A study that evaluated critically ill patients (49 obese and 59 nonobese patients; 49% with lung infection) who had received broad-spectrum β-lactams (cefepime, piperacillin and tazobactam, or meropenem) at standard dosing regimens found considerable variability in β-lactam serum concentrations (coefficient of variation of 50–92% for all drugs) in obese and nonobese patients . The standard dosing regimens resulted in insufficient plasma concentrations in 32% of patients and overdosed concentrations in 25% . For meropenem, more obese patients had concentrations that did not reach therapeutic targets than nonobese patients (35 versus 0%; P = 0.02), but no differences were observed for cefepime and piperacillin and tazobactam . In the same study, patients on continuous renal replacement therapy were more likely to have supertherapeutic β-lactam serum concentrations and less likely to have insufficient β-lactam serum concentrations .
Piperacillin and tazobactam
There is little information regarding penicillin dosing in the obese population with pneumonia. The pharmacokinetic properties of piperacillin and tazobactam have been described in obese patients with infections other than pneumonia. In a 33-year-old morbidly obese patient (BMI = 55 kg/m2) with a surgical site infection following a transfemoral left leg amputation receiving piperacillin and tazobactam at 4.5 g every 6 h as a 30-min infusion, the percentage free drug T > 4 × MIC and percentage free drug T > MIC were 25 and 60% of the dosing interval, respectively . A study of 14 hospitalized obese patients (weight >120 kg, BMI = 52.3 ± 10.8 kg/m2) receiving piperacillin and tazobactam 4.5 g every 8 h or 6.75 g every 8 h infused over 4 h found the pharmacokinetics were different compared with nonobese patients [10▪]. For piperacillin, the probability of target attainment for at least 50% of free drug T > MIC was at least 91% for doses of at least 4.5 g every 8 h at MICs of 16 μg/ml or less [10▪]. For tazobactam, the probability of target attainment was 57, 84, and 94% for doses of 4.5, 6.75, and 9.0 g every 8 h, respectively [10▪]. On the basis of the available data, higher doses of piperacillin and tazobactam and longer infusion time of up to 4 h may be required in obese patients.
Analysis of serial serum cefepime concentrations after dosing in 10 morbidly obese patients (BMI >40 kg/m2; estimated GFR = 108.4 ± 34.6 ml/min) found that an increased dose of 2 g every 8 h was necessary to maintain an adequate free drug T > MIC throughout the dosing interval [11▪]. Therefore, the use of the upper limit of normal doses of cephalosporins is recommended in obese patients.
In nine ICU patients with BMI of at least 40 kg/m2 who received meropenem (500 mg or 1 g every 6 h, infused over 0.5 h), Monte Carlo simulation was performed for five meropenem dosing regimens (500 mg every 8 h, 1 g every 8 h, 2 g every 8 h, 500 mg every 6 h, and 1 g every 6 h) infused over 0.5 and 3 h [12▪]. The study found that free drug T > MIC for 40% of the dosing interval would be achieved at a probability of at least 90% in four of five regimens infused over 0.5 h and for five of five regimens infused over 3 h [12▪]. Free drug T > MIC for 54% of the dosing interval would be achieved at at least 90% probability in two of five regimens infused over 0.5 h in four of five regimens infused over 3 h [12▪]. In a case report, an obese patient (BMI = 35 kg/m2) with ventilator-associated pneumonia (VAP) due to Pseudomonas aeruginosa (multi-drug resistant but meropenem sensitive with MIC = 2 mg/l) was given meropenem (1 g every 8 h) . On days 2 and 5 of therapy, serum meropenem measurements found that meropenem T > 4 × MIC was less than 40% of the dose interval . When meropenem dose was increased to 3 g every 6 h given as a 3-h extended infusion, T > 4 × MIC increased to nearly 50%. The patient's clinical status improved thereafter with resolution of sepsis signs . A study of doripenem in critically ill adult patients with nosocomial pneumonia found that its administration by extended infusion (4 h) negated much of the pharmacokinetic variability caused by different body weights and renal function, and enabled achievement of the concentrations associated with maximal bacterial killing . Hence, the use of the upper limit of normal doses of carbapenems with extended infusions over approximately 3–4 h is recommended in obese patients.
Data about fluoroquinolones’ pharmacokinetics and pharmacodynamics in obese patients are limited. In a 179-kg man, levofloxacin 750 mg every 12 h versus 750 mg daily resulted in an AUC approximately double that found in the nonobese healthy population . In contrast, another study evaluated levofloxacin (750 mg intravenously over 90 min) in 15 obese people (12 hospitalized and 3 ambulatory volunteers), and found that peak concentrations and Vd were similar in the acutely ill obese patients, the ambulatory obese volunteers, and historical normal-weight volunteers . Additionally, levofloxacin clearance was higher (>2×) in the ambulatory obese than the acutely ill obese patients, which resulted in significantly lower AUC . Moxifloxacin was assessed in 12 morbidly obese patients and found that its serum pharmacokinetics were comparable to historical data in normal-weight individuals . In conclusion, optimal dosing of fluoroquinolones in the obese population is difficult to determine, but dosage adjustment is probably not warranted. Older data suggest that ciprofloxacin is affected by obesity and doses up to 800 mg every 12 h should be considered in morbidly obese patients [4▪].
The effect of macrolides against most bacteria is considered to be time dependent with significant postantibiotic effect. Data on macrolide use in obese patients with pneumonia are scarce. For Helicobacter pylori treatment, higher doses and longer durations of macrolide therapy have been suggested [4▪]. Whether higher doses and longer durations should be used in obese patients with pneumonia remains uncertain.
Aminoglycoside dosing is based on weight and kidney function, with subsequent dosage modifications guided by therapeutic drug monitoring. Dosing on ideal body weight (IBW) tends to underdose obese patients, whereas dosing on TBW tends to overdose them. Adjusted body weight (ABW) is usually recommended for aminoglycosides dosing (Table 1). One study evaluated ABW for weight-based dosing in 31 morbidly obese patients who received gentamicin or tobramycin 5–7 mg/kg every 24 h . Serum drug concentration was therapeutic in 71%, supratherapeutic in 13%, and subtherapeutic in 16% . The only variable that correlated with supratherapeutic levels was older age (P = 0.04) . Another study demonstrated that estimated lean body weight (LBW) (Table 1) was better than TBW and IBW to predict aminoglycoside Vd, and showed an improved prediction of aminoglycoside clearance using equations that estimate GFR rather than CLcr (Table 1) . Even when aminoglycosides achieve therapeutic lung concentrations, they might be inactivated by local conditions in the infected areas of the lung, including local hypoxia, cellular debris, and tissue acidosis, thus decreasing their effectiveness in pneumonia. In conclusion, aminoglycosides should be used in combination regimens for pneumonia treatment. Loading dose should be based on ABW or LBW, with subsequent dose and interval based on estimated GFR and drug level.
Studies in obese patients demonstrated higher vancomycin clearance in young adult morbidly obese patients that necessitates higher doses to have adequate trough concentration [4▪]. Vancomycin loading below the recommended dose was thought to contribute to delay in the achievement of therapeutic drug concentrations in one trial for methicillin-resistant Staphylococcus aureus (MRSA) pneumonia . The 2011 Infectious Diseases Society of America (IDSA) guidelines recommend the following antibiotic regimens for healthcare-associated or community-acquired MRSA pneumonia: intravenous vancomycin (15–20 mg/kg of TBW every 8–12 h, not to exceed 2 g per dose for patients with normal kidney function) or linezolid (600 mg orally/intravenously twice daily), or clindamycin (600 mg orally/intravenously three times daily) for susceptible strains . The guidelines also suggest vancomycin loading dose of 25–30 mg/kg of TBW in seriously ill patients and recommend serum trough concentration measurements prior to the fourth or fifth dose and having vancomycin trough concentrations of 15–20 μg/ml . Individual doses of 1.5 g or greater should be infused over at least 1.5–2 h .
Twenty adult obese volunteers (BMI = 30–54.9 kg/m2) receiving five linezolid doses (600 mg intravenously every 12 h) had AUC exposures similar to those of nonobese patients . In 12 critically ill patients with VAP (median weight = 80 kg), linezolid (loading dose = 600 mg followed by 1200 mg/day by continuous infusion) resulted in a linezolid alveolar diffusion of 100% and concentrations exceeding almost twice the susceptibility breakpoint for Staphylococcus aureus (4 mg/l) in both serum and epithelial lining fluid for 100% of the time [22▪]. Hence, it is recommended to use standard linezolid dosing in obese patients with pneumonia with consideration of continuous infusion.
Colistin is a metabolite of the prodrug colistimethate sodium (CMS), which has limited data on its colistin pharmacokinetics behavior . Colistin dosing is based on weight and kidney function. Manufacturers of European colistin products recommend 50 000–75 000 IU/kg/day of CMS in 2–3 divided doses (CMS potency = 12 500 IU per mg). Manufacturers of the U.S. product (Coly-Mycin) recommend 2.5–5 mg/kg colistin base activity daily divided in 2–4 doses (colistin base potency = 30 000 IU per mg) . IBW is the recommended dosing weight in obese patients. In critically ill patients with normal kidney function, including those with pneumonia due to multi-drug resistant pathogens, loading dose of 9 million IU followed by 4.5 million IU every 12 h may be the best dose regimen . However, a recent study found that providing 480 mg of CMS as a loading dose in 10 critically ill patients (for VAP in 8, only 1 patient was obese) was associated with significant reduction in the time to bacterial eradication compared with maintenance therapy alone . Notably, obesity (BMI ≥31.5 kg/m2) has been found to be a risk factor for nephrotoxicity (OR, 3.1; 95% CI, 1.15–8.35) in another study . For serum creatinine levels of 1.3–1.5, 1.6–2.5, or at least 2.6 mg/dl, the recommended dosage of intravenous colistin is 2 million IU (160 mg CMS) every 8, 12, or 24 h, respectively . On the basis of the available studies, using IBW in colistin dosing is recommended, taking into consideration the kidney function. Loading doses may be required.
A study compared voriconazole plasma trough concentrations and toxicities in obese (BMI >35 kg/m2) versus normal-weight patients receiving 4 mg/kg voriconazole every 12 h. The obese group had significantly higher trough concentrations (6.2 versus 3.5 mg/l, P < 0.0001) and higher rates of supratherapeutic levels (67 versus 17%, P < 0.0001) . Therapeutic voriconazole concentrations (2.0–5.5 mg/l) occurred in 29% of obese patients when dosed on TBW, and 45 and 80% of patients when dosed on IBW and ABW, respectively . A retrospective study in patients with hematologic malignancies and hematopoietic stem cell transplants found that patients with higher BMI had higher random voriconazole concentrations with intravenous administration (6.4 mg/l for BMI ≥25 kg/m2 versus 2.8 mg/l for BMI <25 kg/m2, P = 0.04) [26▪]. This was not noted with the oral formulation [26▪]. In a study of 61 ICU patients and patients with hematological malignancies, multivariate analysis revealed that higher BMI was associated with potentially toxic voriconazole plasma concentrations . Dosing based on ABW or IBW is recommended for voriconazole and similarly for amphotericin B.
Oseltamivir is used to treat severe influenza pneumonia. In a study of obese and lean mice treated with weight-adjusted dosages of oseltamivir, both groups had reduced lung inflammation and similar rates of epithelial cell regeneration rates and were completely protected from influenza mortality . A study in critically ill patients with pandemic H1N1 influenza found that the Vd of the oseltamivir carboxylate metabolite did not increase with increasing body weight . Studies on the effectiveness of antiviral therapy in obese patients with severe influenza are lacking. Early standard oseltamivir dosing is recommended in obese patients with the dose increased to 150 mg every 12 h in severe disease and normal kidney function.
Because insufficient antibiotic concentrations in the lungs after intravenous administration may lead to poor outcomes, the use of nebulized antibiotics has been suggested to achieve high lung concentrations. A randomized phase II trial of nebulized ceftazidime (15 mg/kg/3 h) and amikacin (25 mg/kg/day) versus intravenous ceftazidime (90 mg/kg/day, continuous infusion) and amikacin (15 mg/kg/day) found similar outcomes in both groups . However, nebulization was associated with obstruction of the expiratory filter in three patients and cardiac arrest in one . A matched case–control study of adjunctive aerosolized and intravenous colistin versus intravenous colistin alone in 208 ICU patients with VAP caused by multi-drug resistant organisms found that aerosolized and intravenous colistin patients had a higher clinical cure rate (69.2 versus 54.8%, P = 0.03), fewer days of mechanical ventilation after VAP onset (8 versus 12 days, P = 0.001), but similar all-cause mortality . At present, the available evidence does not support modifying the dose or frequency of nebulized antibiotics in obese patients.
ANTIBIOTIC DOSING AFTER BARIATRIC SURGERY
Limited data exist on antibiotic dosing after bariatric surgery. In one study of intravenous and oral moxifloxacin, Roux-en-Y gastric bypass surgery patients compared with healthy volunteers had higher AUC∞ (+51 and +54%, respectively) and Cmax (+25 and +35%, respectively), likely because of higher enterohepatic recirculation after gastric bypass . In a single-dose pharmacokinetic study, azithromycin concentrations and the AUC0–24 in gastric bypass patients were lower by 32% (P = 0.008) compared with controls . On the other hand, linezolid bioavailability was not changed by Roux-en-Y gastric bypass surgery in one study . In conclusion, there are limited data on antibiotic dosing after bariatric surgery and no recommendations can be made.
Data regarding the dosing of antibiotics in obese patients with pneumonia are limited. With the exception of aminoglycosides and vancomycin, the pharmacokinetics and pharmacodynamics of most other antibiotics have not been extensively investigated in the obese population. The role of antibiotic loading doses and therapeutic drug monitoring for antibiotics other than vancomycin and aminoglycosides need further investigation. The correlation between plasma antibiotic concentrations and lung tissue levels in obese patients is lacking and warrants further study. Further studies on the effect of dosing of antibiotics in obese patients with pneumonia on patient-centered outcomes, including recovery, relapse, and mortality, are needed.
Obese patients with pneumonia may be incorrectly dosed when obesity-related pharmacokinetics and pharmacodynamics alterations are not recognized. Recommendations for dosing in the obese patient are antibiotic group specific but are generally based on limited evidence. Further studies on the effect of antibiotic dosing in obese patients with pneumonia on patient-centered outcomes are greatly needed.
Conflicts of interest
There are no conflicts of interest.
REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have been highlighted as:
▪ of special interest
▪▪ of outstanding interest
1. Arabi YM, Dara SI, Tamim HM, et al. Clinical characteristics, sepsis interventions and outcomes in the obese patients with septic shock: an international multicenter cohort study. Crit Care 2013; 17:R72.
2. Roe JL, Fuentes JM, Mullins ME. Underdosing of common antibiotics for obese patients in the ED. Am J Emerg Med 2012; 30:1212–1214.
3. Longo C, Bartlett G, Macgibbon B, et al. The effect of obesity on antibiotic treatment failure: a historical cohort study. Pharmacoepidemiol Drug Saf 2013; 22:970–976.
4▪. Janson B, Thursky K. Dosing of antibiotics in obesity. Curr Opin Infect Dis 2012; 25:634–649.
This is a review article on dosing antibiotics in critically ill obese patients.
5. Udy AA, Roberts JA, Lipman J. Clinical implications of antibiotic pharmacokinetic principles in the critically ill. Intensive Care Med 2013; 39:2070–2082.
6. Claus BO, Hoste EA, Colpaert K, et al. Augmented renal clearance is a common finding with worse clinical outcome in critically ill patients receiving antimicrobial therapy. J Crit Care 2013; 28:695–700.
7. Anderson AH, Yang W, Hsu CY, et al. Estimating GFR among participants in the Chronic Renal Insufficiency Cohort (CRIC) Study. Am J Kidney Dis 2012; 60:250–261.
8. Aggarwal N, Porter AC, Tang IY, et al. Creatinine-based estimations of kidney function are unreliable in obese kidney donors. J Transplant 2012; 2012:872894.
9. Deman H, Verhaegen J, Willems L, Spriet I. Dosing of piperacillin/tazobactam in a morbidly obese patient. J Antimicrob Chemother 2012; 67:782–783.
10▪. 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; 41:52–56.
This article evaluates piperacillin and tazobactam pharmacokinetics and pharmacodynamics in morbid obesity, and describes piperacillin and tazobactam dosing and delivery to achieve higher T > MIC.
11▪. Rich BS, Keel R, Ho VP, et al. Cefepime dosing in the morbidly obese patient population. Obes Surg 2012; 22:465–471.
This article describes cefipime dosing to achieve the best T > MIC.
12▪. 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 2013; [Epub ahead of print].
This article evaluates meropenem pharmacokinetics and pharmacodynamics in morbid obesity, and describes meropenem dosing and delivery to achieve higher T > MIC.
13. Taccone FS, Cotton F, Roisin S, et al. Optimal meropenem concentrations to treat multidrug-resistant Pseudomonas aeruginosa
septic shock. Antimicrob Agents Chemother 2012; 56:2129–2131.
14. 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; 41:489–495.
15. Luque S, Grau S, Valle M, et al. Levofloxacin weight-adjusted dosing and pharmacokinetic disposition in a morbidly obese patient. J Antimicrob Chemother 2011; 66:1653–1654.
16. Cook AM, Martin C, Adams VR, Morehead RS. Pharmacokinetics of intravenous levofloxacin administered at 750 milligrams in obese adults. Antimicrob Agents Chemother 2011; 55:3240–3243.
17. Kees MG, Weber S, Kees F, Horbach T. Pharmacokinetics of moxifloxacin in plasma and tissue of morbidly obese patients. J Antimicrob Chemother 2011; 66:2330–2335.
18. Ross AL, Tharp JL, Hobbs GR, et al. Evaluation of extended interval dosing aminoglycosides in the morbidly obese population. Adv Pharmacol Sci 2013; 2013:194389.
19. Pai MP, Nafziger AN, Bertino JS Jr. Simplified estimation of aminoglycoside pharmacokinetics in underweight and obese adult patients. Antimicrob Agents Chemother 2011; 55:4006–4011.
20. 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: executive summary. Clin Infect Dis 2011; 52:285–292.
21. Bhalodi AA, Papasavas PK, Tishler DS, et al. Pharmacokinetics of intravenous linezolid in moderately to morbidly obese adults. Antimicrob Agents Chemother 2013; 57:1144–1149.
22▪. Boselli E, Breilh D, Caillault-Sergent A, et al. Alveolar diffusion and pharmacokinetics of linezolid administered in continuous infusion to critically ill patients with ventilator-associated pneumonia. J Antimicrob Chemother 2012; 67:1207–1210.
This study describes a linezolid dosing regimen that corresponded to high linezolid alveolar diffusion.
23. Michalopoulos AS, Falagas ME. Colistin: recent data on pharmacodynamics properties and clinical efficacy in critically ill patients. Ann Intensive Care 2011; 1:30.
24. Mohamed AF, Karaiskos I, Plachouras D, et al. Application of a loading dose of colistin methanesulfonate in critically ill patients: population pharmacokinetics, protein binding, and prediction of bacterial kill. Antimicrob Agents Chemother 2012; 56:4241–4249.
25. Koselke E, Kraft S, Smith J, Nagel J. Evaluation of the effect of obesity on voriconazole serum concentrations. J Antimicrob Chemother 2012; 67:2957–2962.
26▪. Davies-Vorbrodt S, Ito JI, Tegtmeier BR, et al. Voriconazole serum concentrations in obese and overweight immunocompromised patients: a retrospective review. Pharmacotherapy 2013; 33:22–30.
This study describes the pharmacokinetics and pharmacodynamics of standard voriconazole dosing in obese and overweight immunocompromised patients.
27. Hoenigl M, Duettmann W, Raggam RB, et al. Potential factors for inadequate voriconazole plasma concentrations in intensive care unit patients and patients with hematological malignancies. Antimicrob Agents Chemother 2013; 57:3262–3267.
28. O’Brien KB, Vogel P, Duan S, et al. Impaired wound healing predisposes obese mice to severe influenza virus infection. J Infect Dis 2012; 205:252–261.
29. Ariano RE, Sitar DS, Zelenitsky SA, et al. Enteric absorption and pharmacokinetics of oseltamivir in critically ill patients with pandemic (H1N1) influenza. CMAJ 2010; 182:357–363.
30. Hites M, Taccone FS, Wolff F, et al. Case–control study of drug monitoring of beta-lactams in obese critically ill patients. Antimicrob Agents Chemother 2013; 57:708–715.
31. Taccone FS, Vincent JL, Denis O, Jacobs F. Should we abandon vancomycin for treatment of methicillin-resistant Staphylococcus aureus
pneumonia? Still questions to answer. Clin Infect Dis 2012; 55:161–163.author reply 3–5.
32. Gauthier TP, Wolowich WR, Reddy A, et al. Incidence and predictors of nephrotoxicity associated with intravenous colistin in overweight and obese patients. Antimicrob Agents Chemother 2012; 56:2392–2396.
33. Lu Q, Yang J, Liu Z, et al. Nebulized ceftazidime and amikacin in ventilator-associated pneumonia caused by Pseudomonas aeruginosa
. Am J Respir Crit Care Med 2011; 184:106–115.
34. Tumbarello M, De Pascale G, Trecarichi EM, et al. Effect of aerosolized colistin as adjunctive treatment on the outcomes of microbiologically documented ventilator-associated pneumonia caused by colistin-only susceptible Gram-negative bacteria. Chest 2013; 144:1768–1775.
35. De Smet J, Colin P, De Paepe P, et al. Oral bioavailability of moxifloxacin after Roux-en-Y gastric bypass surgery. J Antimicrob Chemother 2012; 67:226–229.
36. Padwal RS, Ben-Eltriki M, Wang X, et al. Effect of gastric bypass surgery on azithromycin oral bioavailability. J Antimicrob Chemother 2012; 67:2203–2206.
37. 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; 68:666–673.
Keywords:© 2014 Lippincott Williams & Wilkins, Inc.
antibiotics; dosing; obesity; pharmacodynamics; pharmacokinetics