg/l or less. The goal pharmacokinetic–pharmacodynamic target attainment rate of 90% could not be reached for MIC values of 0.5 mg/l or higher for any class of obesity. The data demonstrated that even normal weight patients may not achieve ‡90% target attainment at a 1 g dose for Enterobacteriaceae isolates with elevated MIC values of 0.5–2 mg/l that are classified as susceptible by the Clinical Laboratory Standards Institute [24]. A recent study evaluated in vivo and in vitro activity of single-dose ertapenem in obese surgery patients. Serum samples demonstrated activity against both gram-positive and gram-negative bacteria, with the exception of bacteria known to produce carbapenemases. One patient in the ertapenem group (n = 32) developed a surgical site infection versus six patients in the control group (n = 31) [25]. An outcomes-based study evaluating ertapenem for surgical prophylaxis documented an increased risk of surgical site infections for patients with a BMI >30 kg/m2 compared with normal weight patients (26.7 vs 12.7%), suggesting that a 1 g dose fails to provide optimal effectiveness for obese persons [21]. Therefore, further evaluation of alternate dosing strategies for ertapenem in obesity is warranted. A pharmacokinetic study of meropenem 1 g was conducted with nine females [26]. The authors stated that no dosage adjustment is needed in spite of the increased Vd and Cl due to the %T>MIC being still ‡50%. Cheatham et al. studied nine intensive care unit patients with a BMI ‡40 kg/m2 [27]. The Vd in these patients was found to be larger than the previously identified Vd in normal weight patients (37.8 vs 21.7– 29.3l). Monte Carlo simulations were performed with the following dosing regimens: 500 mg Q8h, 1 g Q8h, 2 g Q8h, 846

500 mg Q6h and 1 g Q6h. All dosage regimens except 500 mg Q8h achieved a PTA >90% for an MIC of 2 mg/l. Therefore, meropenem likely does not require dose adjustment in morbid obesity when targeting susceptible pathogens. To our knowledge, no data are available assessing the effect of obesity on imipenem/cilastatin, although the prescribing information provides dosing recommendations for TBW ranges. A correlation between body weight and pharmacokinetic parameters was seen in normal weight patients receiving doripenem [28]. Roberts and colleagues conducted doripenem dosing simulations in critically ill obese patients and observed that Vd was positively correlated with weight, while drug Cl was correlated with the creatinine Cl [29]. Unsurprisingly, extended infusion dosing increased drug exposure. Therefore, clinicians should consider administering larger doses or utilizing extended infusions when treating obese patients with doripenem. Kays et al. compared pharmacokinetic and pharmacodynamic parameters of doripenem and meropenem in hospitalized obese patients [30]. While meropenem pharmacokinetic parameters were found to be similar to those of previously published nonobese patients, doripenem parameters were found to be significantly different. Doripenem had significantly lower Cmax, Cmin and AUC values compared with meropenem. Doripenem Vd was found to be significantly related to both TBW and BMI (r2 = 0.719 and 0.502, respectively), while meropenem Vd had a poor relationship with all evaluated weights and BMI. However, a PTA >90% was achieved for both doripenem 500 mg Q8h and meropenem 1 g Q8h at an MIC £2 mg/l. Based on these studies, weight does influence doripenem pharmacokinetics. However, the available data suggest that current dosing regimens are able to achieve optimal PTA rates for obese patients. In January 2012, the FDA released a statement that doripenem should not be used to treat any type of pneumonia, based on the prematurely terminated study finding an increased mortality in patients with ventilator-associated pneumonia treated with doripenem [31]. Glycopeptides

Multiple studies have concluded that TBW is the optimal weight-based dosing strategy for vancomycin. Blouin and colleagues evaluated the pharmacokinetics of a single 1 g dose given to four normal patients and six morbidly obese patients post-gastric bypass [32]. Both the Vd and Cl were strongly correlated with TBW. These values were found to be elevated in comparison to the normal weight cohorts. In a retrospective study with 230 adult patients receiving multidose weight-based infusions, investigators found TBW to be an independent predictor of Vd. TBW, not IBW, was determined to be a predictor of decreasing Cl [33]. A study of 24 morbidly obese patients matched with a normal weight cohort determined a strong correlation of TBW with Cl and a moderate correlation of TBW with Vd [34]. Further, this study illustrated that higher total daily doses were required in the obese population to achieve similar steady-state concentrations as their normal weight counterparts. When the doses were adjusted for TBW, the resulting Expert Rev. Anti Infect. Ther. 12(7), (2014)



value was similar between groups. A recent study advocates the use of adjusted body weight as a superior method to decrease the variability of vancomycin serum concentrations, but requires confirmation prior to implementation as standard of care [35]. Based upon the preponderance of the current data, current consensus guidelines recommend dosing vancomycin based on TBW, with a maximum of 2 g per dose prior to adjustment with therapeutic drug monitoring [36,37]. A multicenter study of 421 patients evaluated whether the weight-based dosing recommended by the vancomycin guidelines was followed in clinical practice [38]. Only 27.7% of obese patients received >10 mg/kg/dose, which is still less than the guideline-recommended 15 mg/kg/dose. Further analysis revealed that no patient with class III obesity received this lenient assessment of weight-based dosing. These findings illustrate that vancomycin is still being dosed inappropriately despite available guideline recommendations. Puzniak et al. evaluated the effect of weight quartile on the clinical success rates of vancomycin (quartile 1: 57.5 kg; quartile 2: 71.8 kg; quartile 3: 86.4 kg; quartile 4: 119.8 kg) in complicated skin and skin structure infections and nosocomial pneumonia [39]. The only difference observed by these investigators was for the highest quartile of weight in complicated skin and skin structure infections. Division of patients into quartiles minimizes the statistical power of the data set compared with using weight as a continuous measure. Therefore, the study carries a higher risk of showing no difference when there is actually is a difference in the larger population. Hall and colleagues investigated whether weight-based dosing affected mortality and/or nephrotoxicity in methicillin-resistant S. aureus (MRSA) bacteremia [40,41]. Weight-based dosing was not associated with increased mortality or nephrotoxicity. Approximately 85% of patients in this study received vancomycin 1 g iv. Q12h, so further studies are needed to determine the effect of weightbased dosing on clinical outcomes of obese patients. However, patients who weighed >100 kg were at an increased risk of nephrotoxicity. Lodise and colleagues have similarly found that increased weight (‡101.4 kg) is associated with an increased risk of nephrotoxicity [42]. The mechanism behind this finding is unknown. It is possible that increased weight is a proxy for other conditions such as diabetes that could increase the risk of nephrotoxicity. While not a direct measure of vancomycin efficacy, vancomycin treatment failure has been associated with initial trough values 1000 units/l occurred in 1 (3.6%) class I patient, 3 (10.3%) class II patients and 4 (10.5%) class III patients. While eight (6.3%) patients discontinued therapy due to adverse drug events, there were no differences among BMI classes for discontinuation. The secondary endpoint of this study was clinical effectiveness, which was found to be similar across classes. The evidence indicates that TBW should be used for daptomycin dosing with increased monitoring of CPK and adverse events in the obese patients. Oxazolidinone

A case report of a 286 kg male receiving 600 mg oral linezolid every 12 h for bacterial cellulitis found decreased Cmax and increased Vd as compared with normal weight patients [48]. The increased Vd was not proportional to TBW, suggesting adjusted body weight dosing would be necessary to achieve equivalent serum concentrations. Despite the altered pharmacokinetic values observed, the patient achieved a successful resolution of infection, indicating that equivalent serum concentrations may not be necessary for positive clinical outcomes. Meagher and colleagues observed a statistically 847


Review

Payne & Hall II

significantly increased Vd and Cl in obese individuals [49]. This may contribute to the lowered Cmax and AUC observed in obese individuals. In a study of nine obese patients receiving intravenous linezolid with varying doses and intervals, highly variable serum concentrations with an overall increased Vd were observed [50]. The authors concluded that TBW should be used when dosing linezolid. A decrease in Cmax and AUC was observed in seven obese patients receiving multiple doses of oral linezolid 600 mg every 12 h for cellulitis compared with previously published values in normal weight patients [51]. Prolonged inhibitory activity was observed for all studied bacterial strains except MRSA isolates with an MIC at 4 mg/l using serum dilution despite the decrease of serum drug concentrations. Specific isolates included MRSA, vancomycin-resistant Enterococcus faecium, Bacteroides fragilis and Peptostreptococcus magnus. All patients achieved clinical resolution of their infection, leading investigators to conclude a typical dose of oral linezolid 600 mg every 12 h to be an adequate regimen in obese patients regardless of decreased serum drug concentrations. Puzniak et al. evaluated the effect of weight quartile on the clinical success rates of linezolid (quartile 1: 58.7 kg; quartile 2: 72.5 kg; quartile 3: 86.9 kg; quartile 4: 119.7 kg) in complicated skin and skin structure infections and nosocomial pneumonia [39]. No differences in clinical success were observed by weight quartile for either disease state. Because these studies center on cellulitis, which has a very high cure rate even without effective antibacterial treatment [52], there is a danger in extrapolating that a typical dose of linezolid would be adequate for other disease states in obese patients. In a case report of a 265-kg patient receiving linezolid for MRSA pneumonia, the authors found an increased Vd and subtherapeutic serum concentrations [53]. The patient experienced a poor clinical response to linezolid, requiring addition of vancomycin intravenously to his antibiotic regimen. Two other obese patients (102 and 116 kg) being empirically treated for pneumonia had >100% linezolid penetration into the lung based on bronchoalveolar lavage concentrations [54]. However, the AUC for both patients was 0.25 vs ‡1 mg/l, respectively). Further studies are needed to determine whether these differences in pharmacokinetics and pharmacodynamics result in changes in outcomes. Glycylcycline

Van Wart et al. found increased Cl correlated with higher patient weight when analyzing 169 patients receiving tigecycline [57]. The authors theorized that this elevation could be due to increased nonrenal elimination or use of weight as a calculation factor for creatinine Cl estimations. Patient data from a prospective study of tigecycline in intra-abdominal infections were retrospectively analyzed to identify patient covariates associated with clinical failure [58]. Researchers identified six factors predictive of patient clinical response: patient weight 48 kg) [80]. Another study compared weight-based doses of pyrazinamide and concluded that hepatotoxicity was not significantly increased in patients receiving high-dose pyrazinamide [81]. Doses higher than 2 g per day, even in normal weight adults, are likely needed to achieve an AUC/MIC associated with optimal sterilizing effect in 90% of patients based on Monte Carlo simulations [82]. It was originally thought that diabetes mellitus had an effect on the pharmacokinetics of rifampin in patients with active TB; however, this was refuted by a subsequent study [83–85]. In study of patients with TB, treatment failure was overwhelmingly associated with increased weight in both the DM and the non-DM groups (r2 = 0.96 and 0.99, respectively) [86]. This study was a follow-up to a retrospective analysis of 554 patients receiving treatment for active tuberculosis that determined that increased weight was associated with treatment failure (r2 = 0.94) [87]. These authors concluded that the influence of increased weight on the pharmacokinetics of antituberculosis therapy is one potential reason for this relationship. An even greater impact of suboptimal rifampin dosing is likely seen in 850

patients receiving intermittent therapy as a higher risk of relapse has been observed with rifampin when fewer doses per week are administered [88]. Obese patients receiving treatment for tuberculosis should be monitored closely for clinical failure. Expert commentary

Obesity remains a growing concern in the USA and other developed countries. In the USA, approximately one-third of the population is considered obese [2]. When expanded to include the number of overweight as well, the figure encompasses two-thirds of the population. While obesity carries with it a risk for chronic disease states such as hypertension and diabetes, it also has been correlated with an increased risk of infection and poorer resolution from infectious diseases [89–91]. Prevention programs are currently a major focus of international health groups and government-supported programs. While this is an important step for helping to decrease the prevalence of obesity, little research has been undertaken to know how obesity specifically affects the standard treatment and successful resolution of infections in those patients who are already obese or overweight. Specific alterations that have been observed in obese patients using antibacterial therapy include an overall increase in Vd and Cl. Agents with a %T>MIC (i.e., b-lactams) or AUC/MIC (vancomycin, fluoroquinolones, etc.) pharmacodynamic profile are most affected by increases in Cl. Cl is thought to increase in obese persons due to an increase in overall organ size and GFR [5]. Vancomycin was found to have a high correlation with TBW and Cl, leading to use of TBW for calculation of empiric dosing [32–34]. Agents with a Cmax/MIC (aminoglycosides, daptomycin, etc.) pharmacodynamic profile are more affected by alterations in Vd. The aminoglycosides have been studied in the obese with a dosing weight correction factor of 40% excess weight added to IBW. This has been widely accepted as an initial dosing strategy to overcome the alterations in Vd observed in obese patients. Obesity may also alter Vd of a drug due to the increased amount of adipose tissue for lipophilic drugs to penetrate or due to the corresponding increases in extracellular fluid, which will increase distribution of hydrophilic drugs. Moreover, lipophilicity is not the only chemical characteristic that is important for predicting how antibacterial agents will be altered in the obese. Polarity and the ability to form ions are also of great importance and can alter the general characteristics of the drugs in an obese patient. For example, ciprofloxacin has a lipophilic log P value of 1.308 [92], but also distributes into the aqueous fluids due to its status as a zwitterion allowing ion trapping in areas of varying pH values [93]. Conclusions can be drawn that there is no predictable way to make generalizations about specific agents or drug classes simply using a lipophilicity measurement alone. There is general agreement that ciprofloxacin needs an adjustment for obese patients; however, no consensus on the best method has been achieved. All chemical characteristics combined are of importance for the overall tissue penetration of the medications. As such, no particular pattern for prediction of what alterations will occur Expert Rev. Anti Infect. Ther. 12(7), (2014)



with each class of antibacterial in obese patients can be made, making study of each specific drug necessary to know the pharmacokinetic alterations that will occur. Unfortunately, there is a great variance in the manner of study of antibacterial agents in obese patients. Some studies use weight stratification, while others use BMI groups or skin fold or body composition testing. BMI may be problematic because it does not take into account the actual percentage of tissue that is adipose or lean body mass, only the overall increased weight. Patients could be in the same BMI category but have significantly different lean and adipose tissue percentages [94]. This may make a difference in the outcomes of the studies performed using BMI as the marker for obesity. Additionally, most studies testing the pharmacokinetic alterations have been performed as a single dose. Any results from these studies would be adequate for initial dosing alterations, but may not give enough information to guide long-term maintenance dosing. Increased dosing in obese patients may also present a risk for increased toxicity, especially if the agent forms a reservoir in adipose tissues. Toxicity has not been a focus of research in the obese population, and therefore very little is known about the safety of using high doses in these patients. Additional areas of study could be use of continuous infusion for those agents that are %T>MIC drugs. To date, the authors are not aware of any studies being performed in this manner for obese patients experiencing infection. In obese patients, this method of antimicrobial dosing is risky as subtherapeutic dosing results in 0% T>MIC and therefore carries a greater risk of poor outcomes if adequate doses are not initially given. Moreover, there is no requirement for medications to be studied specifically in this patient population despite the high prevalence of obesity. Determination of one-size-fits-all dosing adjustment for obese patients is not adequate due to differences

Review

in both the medications and between individuals. The failure to include obese patients in all stages of drug development greatly hinders the ability to make definitive dosing adjustments and may detrimentally affect clinical outcomes. In addition to pharmacokinetic and pharmacodynamic changes associated with obesity, considerations should be given for severity of infection, infection site, infecting pathogen and local susceptibilities when dosing antibiotic agents. Five-year view

A mandate by regulatory agencies such as the FDA to include obese persons in all stages of drug development is necessary to design optimized dosing regimens for these patients. Complications arise as many of the agents have been approved for years and would likely be ‘grandfathered’ into these requirements. Additionally, few antibacterial agents are being developed and further cost increasing studies would likely further hinder the development of new agents. The current political environment that focuses on prevention and cure of obesity also hinders study of the use of medications in the obese population. While prevention is important, it does little to satisfy what methods practitioners have to optimize patient care and clinical outcomes for those patients who are currently designated as obese or overweight. Medications must be studied in the obese to better address the needs of this population. Financial & competing interests disclosure

The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.

Key issues • Obesity is a global pandemic. • Obesity alters pharmacokinetic parameters such as the volume of distribution, clearance, maximum and minimum drug concentrations (Cmax, Cmin), area under the curve and half-life. • Few studies have been performed to assess what weight descriptors or overall method of creatinine clearance estimation is most accurate for obese patients. • Few studies have been performed in the obese populations for most antibacterial agents. • Existing data for dosing antibacterials in obese persons are limited by small sample sizes. • Vancomycin initial doses should be calculated using total body weight with patient-specific dosing adjustments performed based on steady-state trough concentrations following the initial dose. • Aminoglycosides (amikacin, gentamicin, tobramycin) initial dosing should utilize ideal body weight plus a 40% excess body weight (total body weight-ideal body weight) correction factor with patient-specific adjustments based on peak and trough concentrations for subsequent doses. • Obese patients have a higher risk of failing antituberculosis therapy than normal weight patients due to alterations in pharmacokinetic parameters. • Other antimicrobial classes have varying alterations of pharmacokinetic parameters, necessitating evaluation of each individual agent. • When dosing antibiotic agents, considerations should be given for severity of infection, infection site, infecting pathogen, local susceptibilities and patient-specific factors that affect the pharmacokinetics and pharmacodynamics of the medications.


851

Review

Payne & Hall II

individual. Ann Pharmacother 2007;41(10): 1734-9

References Papers of special note have been highlighted as: • of interest •• of considerable interest


1.

Finucane MM, Stevens GA, Cowan MJ, et al. National. regional, and global trends in body-mass index since 1980: systematic analysis of health examination surveys and epidemiological studies with 960 country-years and 9.1 million participants. Lancet 2011;377(9765):557-67

13.

14.

Sturm AW, Allen N, Rafferty KD, et al. Pharmacokinetic analysis of piperacillin administered with tazobactam in critically ill, morbidly obese surgical patients. Pharmacotherapy 2014;34(1):28-35 Cheatham SC, Fleming MR, Healy DP, et al. Steady-state pharmacokinetics and pharmacodynamics of piperacillin and tazobactam administered by prolonged infusion in obese patients. Int J Antimicrob Agents 2013;41(1):52-6

•

Report detailing the worldwide pandemic of obesity.

2.

Flegal KM, Carroll MD, Ogden CL, Curtin LR. Prevalence and trends in obesity among US adults, 1999-2008. JAMA 2010; 303(3(235):41

3.

F as in fat: how obesity threatens America’s future. 2013. Available from: http:// healthyamericans.org/assets/files/ TFAH2013FasInFatReportFinal%209.9.pdf [Last accessed on 16 January 2014]

4.

Pai MP. Estimating the glomerular filtration rate in obese adult patients for drug dosing. Adv Chronic Kidney Dis 2010;17(5):e53-62

15.

Cheadle WG. Risk factors for surgical site infection. Surg Infect (Larchmt) 2006; 7(Suppl 1):S7-11

5.

West GB, Brown JH, Enquist BJ. A general model for the origin of allometric scaling laws in biology. Science 1997;276(5309): 122-6

16.

Forse RA, Karam B, MacLean LD, Christou NV. Antibiotic prophylaxis for surgery in morbidly obese patients. Surgery 1989;106(4):750-6.discussion 756-757

•

••

Pharmacokinetic study that evaluated extended interval infusion of pipercillin/ tazobactam and identified that higher doses are likely needed in patients with a higher BMI to maintain similar pharmacokinetic profiles with normal weight patients, which provides practitioners with quantifiable dose adjustment recommendations.

Pivotal study evaluating cefazolin dosing for surgical prophylaxis in obese and normal weight patients. Increasing from a 1 g to 2 g prophylactic dose of cefazolin in obese patients decreased the institution’s surgical site infection rate in this patient population.

6.

West GB, Brown JH, Enquist BJ. The fourth dimension of life: fractal geometry and allometric scaling of organisms. Science 1999;284(5420):1677-9

7.

Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 1976;16(1):31-41

8.

Winter MA, Guhr KN, Berg GM. Impact of various body weights and serum creatinine concentrations on the bias and accuracy of the Cockcroft-Gault equation. Pharmacotherapy 2012;32(7):604-12

17.

9.

Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group. KDIGO clinical practice guideline for the evaluation and management of chronic kidney disease. Kidney Int Suppl 2013;3:1-150

18.

van Kralingen S, Taks M, Diepstraten J, et al. Pharmacokinetics and protein binding of cefazolin in morbidly obese patients. Eur J Clin Pharmacol 2011;67(10):985-92

19.

10.

National Kidney Disease Education Program. CKD and drug dosing: information for providers. 2012. Available from: http://nkdep.nih.gov/resources/CKDdrug-dosing.shtml [Last accessed on March 6 [2014]

Barbour A, Schmidt S, Rout WR, et al. Soft tissue penetration of cefuroxime determined by clinical microdialysis in morbidly obese patients undergoing abdominal surgery. Int J Antimicrob Agents 2009;34(3):231-5

20.

Toma O, Suntrup P, Stefanescu A, et al. Pharmacokinetics and tissue penetration of cefoxitin in obesity: implications for risk of surgical site infection. Anesth Analg 2011; 113(4):730-7

21.

Itani KM, Jensen EH, Finn TS, et al. Effect of body mass index and ertapenem versus

11.

Yuk J, Nightingale CH, Sweeney K, et al. Pharmacokinetics of nafcillin in obesity. J Infect Dis 1988;157(5):1088-9

12.

Newman D, Scheetz MH, Adeyemi OA, et al. Serum piperacillin/tazobactam pharmacokinetics in a morbidly obese

852

Edmiston CE, Krepel C, Kelly H, et al. Perioperative antibiotic prophylaxis in the gastric bypass patient: do we achieve therapeutic levels? Surgery 2004;136(4): 738-47

cefotetan prophylaxis on surgical site infection in elective colorectal surgery. Surg Infect (Larchmt) 2008;9(2):131-7 •

An outcome based study demonstrating that 1 g doses of ertapenem may fail to provide optimal effectiveness for obese persons versus normal weight.

22.

Yost RL, Derendorf H. Disposition of cefotaxime and its desacetyl metabolite in morbidly obese male and female subjects. Ther Drug Monit 1986;8(2):189-94

23.

Chen M, Nafziger AN, Drusano GL, et al. Comparative pharmacokinetics and pharmacodynamic target attainment of ertapenem in normal-weight, obese, and extremely obese adults. Antimicrob Agents Chemother 2006;50(4):1222-7

24.

Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Antimicrobial Susceptibility Testing – 22nd Information Supplement. CLSI Document M100-S22. CLSI; Wayne, PA: 2012

25.

de Werra C, Di Micco R, Pilone V, et al. Serum in vivo and in vitro activity of single dose of ertapenem in surgical obese patients for prevention of SSIs. Obes Surg 2013; 23(7):911-19

26.

Bearden DT ES, Mcconnell DB, Belle DJ, Kohlhepp SJ. Pharmacokinetics of meropenem in extreme obesity. Presented at 45th Interscience Conference on Antimicrobial Agents and Chemotherapy; 16–19 December 2005; Washington, DC, USA

27.

Cheatham SC, Fleming MR, Healy DP, et al. Steady-state pharmacokinetics and pharmacodynamics of meropenem in morbidly obese patients hospitalized in an intensive care unit. J Clin Pharmacol 2014; 54(3):324-30

28.

Nandy P, Samtani MN, Lin R. Population pharmacokinetics of doripenem based on data from phase 1 studies with healthy volunteers and phase 2 and 3 studies with critically ill patients. Antimicrob Agents Chemother 2010;54(6):2354-9

29.

Roberts JA, Lipman J. Optimal doripenem dosing simulations in critically ill nosocomial pneumonia patients with obesity, augmented renal clearance, and decreased bacterial susceptibility. Crit Care Med 2013;41(2):489-95

30.

Kays MB, Fleming MR, Cheatham SC, et al. Comparative pharmacokinetics and pharmacodynamics of doripenem and meropenem in obese patients. Ann Pharmacother 2014;48(2):178-86

31.

US FDA. FDA Drug Safety Communication: FDA Statement on



recently terminated clinical trial with Doribax (doripenem). 2012.Available from: www.fda.gov/Drugs/DrugSafety/ ucm285883.htm [Last accessed on 28 March 2014]


32.

••

33.

34.

Blouin RA, Bauer LA, Miller DD, et al. Vancomycin pharmacokinetics in normal and morbidly obese subjects. Antimicrob Agents Chemother 1982;21(4):575-80 Pivotal pharmacokinetic study demonstrating that vancomycin weight-based dosing should be calculated using actual body weight, which is now consensus-guideline recommendation. Vance-Bryan K, Guay DR, Gilliland SS, et al. Effect of obesity on vancomycin pharmacokinetic parameters as determined by using a Bayesian forecasting technique. Antimicrob Agents Chemother 1993;37(3): 436-40

42.

43.

44.

Bauer LA, Black DJ, Lill JS. Vancomycin dosing in morbidly obese patients. Eur J Clin Pharmacol 1998;54(8):621-5

35.

Leong JV, Boro MS, Winter M. Determining vancomycin clearance in an overweight and obese population. Am J Health Syst Pharm 2011;68(7):599-603

36.

Rybak M, Lomaestro B, Rotschafer JC, et al. Therapeutic monitoring of vancomycin in adult patients: a consensus review of the American Society of Health-System Pharmacists, the Infectious Diseases Society of America, and the Society of Infectious Diseases Pharmacists. Am J Health Syst Pharm 2009;66(1):82-98

37.

Liu C, Bayer A, Cosgrove SE, et al. Clinical practice guidelines by the Infectious Diseases Society of America for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children. Clin Infect Dis 2011;52(3):285-92

38.

Hall RG 2nd, Payne KD, Bain AM, et al. Multicenter evaluation of vancomycin dosing: emphasis on obesity. Am J Med 2008;121(6):515-18

39.

Puzniak LA, Morrow LE, Huang DB, Barreto JN. Impact of weight on treatment efficacy and safety in complicated skin and skin structure infections and nosocomial pneumonia caused by methicillin-resistant Staphylococcus aureus. Clin Ther 2013; 35(10):1557-70

40.

41.

Hall RG 2nd, Giuliano CA, Haase KK, et al. Empiric guideline-recommended weight-based vancomycin dosing and mortality in methicillin-resistant Staphylococcus aureus bacteremia: a retrospective cohort study. BMC Infect Dis 2012;12:104


45.

46.

Hall RG 2nd, Hazlewood KA, Brouse SD, et al. Empiric guideline-recommended weight-based vancomycin dosing and nephrotoxicity rates in patients with methicillin-resistant Staphylococcus aureus bacteremia: a retrospective cohort study. BMC Pharmacol Toxicol 2013;14:12 Lodise TP, Patel N, Lomaestro MB, et al. Relationship between initial vancomycin concentration-time profile and nephrotoxicity among hospitalized patients. Clin Infect Dis 2009;49(4):507-14 Kullar R, Davis SL, Levine DP, Rybak MJ. Impact of vancomycin exposure on outcomes in patients with methicillin-resistant Staphylococcus aureus bacteremia: support for consensus guidelines suggested targets. Clin Infect Dis 2011; 52(8):975-81 Dvorchik BH, Damphousse D. The pharmacokinetics of daptomycin in moderately obese, morbidly obese, and matched nonobese subjects. J Clin Pharmacol 2005;45(1):48-56 Pai MP, Norenberg JP, Anderson T, et al. Influence of morbid obesity on the single-dose pharmacokinetics of daptomycin. Antimicrob Agents Chemother 2007;51(8): 2741-7 Bhavnani SM, Rubino CM, Ambrose PG, Drusano GL. Daptomycin exposure and the probability of elevations in the creatine phosphokinase level: data from a randomized trial of patients with bacteremia and endocarditis. Clin Infect Dis 2010; 50(12):1568-74

Review

doses. Presented at 51st Interscience Conference on Antimicrobial Agents and Chemotherapy; 17–20 September 2011; Chicago, IL, USA 51.

Stein GE, Schooley SL, Peloquin CA, et al. Pharmacokinetics and pharmacodynamics of linezolid in obese patients with cellulitis. Ann Pharmacother 2005;39(3):427-32

52.

Rajendran PM, Young D, Maurer T, et al. Randomized, double-blind, placebocontrolled trial of cephalexin for treatment of uncomplicated skin abscesses in a population at risk for community-acquired methicillin-resistant Staphylococcus aureus infection. Antimicrob Agents Chemother 2007;51(11):4044-8

53.

Muzevich KM, Lee KB. Subtherapeutic linezolid concentrations in a patient with morbid obesity and methicillin-resistant Staphylococcus aureus pneumonia: case report and review of the literature. Ann Pharmacother 2013;47(6):e25

54.

De Pascale G, Fortuna S, Navarra P, Antonelli M. Linezolid use in ventilator-associated pneumonia: look at the body weight of your patient!. Minerva Anestesiol 2012;78(12):1418-19

55.

Bhalodi AA, Papasavas PK, Tishler DS, et al. Pharmacokinetics of intravenous linezolid in moderately to morbidly obese adults. Antimicrob Agents Chemother 2013; 57(3):1144-9

••

Pharmacokinetic study demonstrating that recommended doses result in similar exposure for obese patients up to 150 kg.

56.

Hamilton R, Thai XC, Ameri D, Pai MP. Oral bioavailability of linezolid before and after Roux-en-Y gastric bypass surgery: is dose modification necessary in obese subjects? J Antimicrob Chemother 2013; 68(3):666-73

57.

Van Wart SA, Owen JS, Ludwig EA, et al. Population pharmacokinetics of tigecycline in patients with complicated intra-abdominal or skin and skin structure infections. Antimicrob Agents Chemother 2006;50(11):3701-7

58.

Bhavnani SM, Rubino CM, Ambrose PG, et al. Impact of different factors on the probability of clinical response in tigecycline-treated patients with intra-abdominal infections. Antimicrob Agents Chemother 2010;54(3):1207-12

47.

Bookstaver PB, Bland CM, Qureshi ZP, et al. Safety and effectiveness of daptomycin across a hospitalized obese population: results of a multicenter investigation in the southeastern United States. Pharmacotherapy 2013;33(12):1322-30

•

Outcomes based study demonstrating no difference in adverse effects or clinical effectiveness between obese and normal weight patients, confirming that daptomycin weight-based doses should be calculated using actual body weight.

48.

Mersfelder TL, Smith CL. Linezolid pharmacokinetics in an obese patient. Am J Health Syst Pharm 2005;62(5):464-7

49.

Meagher AK, Forrest A, Rayner CR, et al. Population pharmacokinetics of linezolid in patients treated in a compassionate-use program. Antimicrob Agents Chemother 2003;47(2):548-53

59.

Cheatham SC, Kays MB, Fleming MR, Shawa I. Pharmacokinetics of linezolid in obese hospitalized patients utilizing higher

Pai MP. Serum and urine pharmacokinetics of tigecycline in obese class III and normal weight adults. J Antimicrob Chemother 2014;69(1):190-9

60.

US FDA. FDA Drug Safety Communication: FDA warns of increased risk of death with IV

50.

853

Review

Payne & Hall II


antibacterial Tygacil (tigecycline) and approves new Boxed Warning. 2013.Available from: www.fda.gov/Drugs/DrugSafety/ucm369580. htm [Last accessed on 16 January 2014]

73.

Leader WG, Tsubaki T, Chandler MH. Creatinine-clearance estimates for predicting gentamicin pharmacokinetic values in obese patients. Am J Hosp Pharm 1994;51(17): 2125-30

61.

Abdullahi M, Annibale B, Capoccia D, et al. The eradication of Helicobacter pylori is affected by body mass index (BMI). Obes Surg 2008;18(11):1450-4

62.

Allard S, Kinzig M, Boivin G, et al. Intravenous ciprofloxacin disposition in obesity. Clin Pharmacol Ther 1993;54(4): 368-73

63.

Hollenstein UM, Brunner M, Schmid R, Muller M. Soft tissue concentrations of ciprofloxacin in obese and lean subjects following weight-adjusted dosing. Int J Obes Relat Metab Disord 2001;25(3):354-8

75.

Utrup TR, Mueller EW, Healy DP, et al. High-dose ciprofloxacin for serious gram-negative infection in an obese, critically ill patient receiving continuous venovenous hemodiafiltration. Ann Pharmacother 2010;44(10):1660-4

76.

American Thoracic Society, CDC. Treatment of tuberculosis. MMWR Recomm Rep 2003;52(RR-11):1-77

77.

Hasenbosch RE, Alffenaar JW, Koopmans SA, et al. Ethambutol-induced optical neuropathy: risk of overdosing in obese subjects. Int J Tuberc Lung Dis 2008;12(8):967-71

64.

65.

66.

67.

••

68.

69.

Kees MG, Weber S, Kees F, Horbach T. Pharmacokinetics of moxifloxacin in plasma and tissue of morbidly obese patients. J Antimicrob Chemother 2011;66(10):2330-5 Cook AM, Martin C, Adams VR, Morehead RS. Pharmacokinetics of intravenous levofloxacin administered at 750 milligrams in obese adults. Antimicrob Agents Chemother 2011;55(7):3240-3 Schwartz SN, Pazin GJ, Lyon JA, et al. A controlled investigation of the pharmacokinetics of gentamicin and tobramycin in obese subjects. J Infect Dis 1978;138(4):499-505 Pivotal study that identified a correction factor for weight in obese patients, which is now commonly used in calculating aminoglycoside doses. Blouin RA, Mann HJ, Griffen WO Jr, et al. Tobramycin pharmacokinetics in morbidly obese patients. Clin Pharmacol Ther 1979;26(4):508-12 Bauer LA, Blouin RA, Griffen WO Jr, et al. Amikacin pharmacokinetics in morbidly obese patients. Am J Hosp Pharm 1980; 37(4):519-22

70.

Korsager S. Administration of gentamicin to obese patients. Int J Clin Pharmacol Ther Toxicol 1980;18(12):549-53

71.

Sketris I, Lesar T, Zaske DE, Cipolle RJ. Effect of obesity on gentamicin pharmacokinetics. J Clin Pharmacol 1981;21(7):288-93

72.

Bauer LA, Edwards WA, Dellinger EP, Simonowitz DA. Influence of weight on aminoglycoside pharmacokinetics in normal

854

dose in pulmonary tuberculosis patients. Antimicrob Agents Chemother 2007;51(7): 2546-51

weight and morbidly obese patients. Eur J Clin Pharmacol 1983;24(5):643-7

74.

78.

•

79.

80.

81.

82.

83.

Traynor AM, Nafziger AN, Bertino JS Jr. Aminoglycoside dosing weight correction factors for patients of various body sizes. Antimicrob Agents Chemother 1995;39(2): 545-8 Pai MP, Nafziger AN, Bertino JS Jr. Simplified estimation of aminoglycoside pharmacokinetics in underweight and obese adult patients. Antimicrob Agents Chemother 2011;55(9):4006-11

Hall RG 2nd, Swancutt MA, Meek C, et al. Ethambutol pharmacokinetic variability is linked to body mass in overweight, obese, and extremely obese people. Antimicrob Agents Chemother 2012;56(3):1502-7 Pharmacokinetic study demonstrating that weight, not BMI, was a significant covariate of ethambutol clearance using the 3/4 power law. Kinzig-Schippers M, Tomalik-Scharte D, Jetter A, et al. Should we use N-acetyltransferase type 2 genotyping to personalize isoniazid doses? Antimicrob Agents Chemother 2005;49(5):1733-8 Wilkins JJ, Langdon G, McIlleron H, et al. Variability in the population pharmacokinetics of pyrazinamide in South African tuberculosis patients. Eur J Clin Pharmacol 2006;62(9):727-35 Pasipanodya JG, Gumbo T. Clinical and toxicodynamic evidence that high-dose pyrazinamide is not more hepatotoxic than the low doses currently used. Antimicrob Agents Chemother 2010;54(7):2847-54 Gumbo T, Dona CS, Meek C, Leff R. Pharmacokinetics-pharmacodynamics of pyrazinamide in a novel in vitro model of tuberculosis for sterilizing effect: a paradigm for faster assessment of new antituberculosis drugs. Antimicrob Agents Chemother 2009; 53(8):3197-204 Ruslami R, Nijland HM, Alisjahbana B, et al. Pharmacokinetics and tolerability of a higher rifampin dose versus the standard

84.

Ruslami R, Nijland HM, Adhiarta IG, et al. Pharmacokinetics of antituberculosis drugs in pulmonary tuberculosis patients with type 2 diabetes. Antimicrob Agents Chemother 2010;54(3):1068-74

85.

Nijland HM, Ruslami R, Stalenhoef JE, et al. Exposure to rifampicin is strongly reduced in patients with tuberculosis and type 2 diabetes. Clin Infect Dis 2006;43(7): 848-54

86.

Pasipanodya JG, Weis S, Gumbo T. Weight, not diabetes mellitus predicts failure of anti-tuberculosis therapy in treated tuberculosis patients with concurrent diabetes mellitus. Presented at 50th Interscience Conference on Antimicrobial Agents and Chemotherapy; 12-15 September 2010;Boston, MA, USA

87.

Pasipanodya J, Hall R, Weis S, Gumbo T. Fats, fractals, and failure of antituberculosis pharmacotherapy. Presented at 50th Interscience Conference on Antimicrobial Agents and Chemotherapy; 12-15 September 2010; Boston, MA, USA

88.

Chang KC, Leung CC, Yew WW, et al. Dosing schedules of 6-month regimens and relapse for pulmonary tuberculosis. Am J Respir Crit Care Med 2006;174(10):1153-8

89.

Dowsey MM, Choong PF. Obesity is a major risk factor for prosthetic infection after primary hip arthroplasty. Clin Orthop Relat Res 2008;466(1):153-8

90.

Dossett LA, Dageforde LA, Swenson BR, et al. Obesity and site-specific nosocomial infection risk in the intensive care unit. Surg Infect (Larchmt) 2009;10(2):137-42

91.

Huttunen R, Syrjanen J. Obesity and the outcome of infection. Lancet Infect Dis 2010;10(7):442-3

92.

Kiem S, Schentag JJ. Interpretation of antibiotic concentration ratios measured in epithelial lining fluid. Antimicrob Agents Chemother 2008;52(1):24-36

93.

Bergan T. Extravascular penetration of ciprofloxacin. A review. Diagn Microb Infect Dis 1990;13(2):103-14

94.

Gallagher D, Visser M, Sepulveda D, et al. How useful is body mass index for comparison of body fatness across age, sex, and ethnic groups? Am J Epidemiol 1996; 143(3):228-39

•

Study demonstrating that BMI is not a reliable indicator of adiposity across different patient populations.


One size does not fit all!

One-size MAP does not fit all.

Antibiotic dosing during renal replacement therapy: one size does not fit all*.

Immunonutrition in Critically Ill Patients: Does One Size Fit All?

Treating constipation with prucalopride: one size does not fit all.

Survivorship care planning: one size does not fit all.

Tranexamic acid reduces surgical bleeding: does one size fit all?

One size does not fit all for a good death.

Breast reconstruction: one size does not fit all.

One size does not fit all: opioid dose range orders.

One size cannot fit all.

One size does not fit all: older adults benefit from redundant text in multimedia instruction.

Risk markers for excess mortality in adults with congenital heart disease: does one size fit all?

Anxiety disorders: does one treatment fit all?

Endothelial Mechanosignaling: Does One Sensor Fit All?

Mechanisms of iron mineralization in ferritins: one size does not fit all.

Thiamine as a metabolic resuscitator in septic shock: one size does not fit all.

One Size Does Not Fit All: A Cliché or a Hard Fact in Cardiac Chamber Quantification?

Assessing statistical competencies in clinical and translational science education: one size does not fit all.

The "obesity-mortality paradox" phenomenon in critically ill patients: one size does not fit all.

One size does not fit all: the emerging frontier in large-scale marine conservation.

Ethnic Variation in Partnered Women's and Men's Housework: Does One Size Fit All?

Dissecting microsatellite instability in colorectal cancer: one size does not fit all.

R-CHOP: does one size fit all in diffuse large B cell lymphoma?