Next Article in Journal
Voriconazole Pharmacokinetics in Critically Ill Patients and Extracorporeal Membrane Oxygenation Support: A Retrospective Comparative Case-Control Study
Next Article in Special Issue
Real-Time Monitoring of Antibiotics in the Critically Ill Using Biosensors
Previous Article in Journal
Plant Extracts as Antimicrobial Agents in Sustainable Conservation of Erythrina caffra (Fabaceae) Historical Trees
Previous Article in Special Issue
Beta-Lactam Dose Optimisation in the Intensive Care Unit: Targets, Therapeutic Drug Monitoring and Toxicity
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Antibiotics
Volume 12
Issue 7
10.3390/antibiotics12071099
antibiotics-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Brief Report

Therapeutic Drug Monitoring of Antimicrobials in Critically Ill Obese Patients

by
Julie Gorham
1,
Fabio S. Taccone
1 and
Maya Hites
2,*
1
Department of Intensive Care, Hôpital Universitaire de Bruxelles (H.U.B), 1070 Brussels, Belgium
2
Clinic of Infectious Diseases, Hôpital Universitaire de Bruxelles (H.U.B), 1070 Brussels, Belgium
*
Author to whom correspondence should be addressed.
Antibiotics 2023, 12(7), 1099; https://doi.org/10.3390/antibiotics12071099
Submission received: 10 May 2023 / Revised: 14 June 2023 / Accepted: 21 June 2023 / Published: 24 June 2023
(This article belongs to the Special Issue Therapeutic Drug Monitoring in Intensive Care)
Browse Figure
Review Reports Versions Notes

Abstract

:
Obesity is a significant global public health concern that is associated with an elevated risk of comorbidities as well as severe postoperative and nosocomial infections. The treatment of infections in critically ill obese patients can be challenging because obesity affects the pharmacokinetics and pharmacodynamics of antibiotics, leading to an increased risk of antibiotic therapy failure and toxicity due to inappropriate dosages. Precision dosing of antibiotics using therapeutic drug monitoring may help to improve the management of this patient population. This narrative review outlines the pharmacokinetic and pharmacodynamic changes that result from obesity and provides a comprehensive critical review of the current available data on dosage adjustment of antibiotics in critically ill obese patients.

1. Introduction

Obesity is characterized by excessive accumulation of body fat and is typically classified using various size metrics such as body mass index (BMI), body surface area (BSA), total body weight (TBW), a percentage of ideal bodyweight (IBW), adjusted bodyweight (ABW), lean bodyweight (LBW) and predicted normal weight (PNWT) [1,2]. BMI is calculated by dividing TBW in kilograms by height in meters squared (i.e., kg/m2), and overweight is defined as a BMI ≥ 25 kg/m2, while obesity is defined as a BMI ≥ 30 kg/m2. According to the World Health Organization (WHO), the prevalence of obesity is increasing globally, with 13% of adults affected in 2016, and one-third in the United States [3,4]. Obesity is a significant public health issue that is responsible for increased morbidity and mortality [5]. It also increases the risk of various infections, such as bacteremia, skin, surgical site, community-related infections, and healthcare-related infections [6,7,8], which can result in ICU admission. In critically ill patients with severe infections, achieving adequate antimicrobial concentrations is vital to treatment success. However, managing infections in critically ill obese patients is challenging due to the pharmacokinetic (PK) variations induced by both critical illness and obesity on the antimicrobials. There are limited data on optimal dosing for this patient population, making it a crucial area for research. Therefore, the purpose of this review is to identify PK changes caused by obesity and provide a critical review of the available data on dosage adjustment of antimicrobials guided by therapeutic drug monitoring (TDM) in critically ill obese patients.

2. Methods

A literature search was conducted on PubMed/MEDLINE from inception to May 2023 in order to retrieve prospective or retrospective studies, case series/reports, and clinical trials concerning the use and dosing adjustments guided by TDM of antimicrobials in critically ill obese patients. Only articles published in English were included. No additional analyses on the risk of bias of each study or a meta-analysis of the existing data was performed, as the available literature is limited and the intention of this review was purely descriptive.

3. The Concept of PK/PD Changes in Critically Ill Patients

Critically ill patients may experience several PK changes that can impact antimicrobial dosing, particularly alterations in volume of distribution (Vd) and clearance (CL) [9,10,11]. Capillary leak syndrome, fluid resuscitation, mechanical ventilation, burn injuries, hypoalbuminemia and extracorporeal circuits can all increase the Vd of hydrophilic drugs, leading to a decrease in their plasma drug concentration [12,13,14,15]. The CL of a drug from the blood is dependent on the properties of the drug and involves the liver and kidneys, with hydrophilic antimicrobials primarily cleared renally, while lipophilic antimicrobials are primarily cleared hepatically [1]. Critically ill patients may experience both extremes of renal clearance, including acute renal failure (ARF) and augmented renal clearance (ARC). In the case of multiple organ dysfunction syndrome, including renal and/or hepatic dysfunction, antimicrobial clearance may be reduced, potentially leading to toxicity due to antimicrobial accumulation. Mechanical ventilation may also decrease antimicrobial clearance [12] due to its effect on positive expiratory pressure, which could lead to a decrease in glomerular filtration rate.
The drug elimination half-life (T1/2) equation, i.e., T1/2 = 0.693 × Vd/CL, suggests that increased drug clearance is likely to reduce drug elimination half-life, whereas an increased Vd is likely to increase it. Hypoalbuminemia, which is commonly seen in critically ill patients, can affect the PK of highly protein-bound antimicrobials due to drug-protein binding. In cases of hypoalbuminemia, the free/unbound proportion of drugs increases in the serum, and only unbound drugs are able to distribute into body tissues and be eliminated from the vascular compartment [16]. Therefore, hypoalbuminemia is a factor that contributes to the greater Vd and CL of many antimicrobials [17,18] in critically ill patients compared to non-critically ill patients. Factors introducing PK/PD changes have been summarized in Figure 1.
Increases in Vd and CL are likely to decrease the maximum plasma drug concentration (Cmax), potentially leading to underdosing and therapeutic failure, particularly in critically ill patients. For time-dependent antibiotics such as β-lactams, increased clearance may lead to a reduced time, during which the concentration of the unbound drug is maintained above the minimal inhibitory concentration (MIC) of the infecting pathogen. For concentration-dependent antibiotics whose bactericidal effect depends mainly on the maximal concentration achieved, the Cmax/MIC ratio may be decreased due to the increased Vd. The AUC/MIC ratio may also be affected, as AUC is a function of CL. Attaining the AUC/MIC ratio may be particularly important in critically ill patients to prevent the development of bacterial resistance [19]. In this setting, obesity per se is another factor that can alter antimicrobial PKs.

4. PK/PD Changes in Obese Patients

Obesity can also contribute to PK variations in antimicrobials due to an increase in adipose and lean muscle tissue. For instance, the Vd of lipophilic antimicrobials can be increased in obesity due to an increase in adipose tissue, whereas an increase in lean mass may increase the Vd of hydrophilic antimicrobials [20]. In obese patients, the accumulation of fat in the liver can alter hepatic blood flow and slow drug metabolism. An increase in cytochrome P450 CYP2E1 and a decrease in cytochrome P450 CYP3A4 activity have also been documented, which may modify the CL of antimicrobial drugs [21]. An increase in renal clearance has been attributed to increased organ mass and renal blood flow in obese patients, but a decrease in renal clearance is sometimes observed due to chronic renal dysfunction in patients with comorbidities [22]. As a result of these changes in Vd and Cl, the T1/2 of antibiotics may be reduced or increased in obesity.
Studies are contradictory regarding how obesity can affect plasma binding proteins. While obesity does not seem to impact drug binding to albumin [23], some studies have described changes in protein binding due to increased plasma concentrations of α1-acid glycoprotein and free fatty acids, which can modify Vd [24,25]. However, even though both critical illness and obesity can cause PK changes, it appears that sepsis is primarily responsible for the PK variations observed in obese critically ill patients for antibiotics, such as meropenem, piperacillin, and cefepime/ceftazidime, rather than obesity itself [26,27], even in patients with a BMI ≥ 40 kg/m². PK/PD changes have been summarized in Figure 1.
In situations of extreme PK/variability, where higher than standard doses may be required [28], therapeutic drug monitoring (TDM) can provide an opportunity to achieve therapeutic antimicrobial exposure and avoid the emergence of resistance and toxicity. In a population of obese critically ill patients, higher empiric doses of vancomycin were associated with a higher risk of vancomycin-induced nephrotoxicity [29,30].

5. Therapeutic Drug Monitoring

Therapeutic drug monitoring of anti-infectious agents has been used since the 1960s to prevent toxicity, therapeutic failure and the emergence of bacterial resistance [31]. Despite the increasing evidence of TDM’s utility, its routine use is limited due to cost, availability, long turnaround time to obtain results in many laboratories (except for aminoglycosides and glycopeptides), and limited data showing favorable clinical outcomes when TDM is performed [32,33]. However, drugs with a narrow therapeutic range, a demonstrated correlation between plasma concentration and efficacy as well as toxicity, and an unpredictable pharmacokinetic profile (e.g., critically ill and obese patients) [34,35] are appropriate candidates for TDM. Guidelines recommend that vancomycin TDM should be performed in patients receiving concomitant nephrotoxic agents, those with burns or altered renal function, ICU and obese patients (Class 1C recommendation), and elderly patients and those with concomitant hepatic disease (Class 2C recommendation) [36]. Several other guidelines on TDM [28,36,37] for antimicrobials are also available, reporting similar recommendations.
In critically ill patients, TDM is routinely recommended when aminoglycosides, β-lactams, glycopeptides, and voriconazole are administered. For fluoroquinolones, polymyxins, antivirals, and all antifungals except voriconazole, TDM is neither recommended nor discouraged [28].

6. TDM in Obese Critically Ill Patients

6.1. Antifungal Agents

6.1.1. Echinocandins

Caspofungin, micafungin, and anidulafungin have demonstrated concentration-dependent reduction of fungal growth [38], with the AUC/MIC ratio used as the PK/PD target [39]. Some studies have reported suboptimal dosing of echinocandins at the current recommended doses in specific groups, such as critically ill and obese patients, due to PK variability [40,41,42,43,44,45,46,47,48,49]. Higher loading doses (LD) and maintenance doses (MD) were necessary to achieve the PK and pharmacodynamic (PD) targets. As there is no consensus on the exact dose that should be administered to this specific population of obese critically ill patients, TDM should be considered [50,51] to determine appropriate dosages.

6.1.2. Azoles

Among the azoles, only TDM of voriconazole should be routinely performed. The standard dosing regimen (SDR) for invasive fungal infections is a loading dose (LD) of 6 mg/kg BID on the first day followed by 3–4 mg/kg BID. The optimal trough concentration (Cmin target) for TDM is between 2 and 6 mg/L. For itraconazole, isavuconazole, posaconazole, and fluconazole, there are no routine recommendations for TDM [52] even though altered PK/PD of azoles have also been demonstrated in specific groups such as critically ill patients [49,51]. For itraconazole, a Cmin range > 0.5–1 mg/L is considered the optimal therapeutic serum concentration, and a Cmin > 1 mg/L for posaconazole [28]. However, according to our knowledge, there are currently no available studies evaluating TDM of antifungals in a population of obese critically ill patients.

6.2. Antiviral Agents

To our knowledge, there are no available studies regarding dosage recommendations for antiviral agents in critically ill obese patients, nor on the use of TDM, particularly for acyclovir, foscarnet, and ganciclovir. However, considering that obesity alters the PKs of many drugs, the administration of higher doses could be considered. In such cases, TDM should be performed to optimize patient outcomes and avoid toxicity. Further studies are needed to evaluate the use of TDM for antivirals in this patient population.

6.3. Antibacterial Drugs

6.3.1. β-Lactams

TDM-guided dosing has been associated with improved clinical and microbiological cure rates, treatment failure, and target attainment in critically ill patients receiving β-lactam antibiotics [53]. Higher doses of β-lactams or extended infusions may be necessary to treat infections caused by less susceptible pathogens in obese critically ill patients [54,55,56,57,58]. Therefore, TDM should be routinely performed in this patient population [26], especially as BMI has been identified as a factor contributing to PK/PD target non-attainment in critically ill patients [59]. However, there are few studies evaluating β-lactam TDM in this vulnerable population.
Hites et al. [26] demonstrated that the SDRs of meropenem, ceftazidime, cefepime, and piperacillin-tazobactam in obese patients resulted in underdosing and overdosing in approximately one-third and one-fourth of the patients, respectively. The authors also showed that the total daily doses of β-lactams needed to attain PK/PD targets were the same in both the obese cohort (BMI > 30 kg/m2) and the non-obese cohort (BMI < 25 kg/m2) of critically ill patients. However, meropenem serum concentrations were significantly lower in obese patients not on renal replacement therapy (RRT) when compared to non-obese patients. Conversely, Alobaid et al. [60] compared piperacillin and meropenem trough concentrations and PK/PD target achievement in critically ill obese (BMI > 30 kg/m2) and non-obese patients; the authors found that obese patients had lower piperacillin trough concentrations and a lower target attainment (100% fT > 4 × MIC), but no difference was found between patients receiving meropenem.

6.3.2. Glycopeptides

Given that the CL and Vd of vancomycin are increased in obesity [61], it is recommended that the LD be based on TBW, with a risk of nephrotoxicity when a dose of ≥4 g/day is administered [29]. The SDR of vancomycin is a LD of 30–35 mg/kg followed by a maintenance dose (MD) based on creatinine clearance (CrCL) and TDM [62,63]. Clinical studies have shown that for intermittent infusion of vancomycin, a Cmin > 10 mg/L or ≥15–20 mg/L for severe infections and for continuous infusion, a steady-state concentration (Css) between 20–25 mg/L achieves clinical efficacy and avoids toxicity [28]. However, there is limited literature on vancomycin TDM in obese critically ill patients [63,64,65,66,67,68].
A study comparing a revised vancomycin dosing protocol (10 mg/kg twice daily or 15 mg/kg once daily) to an original protocol (15 mg/kg twice daily or thrice daily) in 138 obese patients, including 31 critically ill patients, showed that the revised protocol resulted in higher therapeutic (59% vs. 36%, p = 0.006) and subtherapeutic (23% vs. 9%, p = 0.033) trough concentrations and lower excessive (18% vs. 55%, p < 0.001) trough concentrations than the original protocol [66]. A retrospective study of 48 obese patients, including 33% critically ill patients, treated with a new dosing strategy of vancomycin to avoid excessive trough concentrations in obese patients [67]––namely, a LD of 25 mg/kg based on TBW and an MD of 10 mg/kg––showed that therapeutic and subtherapeutic trough concentrations were attained for 35.4% and 56.3% of patients, respectively. The authors also demonstrated that age and renal function influence the trough concentration obtained, but not the weight or percentage of TBW above the ideal body weight. However, another study by Tafelski et al. [68] showed that obese critically ill patients achieved the target trough concentrations of vancomycin (10–20 mg/dL) less often than non-obese critically ill patients. A study of 150 obese patients (BMI ≥ 30 kg/m2) treated with vancomycin, including 33 critically ill patients, compared a pre-intervention group (trough dosing only) and a post-intervention group (peak and trough vancomycin serum concentrations), and demonstrated that measuring two serum vancomycin concentrations in this population of obese patients significantly improves target trough concentration attainment [69]. Therefore, TDM should be performed routinely in critically ill obese patients receiving vancomycin to optimize patient outcomes and avoid toxicity, but more studies are needed to evaluate the optimal dosing and TDM strategy in this population.

6.3.3. Quinolones

In a case report evaluating quinolones in a critically ill obese patient (BMI 53.7 kg/m2) receiving a greater than SDR of ciprofloxacin (800 mg BID) and renal replacement therapy (RRT) for Enterobacter aerogenes lumbar osteomyelitis, authors recommended higher than SDR to treat this infection due to a less susceptible pathogen and to achieve the PK/PD target. Although it is difficult to know in this case whether it is obesity, CRRT, or less susceptible pathogen that makes higher doses necessary, TDM could be helpful in this population of obese patients to avoid toxicity and treatment failure [70]. Indeed, in another case report of a critically ill obese adolescent (BMI 72 kg/m2) treated with levofloxacin for an intra-abdominal Pseudomonas aeruginosa abscess, adjustment of the antibiotic regimen through TDM allowed a successful clinical outcome. A Cmax/MIC of 8–12, 30 min after the end of the infusion, was related to a better clinical cure in this setting [71].

6.3.4. Aminoglycosides

Obesity can cause PK/PD variations of hydrophilic agents, such as aminoglycosides. Therefore, literature supports the need for aminoglycoside dosage modification in critically ill obese patients, but data are limited [72,73,74,75]. A loading dose of 7–8 mg/kg for tobramycin and gentamicin and 25 mg/kg for amikacin, followed by further doses based on TDM, are the recommended doses of aminoglycosides [76,77]. For aminoglycosides, a Cmax/MIC ≥ 8–10 is associated with increased efficacy, and toxicity is related to the Cmin, which is taken from a blood sample 30 min or just before the next dosing. The recommended Cmin for gentamicin and tobramycin is <0.5 mg/L and <2.5 mg/L for amikacin [28].

7. Recommendations

TDM is crucial in this patient population, but there is a lack of studies to make recommendations. While waiting for more robust studies, we propose to follow the TDM recommendations and targets of the Infection Section of the European Society of Intensive Care Medicine (ESICM) summarized in Table 1 concerning critically ill patients but not specific to obese patients.

8. Conclusions

While TDM is recommended for several antibiotics, there is a lack of data in the literature regarding TDM of antimicrobials in critically ill obese patients, and most studies have only focused on patients with moderate obesity. Therefore, more robust studies should be conducted specifically in the population of obese critically ill patients to better demonstrate the potential advantages of performing routine TDM in this patient population.

Author Contributions

Conceptualization, J.G. and M.H.; methodology, J.G. and M.H.; software, not applicable; validation, J.G., F.S.T. and M.H.; writing—original draft preparation, J.G.; writing—review and editing, F.S.T. and M.H.; supervision, F.S.T. and M.H. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Hanley, M.J.; Abernethy, D.R.; Greenblatt, D.J. Effect of Obesity on the Pharmacokinetics of Drugs in Humans. Clin. Pharmacokinet. 2010, 49, 71–87. [Google Scholar] [CrossRef] [PubMed]
  2. Pai, M.P.; Bearden, D.T. Antimicrobial Dosing Considerations in Obese Adult Patients: Insights from the Society of Infectious Diseases Pharmacists. Pharmacotherapy 2007, 27, 1081–1091. [Google Scholar] [CrossRef] [PubMed]
  3. Keating, C.; Backholer, K.; Gearon, E.; Stevenson, C.; Swinburn, B.; Moodie, M.; Carter, R.; Peeters, A. Prevalence of class-I, class-II and class-III obesity in Australian adults between 1995 and 2011–12. Obes. Res. Clin. Pract. 2015, 9, 553–562. [Google Scholar] [CrossRef]
  4. Kelly, T.; Yang, W.; Chen, C.-S.; Reynolds, K.; He, J. Global burden of obesity in 2005 and projections to 2030. Int. J. Obes. 2008, 32, 1431–1437. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  5. El-Solh, A.; Sikka, P.; Bozkanat, E.; Jaafar, W.; Davies, J. Morbid Obesity in the Medical ICU. Chest 2001, 120, 1989–1997. [Google Scholar] [CrossRef] [Green Version]
  6. Fgren, M.L.; Poromaa, I.S.M.; Stjerndahl, J.H. Postoperative infections and antibiotic prophylaxis for hysterectomy in Sweden: A study by the Swedish National Register for Gynecologic Surgery. Acta Obstet. Gynecol. Scand. 2004, 83, 1202–1207. [Google Scholar]
  7. Baik, I.; Curhan, G.C.; Rimm, E.B.; Bendich, A.; Willett, W.C.; Fawzi, W.W. A Prospective Study of Age and Lifestyle Factors in Relation to Community-Acquired Pneumonia in US Men and Women. Arch. Intern. Med. 2000, 160, 3082–3088. [Google Scholar] [CrossRef] [Green Version]
  8. Huttunen, R.; Syrjänen, J. Obesity and the risk and outcome of infection. Int. J. Obes. 2012, 37, 333–340. [Google Scholar] [CrossRef] [Green Version]
  9. Roberts, J.A.; Lipman, J. Pharmacokinetic issues for antibiotics in the critically ill patient. Crit. Care Med. 2009, 37, 840–851. [Google Scholar] [CrossRef] [Green Version]
  10. Póvoa, P.; Moniz, P.; Pereira, J.G.; Coelho, L. Optimizing Antimicrobial Drug Dosing in Critically Ill Patients. Microorganisms 2021, 9, 1401. [Google Scholar] [CrossRef]
  11. Roberts, J.A.; Roberts, M.S.; Semark, A.; Udy, A.A.; Kirkpatrick, C.M.; Paterson, D.L.; Roberts, M.J.; Kruger, P.; Lipman, J. Antibiotic dosing in the ‘at risk’ critically ill patient: Linking pathophysiology with pharmacokinetics/pharmacodynamics in sepsis and trauma patients. BMC Anesthesiol. 2011, 11, 3. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  12. Conil, J.M.; Georges, B.; Lavit, M.; Laguerre, J.; Samii, K.; Houin, G.; Saivin, S. A population pharmacokinetic approach to ceftazidime use in burn patients: Influence of glomerular filtration, gender and mechanical ventilation. Br. J. Clin. Pharmacol. 2007, 64, 27–35. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  13. Buijk, S.L.C.E.; Gyssens, I.C.; Mouton, J.W.; Van Vliet, A.; Verbrugh, H.A.; Bruining, H.A. Pharmacokinetics of ceftazidime in serum and peritoneal exudate during continuous versus intermittent administration to patients with severe intra-abdominal infections. J. Antimicrob. Chemother. 2002, 49, 121–128. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  14. Hoff, B.M.; Maker, J.H.; Dager, W.E.; Heintz, B.H. Antibiotic Dosing for Critically Ill Adult Patients Receiving Intermittent Hemodialysis, Prolonged Intermittent Renal Replacement Therapy, and Continuous Renal Replacement Therapy: An Update. Ann. Pharmacother. 2020, 54, 43–55. [Google Scholar] [CrossRef] [PubMed]
  15. Ha, M.A.; Sieg, A.C. Evaluation of Altered Drug Pharmacokinetics in Critically Ill Adults Receiving Extracorporeal Membrane Oxygenation. Pharmacother. J. Hum. Pharmacol. Drug Ther. 2017, 37, 221–235. [Google Scholar] [CrossRef]
  16. Liu, P.; Derendorf, H. Antimicrobial tissue concentrations. Infect. Dis. Clin. North Am. 2003, 17, 599–613. [Google Scholar] [CrossRef]
  17. Ulldemolins, M.; Roberts, J.A.; Rello, J.; Paterson, D.L.; Lipman, J. The Effects of Hypoalbuminaemia on Optimizing Antibacterial Dosing in Critically Ill Patients. Clin. Pharmacokinet. 2011, 50, 99–110. [Google Scholar] [CrossRef]
  18. Sime, F.B.; Roberts, M.S.; Peake, S.L.; Lipman, J.; Roberts, J.A. Does Beta-lactam Pharmacokinetic Variability in Critically Ill Patients Justify Therapeutic Drug Monitoring? A Systematic Review. Ann. Intensiv. Care 2012, 2, 35. [Google Scholar] [CrossRef] [Green Version]
  19. Sumi, C.D.; Heffernan, A.J.; Lipman, J.; Roberts, J.A.; Sime, F.B. What Antibiotic Exposures Are Required to Suppress the Emergence of Resistance for Gram-Negative Bacteria? A Systematic Review. Clin. Pharmacokinet. 2019, 58, 1407–1443. [Google Scholar] [CrossRef]
  20. Bauer, L.A.; Edwards, W.A.D.; Dellinger, E.P.; Simonowitz, D.A. Influence of weight on aminoglycoside pharmacokinetics in normal weight and morbidly obese patients. Eur. J. Clin. Pharmacol. 1983, 24, 643–647. [Google Scholar] [CrossRef]
  21. Brill, M.J.E.; Diepstraten, J.; van Rongen, A.; van Kralingen, S.; van den Anker, J.N.; Knibbe, C.A.J. Impact of Obesity on Drug Metabolism and Elimination in Adults and Children. Clin Pharmacokinet. 2012, 51, 277–304. [Google Scholar] [CrossRef]
  22. Meng, L.; Mui, E.; Holubar, M.K.; Deresinski, S.C. Comprehensive Guidance for Antibiotic Dosing in Obese Adults. Pharmacother. J. Hum. Pharmacol. Drug Ther. 2017, 37, 1415–1431. [Google Scholar] [CrossRef] [PubMed]
  23. Abernethy, D.R.; Greenblatt, D.J.; Divoll, M.; Smith, R.B.; Shader, R.I. The Influence of Obesity on the Pharmacokinetics of Oral Alprazolam and Triazolam. Clin. Pharmacokinet. 1984, 9, 177–183. [Google Scholar] [CrossRef]
  24. Benedek’, I.H.; Iii’, W.D.F.; Griffen, W.O.; Bell, R.M.; Blouin, R.A.; Mcnamara’, P.J. Serum al-acid glycoprotein and the binding of drugs in obesity. Br. J. Clin. Pharmacol. 1983, 16, 751–754. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  25. Suh, B.; Craig, W.A.; England, A.C.; Elliott, R.L. Effect of Free Fatty Acids on Protein Binding of Antimicrobial Agents. J. Infect. Dis. 1981, 143, 609–616. [Google Scholar] [CrossRef] [PubMed]
  26. Hites, M.; Taccone, F.S.; Wolff, F.; Cotton, F.; Beumier, M.; De Backer, D.; Roisin, S.; Lorent, S.; Surin, R.; Seyler, L.; et al. Case-Control Study of Drug Monitoring of β-Lactams in Obese Critically Ill Patients. Antimicrob. Agents Chemother. 2013, 57, 708–715. [Google Scholar] [CrossRef] [Green Version]
  27. Alobaid, A.S.; Wallis, S.C.; Jarrett, P.; Starr, T.; Stuart, J.; Lassig-Smith, M.; Mejia, J.L.O.; Roberts, M.S.; Lipman, J.; Roberts, J.A. Effect of Obesity on the Population Pharmacokinetics of Meropenem in Critically Ill Patients. Antimicrob. Agents Chemother. 2016, 60, 4577–4584. [Google Scholar] [CrossRef] [Green Version]
  28. The Infection Section of European Society of Intensive Care Medicine (ESICM); Pharmacokinetic/pharmacodynamic and Critically Ill Patient Study Groups of European Society of Clinical Microbiology and Infectious Diseases (ESCMID); Infectious Diseases Group of International Association of Therapeutic Drug Monitoring and Clinical Toxicology (IATDMCT); Infections in the ICU and Sepsis Working Group of International Society of Antimicrobial Chemotherapy (ISAC); Abdul-Aziz, M.H.; Alffenaar, J.W.C.; Bassetti, M.; Bracht, H.; Dimopoulos, G.; Marriott, D.; et al. Antimicrobial therapeutic drug monitoring in critically ill adult patients: A Position Paper#. Intensive Care Med. 2020, 46, 1127–1153. [Google Scholar]
  29. Lodise, T.P.; Lomaestro, B.; Graves, J.; Drusano, G.L. Larger Vancomycin Doses (at Least Four Grams per Day) Are Associated with an Increased Incidence of Nephrotoxicity. Antimicrob. Agents Chemother. 2008, 52, 1330–1336. [Google Scholar] [CrossRef] [Green Version]
  30. Hall, R.G.; A Hazlewood, K.; Brouse, S.D.; Giuliano, C.A.; Haase, K.K.; Frei, C.R.; Forcade, N.A.; Bell, T.; Bedimo, R.J.; A Alvarez, C. 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. [Google Scholar] [CrossRef] [Green Version]
  31. Wong, G.; Brinkman, A.; Benefield, R.J.; Carlier, M.; De Waele, J.J.; El Helali, N.; Frey, O.; Harbarth, S.; Huttner, A.; McWhinney, B.; et al. An international, multicentre survey of -lactam antibiotic therapeutic drug monitoring practice in intensive care units. J. Antimicrob. Chemother. 2014, 69, 1416–1423. [Google Scholar] [CrossRef] [Green Version]
  32. Liebchen, U.; Paal, M.; Scharf, C.; Schroeder, I.; Grabein, B.; Zander, J.; Siebers, C.; Zoller, M. The ONTAI study–a survey on antimicrobial dosing and the practice of therapeutic drug monitoring in German intensive care units. J. Crit. Care 2020, 60, 260–266. [Google Scholar] [CrossRef] [PubMed]
  33. Sandaradura, I.; Alffenaar, J.; Cotta, M.O.; Daveson, K.; Day, R.O.; Van Hal, S.; Imani, S. Emerging therapeutic drug monitoring of anti-infective agents in Australian hospitals: Availability, performance and barriers to implementation. Br. J. Clin. Pharmacol. 2022, 88, 669–679. [Google Scholar] [CrossRef] [PubMed]
  34. Cusumano, J.A.; Klinker, K.P.; Huttner, A.; Luther, M.K.; Roberts, J.A.; LaPlante, K.L. Towards precision medicine: Therapeutic drug monitoring–guided dosing of vancomycin and β-lactam antibiotics to maximize effectiveness and minimize toxicity. Am. J. Health Syst. Pharm. 2020, 77, 1104–1112. [Google Scholar] [CrossRef]
  35. Dilworth, T.J.; Schulz, L.T.; Micek, S.T.; Kollef, M.H.; Rose, W.E. β-Lactam Therapeutic Drug Monitoring in Critically Ill Patients: Weighing the Challenges and Opportunities to Assess Clinical Value. Crit. Care Explor. 2022, 4, e0726. [Google Scholar] [CrossRef] [PubMed]
  36. Ye, Z.K.; Chen, Y.L.; Chen, K.; Zhang, X.L.; Du, G.H.; He, B.; Li, D.-K.; Liu, Y.-N.; Yang, K.-H.; Zhang, Y.-Y.; et al. Therapeutic drug monitoring of vancomycin: A guideline of the Division of Therapeutic Drug Monitoring, Chinese Pharmacological Society. J. Antimicrob. Chemother. 2016, 71, 3020–3025. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  37. Ashbee, H.R.; Barnes, R.A.; Johnson, E.M.; Richardson, M.D.; Gorton, R.; Hope, W.W. Therapeutic drug monitoring (TDM) of antifungal agents: Guidelines from the British Society for Medical Mycology. J. Antimicrob. Chemother. 2014, 69, 1162–1176. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  38. Van Vianen, W.; de Marie, S.; ten Kate, M.T.; Mathot, R.A.A.; Bakker-Woudenberg, I.A.J.M. Caspofungin: Antifungal activity in vitro, pharmacokinetics, and effects on fungal load and animal survival in neutropenic rats with invasive pulmonary aspergillosis. J Antimicrob Chemother. 2006, 57, 732–740. [Google Scholar] [CrossRef] [PubMed]
  39. Louie, A.; Deziel, M.; Liu, W.; Drusano, M.F.; Gumbo, T.; Drusano, G.L. Pharmacodynamics of Caspofungin in a Murine Model of Systemic Candidiasis: Importance of Persistence of Caspofungin in Tissues to Understanding Drug Activity. Antimicrob. Agents Chemother. 2005, 49, 5058–5068. [Google Scholar] [CrossRef] [Green Version]
  40. Maseda, E.; Grau, S.; Luque, S.; Castillo-Mafla, M.-P.; Suárez-De-La-Rica, A.; Montero-Feijoo, A.; Salgado, P.; Gimenez, M.-J.; García-Bernedo, C.A.; Gilsanz, F.; et al. Population pharmacokinetics/pharmacodynamics of micafungin against Candida species in obese, critically ill, and morbidly obese critically ill patients. Crit. Care 2018, 22, 94. [Google Scholar] [CrossRef] [Green Version]
  41. Borsuk-De Moor, A.; Sysiak-Sławecka, J.; Rypulak, E.; Borys, M.; Piwowarczyk, P.; Raszewski, G.; Onichimowski, D.; Czuczwar, M.; Wiczling, P. Nonstationary Pharmacokinetics of Caspofungin in ICU Patients. Antimicrob. Agents Chemother. 2020, 64, e00345-20. [Google Scholar] [CrossRef]
  42. Märtson, A.-G.; van der Elst, K.C.M.; Veringa, A.; Zijlstra, J.; Beishuizen, A.; van der Werf, T.S.; Kosterink, J.G.W.; Neely, M.; Alffenaar, J.-W. Caspofungin Weight-Based Dosing Supported by a Population Pharmacokinetic Model in Critically Ill Patients. Antimicrob. Agents Chemother. 2020, 64, e00905–e00920. [Google Scholar] [CrossRef] [PubMed]
  43. Nguyen, T.H.; Hoppe-Tichy, T.; Geiss, H.K.; Rastall, A.C.; Swoboda, S.; Schmidt, J.; Weigand, M.A. Factors influencing caspofungin plasma concentrations in patients of a surgical intensive care unit. J. Antimicrob. Chemother. 2007, 60, 100–106. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  44. Ferriols-Lisart, R.; Aguilar, G.; Pérez-Pitarch, A.; Puig, J.; Ezquer-Garín, C.; Alós, M. Plasma concentrations of caspofungin in a critically ill patient with morbid obesity. Crit. Care 2017, 21, 200. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  45. Liu, P.; Ruhnke, M.; Meersseman, W.; Paiva, J.A.; Kantecki, M.; Damle, B. Pharmacokinetics of Anidulafungin in Critically Ill Patients with Candidemia/Invasive Candidiasis. Antimicrob. Agents Chemother. 2013, 57, 1672–1676. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  46. Zomp, A.; Bookstaver, P.B.; Ahmed, Y.; Turner, J.E.; King, C. Micafungin therapy in a critically ill, morbidly obese patient. J. Antimicrob. Chemother. 2011, 66, 2678–2680. [Google Scholar] [CrossRef] [PubMed]
  47. Wasmann, R.E.; Smit, C.; Ter Heine, R.; Koele, S.E.; Van Dongen, E.P.H.; Wiezer, R.M.J.; Burger, D.M.; Knibbe, C.A.J.; Brüggemann, R.J.M. Pharmacokinetics and probability of target attainment for micafungin in normal-weight and morbidly obese adults. J. Antimicrob. Chemother. 2019, 74, 978–985. [Google Scholar] [CrossRef]
  48. Wasmann, R.E.; ter Heine, R.; van Dongen, E.P.; Burger, D.M.; Lempers, V.J.; Knibbe, C.A.J.; Brüggemann, R.J. Pharmacokinetics of Anidulafungin in Obese and Normal-Weight Adults. Antimicrob. Agents Chemother. 2018, 62, e00063-18. [Google Scholar] [CrossRef] [Green Version]
  49. Sinnollareddy, M.G.; Roberts, J.A.; Lipman, J.; Akova, M.; Bassetti, M.; De Waele, J.J.; Kaukonen, K.M.; Koulenti, D.; Martin, C.; Montravers, P.; et al. Pharmacokinetic variability and exposures of fluconazole, anidulafungin, and caspofungin in intensive care unit patients: Data from multinational Defining Antibiotic Levels in Intensive care unit (DALI) patients Study. Crit. Care 2015, 19, 33. [Google Scholar] [CrossRef] [Green Version]
  50. Kim, H.Y.; Baldelli, S.C.; Märtson, A.-G.M.; Stocker, S.; Alffenaar, J.-W.; Cattaneo, D.; Marriott, D.J.F.F. Therapeutic Drug Monitoring of the Echinocandin Antifungal Agents: Is There a Role in Clinical Practice? A Position Statement of the Anti-Infective Drugs Committee of the International Association of Therapeutic Drug Monitoring and Clinical Toxicology. Ther. Drug Monit. 2022, 44, 198–214. [Google Scholar] [CrossRef]
  51. Baracaldo-Santamaría, D.; Cala-Garcia, J.D.; Medina-Rincón, G.J.; Rojas-Rodriguez, L.C.; Calderon-Ospina, C.A. Therapeutic Drug Monitoring of Antifungal Agents in Critically Ill Patients: Is There a Need for Dose Optimisation? Antibiotics 2022, 11, 645. [Google Scholar] [CrossRef] [PubMed]
  52. Gómez-López, A. Antifungal therapeutic drug monitoring: Focus on drugs without a clear recommendation. Clin. Microbiol. Infect. 2020, 26, 1481–1487. [Google Scholar] [CrossRef]
  53. Pai Mangalore, R.; Ashok, A.; Lee, S.J.; Romero, L.; Peel, T.N.; Udy, A.A.; Peleg, A.Y. Beta-Lactam Antibiotic Therapeutic Drug Monitoring in Critically Ill Patients: A Systematic Review and Meta-Analysis. Clin. Infect. Dis. 2022, 75, 1848–1860. [Google Scholar] [CrossRef]
  54. Jung, B.; Mahul, M.; Breilh, D.; Legeron, R.; Signe, J.; Jean-Pierre, H.; Uhlemann, A.C.; Molinari, N.; Jaber, S. Repeated Piperacillin-Tazobactam Plasma Concentration Measurements in Severely Obese Versus Nonobese Critically Ill Septic Patients and the Risk of Under– and Overdosing*. Crit. Care Med. 2017, 45, e470–e478. [Google Scholar] [CrossRef] [PubMed]
  55. Sturm, A.W.; Allen, N.; Rafferty, K.D.; Fish, D.N.; Toschlog, E.; Newell, M.; Waibel, B. Pharmacokinetic Analysis of Piperacillin Administered with Tazobactam in Critically Ill, Morbidly Obese Surgical Patients. Pharmacother. J. Hum. Pharmacol. Drug Ther. 2014, 34, 28–35. [Google Scholar] [CrossRef]
  56. Cheatham, S.C.; Fleming, M.R.; Healy, D.P.; Chung, E.K.; Shea, K.M.; Humphrey, M.L.; Kays, M.B. Steady-state pharmacokinetics and pharmacodynamics of meropenem in morbidly obese patients hospitalized in an intensive care unit: The Journal of Clinical Pharmacology. J. Clin. Pharmacol. 2014, 54, 324–330. [Google Scholar] [CrossRef] [PubMed]
  57. Roberts, J.A.; 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. [Google Scholar] [CrossRef]
  58. Taccone, F.S.; Cotton, F.; Roisin, S.; Vincent, J.-L.; Jacobs, F. Optimal Meropenem Concentrations To Treat Multidrug-Resistant Pseudomonas aeruginosa Septic Shock. Antimicrob. Agents Chemother. 2012, 56, 2129–2131. [Google Scholar] [CrossRef] [Green Version]
  59. Abdulla, A.; Dijkstra, A.; Hunfeld, N.G.M.; Endeman, H.; Bahmany, S.; Ewoldt, T.M.J.; Muller, A.E.; Van Gelder, T.; Gommers, D.; Koch, B.C.P. Failure of target attainment of beta-lactam antibiotics in critically ill patients and associated risk factors: A two-center prospective study (EXPAT). Crit. Care 2020, 24, 558. [Google Scholar] [CrossRef]
  60. Alobaid, A.S.; Brinkmann, A.; Frey, O.R.; Roehr, A.C.; Luque, S.; Grau, S.; Wong, G.; Abdul-Aziz, M.H.; Roberts, M.S.; Lipman, J.; et al. What is the effect of obesity on piperacillin and meropenem trough concentrations in critically ill patients? J. Antimicrob. Chemother. 2016, 71, 696–702. [Google Scholar] [CrossRef] [Green Version]
  61. Blouin, R.A.; Bauer, L.A.; Miller, D.D.; Record, K.E.; Griffen, W.O. Vancomycin pharmacokinetics in normal and morbidly obese subjects. Antimicrob. Agents Chemother. 1982, 21, 575–580. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  62. Roberts, J.A.; Taccone, F.S.; Udy, A.A.; Vincent, J.-L.; Jacobs, F.; Lipman, J. Vancomycin Dosing in Critically Ill Patients: Robust Methods for Improved Continuous-Infusion Regimens. Antimicrob. Agents Chemother. 2011, 55, 2704–2709. [Google Scholar] [CrossRef] [Green Version]
  63. Xu, K.-Y.; Li, D.; Hu, Z.-J.; Zhao, C.-C.; Bai, J.; Du, W.-L. Vancomycin dosing in an obese patient with acute renal failure: A case report and review of literature. World J. Clin. Cases 2022, 10, 6218–6226. [Google Scholar] [CrossRef]
  64. Kane, S.P.; Hanes, S.D. Unexplained increases in serum vancomycin concentration in a morbidly obese patient. Intensiv. Crit. Care Nurs. 2017, 39, 55–58. [Google Scholar] [CrossRef]
  65. Abuhasna, S.; Al Jundi, A.H. Therapeutic drug monitoring of vancomycin in an obese patient with renal insufficiency. J. Anaesthesiol. Clin. Pharmacol. 2011, 27, 531–533. [Google Scholar] [CrossRef]
  66. Reynolds, D.C.; Waite, L.H.; Alexander, D.P.; DeRyke, C.A. Performance of a vancomycin dosage regimen developed for obese patients. Am. J. Health Syst. Pharm. 2012, 69, 944–950. [Google Scholar] [CrossRef] [PubMed]
  67. Kosmisky, D.E.; Griffiths, C.L.; Templin, M.A.; Norton, J.; Martin, K.E. Evaluation of a New Vancomycin Dosing Protocol in Morbidly Obese Patients. Hosp. Pharm. 2015, 50, 789–797. [Google Scholar] [CrossRef] [Green Version]
  68. Tafelski, S.; Yi, H.; Ismaeel, F.; Krannich, A.; Spies, C.; Nachtigall, I. Obesity in critically ill patients is associated with increased need of mechanical ventilation but not with mortality. J. Infect. Public Health 2016, 9, 577–585. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  69. Hong, J.; Krop, L.C.; Johns, T.; Pai, M.P. Individualized Vancomycin Dosing in Obese Patients: A Two-Sample Measurement Approach Improves Target Attainment. Pharmacother. J. Hum. Pharmacol. Drug Ther. 2015, 35, 455–463. [Google Scholar] [CrossRef]
  70. Utrup, T.R.; Mueller, E.W.; Healy, D.P.; Calicut, R.A.; Peterson, J.D.; Hurford, W.E. High-Dose Ciprofloxacin for Serious Gram-Negative Infection in an Obese, Critically III Patient Receiving Continuous Venovenous Hemodiafiltration. Ann. Pharmacother. 2010, 44, 1660–1664. [Google Scholar] [CrossRef]
  71. Hanretty, A.M.; Moore, W.S.; Chopra, A.; Cies, J.J. Therapeutic Drug Monitoring of Levofloxacin in an Obese Adolescent: A Case Report. J. Pediatr. Pharmacol. Ther. 2020, 25, 261–265. [Google Scholar] [CrossRef] [PubMed]
  72. Velissaris, D.; Karamouzos, V.; Marangos, M.; Pierrakos, C.; Karanikolas, M. Pharmacokinetic Changes and Dosing Modification of Aminoglycosides in Critically Ill Obese Patients: A Literature Review. J. Clin. Med. Res. 2014, 6, 227. [Google Scholar] [CrossRef] [Green Version]
  73. Blouin, R.A.; Mann, H.J.; Griffen, W.O.; Bauer, L.A.; Record, K.E. Tobramycin pharmacokinetics in morbidly obese patients. Clin. Pharmacol. Ther. 1979, 26, 508–512. [Google Scholar] [CrossRef] [PubMed]
  74. Erstad, B.L. Dosing of medications in morbidly obese patients in the intensive care unit setting. Intensiv. Care Med. 2004, 30, 18–32. [Google Scholar] [CrossRef] [PubMed]
  75. Polso, A.K.; Lassiter, J.L.; Nagel, J.L. Impact of hospital guideline for weight-based antimicrobial dosing in morbidly obese adults and comprehensive literature review. J. Clin. Pharm. Ther. 2014, 39, 584–608. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  76. Taccone, F.S.; Laterre, P.-F.; Spapen, H.; Dugernier, T.; Delattre, I.; Layeux, B.; De Backer, D.; Wittebole, X.; Wallemacq, P.; Vincent, J.-L.; et al. Revisiting the loading dose of amikacin for patients with severe sepsis and septic shock. Crit. Care 2010, 14, R53. [Google Scholar] [CrossRef] [Green Version]
  77. Buijk, S.; Mouton, J.; Gyssens, I.; Verbrugh, H.; Bruining, H. Experience with a once-daily dosing program of aminoglycosides in critically ill patients. Intensiv. Care Med. 2002, 28, 936–942. [Google Scholar] [CrossRef]
Antibiotics 12 01099 g001 550
Figure 1. Summary of factors influencing antimicrobial pharmacokinetics (PK) during either critical illness or obesity. ARC = augmented renal clearance; AKI = acute kidney injury.
Figure 1. Summary of factors influencing antimicrobial pharmacokinetics (PK) during either critical illness or obesity. ARC = augmented renal clearance; AKI = acute kidney injury.
Antibiotics 12 01099 g001
Table
Table 1. PK/PD and TDM targets for different antimicrobial agents.
Table 1. PK/PD and TDM targets for different antimicrobial agents.
Antimicrobial ClassPK/PD TargetTDM Target
Antifungal Agents
Azoles
VoriconazoleCmin ≥ 1–2 mg/LCmin: 2–6 mg/L (prophylaxis or treatment)
ItraconazoleCmin ≥ 0.25–0.5 mg/L (Prophylaxis)
Cmin ≥ 1 mg/L (treatment)		Cmin > 0.5–1 mg/L
PosaconazoleCmin > 0.5 (prophylaxis)
Cmin > 1 mg/L (treatment)		Cmin > 0.5–0.7 mg/L (prophylaxis)
Cmin > 1 mg/L (treatment)
Fluconazole AUC0–24/MIC ≥ 55–100/
Antiviral agentsUnclear/
Antibacterial agents
β-lactams50–100% fT > MICII: 100% fT > MIC
CI: Css > MIC
Glycopeptides
VancomycinAUC0–24/MIC ≥ 400
Cmin > 10–20 mg/L		II: Cmin ≥ 15–20 mg/L (for severe infections)
CI: Css 20–25 mg/L
TeicoplaninCmin ≥ 10 mg/LCmin ≥ 15–30 mg/L
Linezolid AUC0–24/MIC ≥ 80–120
≥85% fT > MIC		Cmin: 2–7 mg/L
QuinolonesAUC0–24/MIC ≥ 125–250
Cmax/MIC ≥ 12		Cmax/MIC ≥ 8–12
Aminoglycosides
AmikacinCmax/MIC ≥ 8–10Cmax/MIC ≥ 8–10
Cmin < 2.5 mg/L
GentamicinAUC0–24/MIC ≥ 110
Cmax/MIC ≥ 8–10		Cmax/MIC ≥ 8–10
Cmin < 0.5 mg/L
TobramycinAUC0–24/MIC ≥ 110
Cmax/MIC ≥ 8–10		Cmax/MIC ≥ 8–10
Cmin < 0.5 mg/L
Cmin = Trough concentration; MIC = minimal inhibition concentration; II = intermittent infusion; CI = continuous infusion; Css = concentration at steady state; AUC = area under the curve; Cmax = peak concentration; fT > MIC = time the unbound fraction of the drug remains above the MIC.
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Share and Cite

MDPI and ACS Style

Gorham, J.; Taccone, F.S.; Hites, M. Therapeutic Drug Monitoring of Antimicrobials in Critically Ill Obese Patients. Antibiotics 2023, 12, 1099. https://doi.org/10.3390/antibiotics12071099

AMA Style

Gorham J, Taccone FS, Hites M. Therapeutic Drug Monitoring of Antimicrobials in Critically Ill Obese Patients. Antibiotics. 2023; 12(7):1099. https://doi.org/10.3390/antibiotics12071099

Chicago/Turabian Style

Gorham, Julie, Fabio S. Taccone, and Maya Hites. 2023. "Therapeutic Drug Monitoring of Antimicrobials in Critically Ill Obese Patients" Antibiotics 12, no. 7: 1099. https://doi.org/10.3390/antibiotics12071099

APA Style

Gorham, J., Taccone, F. S., & Hites, M. (2023). Therapeutic Drug Monitoring of Antimicrobials in Critically Ill Obese Patients. Antibiotics, 12(7), 1099. https://doi.org/10.3390/antibiotics12071099

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop