Updated antimicrobial dosing recommendations for obese patients

ABSTRACT

The prevalence of obesity has increased considerably in the last few decades. Pathophysiological changes in obese patients lead to pharmacokinetic (PK) and pharmacodynamic (PD) alterations that can condition the correct exposure to antimicrobials if standard dosages are used. Inadequate dosing in obese patients can lead to toxicity or therapeutic failure. In recent years, additional antimicrobial PK/PD data, extended infusion strategies, and studies in critically ill patients have made it possible to obtain data to provide a better dosage in obese patients. Despite this, it is usually difficult to find information on drug dosing in this population, which is sometimes contradictory. This is a comprehensive review of the dosing of different types of antimicrobials (antibiotics, antifungals, antivirals, and antituberculosis drugs) in obese patients, where the literature on PK and possible dosing strategies in obese adults was critically assessed.

INTRODUCTION

Obesity, classified as a body mass index (BMI) ≥ 30 kg/m², is now considered to be one of the most important public health problems. According to the World Health Organization (WHO), in 2016, approximately 2 billion adults were overweight, of which 650 million were affected by obesity (1). If current trends continue, it is estimated that by 2025, 2.7 billion adults will be overweight, more than 1 billion people will be affected by obesity, and 177 million adults will be severely affected by obesity (2).

Obesity is related to increased morbidity and mortality in patients with bacteremia, hospital infections, surgical site infections, skin infections, and periodontal infections (3–11). It is also associated with impaired immune function (12–14), with reports of increased risk of death during the H1N1 (15, 16) and SARS-CoV-2 (17–19) pandemics and reduced immune response to vaccines (20–25). Although several hypotheses have been proposed, the exact mechanism by which obesity determines susceptibility to infection is still unclear. First, obesity can lead to disorders of the innate and adaptive immune system, which are characterized by impaired chemotaxis, altered macrophage differentiation, imbalance of cytokine production, and dysregulated crosstalk between the immune system and fat cells (13, 14). Second, due to the respiratory anatomy and physiology related to obesity, this group of patients presents restricted pulmonary function, reduced lung volume, ventilation-perfusion mismatch, obstructive sleep apnea, and a high risk of pulmonary embolism, which translates into a greater predisposition to develop respiratory infections and their derived complications (26). Finally, due to delayed wound healing, disrupted micro- and macrocirculation, and lymphedema, obesity can also increase the risk of surgical infection (27).

The objective of all antimicrobial therapy is to reach adequate systemic antimicrobial concentrations to eradicate the infectious agent while minimizing toxicity and side effects. In obesity, especially in morbid obesity, drug pharmacodynamics (PD) may be altered due to possible changes in its pharmacokinetic (PK) characteristics (28). The management of infections is a special problem in obese patients because available data on the dosage and PK/PD in this population are still scarce and, sometimes, contradictory, especially for morbidly obese patients (BMI ≥ 40 kg/m²). This is partly because obese subjects are often excluded from clinical trials. Although data have been increasing in recent decades, more studies are still necessary to allow clinicians to establish an optimal antimicrobial dosage in this population (29). This review aims to describe the different physiological changes in obesity, provide the latest knowledge on their impact on different PK and/or PD parameters, and compile antimicrobial dosing recommendations for this population. It is the first work to compile data on all groups of antimicrobials: antibiotics, antifungals, antivirals, and antituberculosis drugs.

METHODS AND DESIGN

The EMBASE and PubMed databases were searched from inception to October 2023 using the following terms: “obesity” or “obese” and “anti-infectives” or “antimicrobials” or “pharmacokinetics” or “antibiotics” or “antifungals” or “antivirals” or “antitubercular.” All articles that provided information on the behavior of the drug in obese people or recommendations on its dosage in this population were selected. Information regarding specific antimicrobials was completed by searching for data related to each drug.

BODY SIZE DESCRIPTORS

Body composition changes in obese people, something that must be considered when dosing drugs. Normal-weight people have a total body weight (TBW) comprising lean and adipose weight in an estimated 4:1 ratio, while in obese individuals, the excess adipose weight is accompanied by a 20%–40% increase in lean body weight. This results in a lean:adipose weight ratio of approximately 3:2 (30). Several body descriptors have been used to date.

Body mass index is calculated by dividing the TBW by the square of the height (kg/m²). This is how the WHO stratifies individuals (31, 32). Its main limitation is the inability to distinguish between adipose tissue and lean muscle mass since the same BMI may not correspond to the same degree of adiposity in different individuals. For this reason, BMI has not been widely adopted as a dosing scalar (33).

Body surface area (BSA) is a function of weight and height, which correlates with cardiac output, blood volume, and renal function, calculated through the Dubois and Dubois or Mosteller formulas (Table 1) (34). However, its use is controversial in patients with extreme weights because, like BMI, it does not account for body composition. BSA is widely used in oncology to determine dosages of many anticancer agents; however, its utility in dosing obese patients is still unclear. Many clinicians assign 2 m² when BSA exceeds this arbitrary cut-off, potentially resulting in sub-therapeutic treatment (35, 36).

TABLE 1.

Equations for body weight descriptors^a

Body weight descriptor	Equation
Body mass index (BMI)	TBW/height (m)2
Body surface area (BSA)	Dubois and Dubois = 0.007184 × TBW (kg)0.425 × height (m)0.725 Mosteller = √ [(height (m) × TBW)/3,600]
Ideal body weight (IBW)	Male = 49.9 + 0.89 × [height (cm) − 152.4] Female = 45.4 + 0.89 × [height (cm) − 152.4]
Lean body weight (LBW)	Male = (9,270 × TBW)/[6,680 + (216 × BMI)] Female = (9,270 × TBW)/[8,780 + (244 × BMI)]
Adjusted body weight (ABW)	IBW + [C x (TBW − IBW)]

^a C, drug-specific correction factor (generally 0.3–0.6).

Total body weight refers to the actual weight of the patient (37), which is equivalent to assuming that the drug pharmacokinetics are linearly scalable from normal-weight patients to obese patients. If the dose is increased with weight, the clearance of the drug should also increase, which may not be correct. Toxicities of high doses of antimicrobials are known, such as nephrotoxicity or neurotoxicity; however, it may also be a risk to use dose reductions that lead to infra-therapeutic exposure and therapeutic failure (30, 33).

Ideal body weight (IBW) was developed for insurance purposes, not for drug dosing, and basically describes what weight a person should have to have the lowest mortality (38). It is only a function of height and sex, without regard to body composition. Using the IBW, all patients of the same height and sex will receive the same dose, which usually leads to underdosing. This parameter is calculated using the Devine equation (Table 1) (39).

Lean body weight (LBW) and fat-free mass describe body weight devoid of adipose tissue, while fat-free mass refers to certain body tissues (muscle, bone, organs, and extracellular fluid), which is usually measured by bioelectric impedance analysis or estimated by an equation. Several studies have suggested that LBW appears to be the best metric to describe the clearance of drugs in the obese population (40). The formula described by Janmahasatian et al. is the most commonly used (Table 1) (41).

Adjusted body weight (ABW) was developed to account for adipose tissue, which does not affect drug clearance. This concept attempts to overcome the limitation of IBW by adding a certain percentage of the difference between TBW and IBW to IBW for dosing purposes (33). The equation that describes ABW contains a correction factor (C), which is commonly between 0.3 and 0.6 (Table 1).

PHARMACOKINETICS IN OBESE PATIENTS

Several physiological changes happen in obese patients that may affect serum antimicrobial concentrations and should be considered when prescribing in this population. These alterations can affect the different stages a drug goes through from its administration until a therapeutic response takes place and is finally eliminated.

Absorption

Oral drug absorption is a complex process affected by several factors, such as formulation, physiochemical properties, the physiology of the gastrointestinal tract, food intake, concomitant drugs, and environmental exposure to other xenobiotics, among others (42, 43). On the one hand, obese patients have been shown to have delayed gastric emptying, possibly because of a higher fat diet or gastric distension, which may result in a lower maximum drug concentration (C_max) or reduced absorption (44, 45) (Fig. 1). On the other hand, intramuscular injections may inadvertently be administered deep subcutaneously, which could affect the absorption efficiency (37). The current limited data show that it is not clear what role these factors may play in the drug absorption of obese patients (40).

Fig 1.

Physiological changes in obesity and its corresponding influence on PK parameters. Image was created with BioRender.com.

Volume of distribution

The volume of distribution (V_d) is affected by the drug’s physiochemical properties and its transfer from the blood to the tissue, its ability to pass through membranes, binding within tissue and blood, and its distribution into fat (33, 42). In obese patients, an augmented V_d is commonly observed due to increased fat and lean muscle mass. Even so, if the drug does not enter the adipose tissue, the V_d may be overestimated based on the TBW, for example, with hydrophilic drugs. ABW may be more appropriate when calculating weight-based loading doses in these cases (46). On the contrary, if the absolute V_d increases, but the V_d/TBW ratio of obese patients and non-obese patients is similar, it indicates that the drug is significantly distributed in the excess body weight (mainly adipose tissue), and then TBW is more suitable for calculation (33). In short, the increase in adipose tissue may increase the V_d of lipophilic agents, while increased lean body mass (which may account for 20%–40% of an overweight individual) and increased blood volume may increase the V_d of hydrophilic drugs (47). V_d is particularly important in surgical prophylaxis where high skin/adipose concentrations are necessary for the duration of surgery, with perfusion in these tissues being low. The local blood flow into the adipose tissue is estimated to account for only 5% of the cardiac output, while the lean tissue receives about 73% of the cardiac output (48). Therefore, obese individuals may have poor peripheral perfusion, resulting in lower concentrations of antimicrobial drugs in subcutaneous adipose tissue (49) (Fig. 1).

Protein binding

Obesity does not significantly alter the albumin binding of drugs, but plasma concentrations of α1-acid glycoprotein and free fatty acids are increased in obese patients, so changes in the binding of antimicrobial drugs to proteins can increase or decrease their V_d (50–52). There is a positive correlation between the level of acid glycoprotein and the protein binding of vancomycin, but the clinical relevance is still unclear (53, 54). In addition, high concentrations of free fatty acids are associated with a significant decrease in the protein binding of cefamandole, dicloxacillin, and sulfamethoxazole, but they are also related to an increase in the protein binding of benzylpenicillin, cephalothin, and cefoxitin (51). The impact of these data on changing the dosing regimen remains unclear.

Clearance

Clearance (Cl) is the PK parameter with the greatest impact on clinical applications, with a direct implication in maintenance doses. Unlike V_d, the physical and chemical properties of the drug have almost no effect on Cl, because this parameter is mainly controlled by physiology. For any organ, Cl can be defined as the volume of plasma that completely removes the drug in a given time, depending on the blood flow to the organ and the organ’s ability to extract the drug (33).

Obesity is related to increased liver volume due to fatty infiltration but without increased metabolic capacity, leading to the risk of steatosis, hepatitis, and fibrosis, altering hepatic blood flow, and affecting the hepatic Cl. Among the cytochrome P450 enzymes related to phase I oxidative metabolism, CYP2E1 and possibly CYP1A2 and CYP2C9 levels are elevated, while CYP3A4 levels are low (29, 55). Regarding CYP2C19 and CYP2D6, there are no conclusive data (56) (Fig. 1). There is limited information about increased phase II combined metabolism involving glucuronidation and sulfation (37).

The effect of obesity on renal clearance (Cl_r) is unclear. The increased organ mass during obesity may increase kidney functionality and renal blood flow in obese patients, which may affect the elimination rate (k), although organ size or weight may not fully reflect its function (Fig. 1). Obesity predisposes individuals to hypertension and diabetes, making it difficult to assess the effects on glomerular filtration rate (GFR) (57). In addition, Cl estimations are affected by the weight used, and weight-normalized Cl usually has a better correlation with the modified weight, such as LBW instead of TBW (46, 47, 58). Currently, there is no single, well-validated weight descriptor to characterize drug Cl in obese individuals.

REVIEW OF SPECIFIC ANTIMICROBIAL AGENTS

According to the relationship between drug exposure, pathogen susceptibility, and clinical response to antimicrobial treatment, antimicrobial drugs can be divided into three PK/PD categories (59–61). Time-dependent antimicrobials are those whose effect is best described by the percentage of time that the free concentration of the drug remains above the minimum inhibitory concentration (MIC) throughout the dosing interval (fT > MIC). Concentration-dependent antimicrobials achieve an increasing killing effect with increased serum concentration of the drug (C_max/MIC). These drugs are dosed to achieve maximum safe concentrations at the infection site for optimal bactericidal activity. Finally, in the case of concentration-dependent with time-dependent antimicrobials, the efficacy depends on the total drug concentration achieved over 24 h above the MIC of the microorganism [area under the plasma concentration–time curve over 24 h (AUC_0-24)/MIC]. The available evidence on the dosing of antimicrobials in obese patients is detailed below by pharmacological groups and subgroups. Recommendations are summarized in Table 2.

TABLE 2.

Recommended antimicrobial dosing in obese patients (assuming normal renal function)^a

Antimicrobials	Recommended setting	Dose	TDM	Remarks	References
Antibiotics
Aminoglycosides
Amikacin	ABW (C = 0.4) for the initial dose. TDM to guide following doses.	15–20 mg/kg/24 h IV	Always recommended	–	(62–64)
Gentamicin		5–7 mg/kg/24 h IV			(65)
Tobramycin		5–7 mg/kg/24 h IV			(62–64)
β-lactams
Ampicillin	Maximum dose In case of sepsis or severe infection, loading doses followed by an extended/continuous infusion are recommended to maximize clinical benefit.	2 g/4 h IV	Recommended if possible	–	(66, 67)
Cloxacillin		2 g/4 h IV			(66, 67)
Amoxicillin/clavulanic		No data available. Usual maximum dose: IV: 2 g/200 mg/8 h OR: 875 mg/125 mg/8 h			(66–68)
Aztreonam		2 g/6–8 h IV			(66, 67)
Cefazolin		2 g/8 h in continuous infusion or 1.5–2 g/6 h intermittent infusion IV		Surgical prophylaxis: 2 g single dose If >120 kg use 3 g	(66, 67, 69, 70)
Cefuroxime		1.5 g/6 h IV		–	(66, 67)
Ceftriaxone		2 g/12 h IV			(66, 67)
Cefotaxime		Maximum doses as indicated up to a maximum of 2 g/4 h IV			(66, 67)
Ceftazidime		2 g/8 h IV			(66, 67)
Cefepime		2 g/8 h IV			(66, 67)
Ceftaroline		600 mg/12 h IV			(66, 67, 71)
Ceftazidime/avibactam		2 g/0.5 g every 8 h IV			(66, 67)
Ceftolozane/tazobactam		1 g/0.5 g every 8 h IV Nosocomial pneumonia: 2 g/1 g every 8 h IV			(66, 67)
Piperacillin/tazobactam		4 g/0.5 g every 6 h IV			(66, 67, 72)
Cefiderocol		2 g every 6–8 h IV		If CrCl ≥120 mL/min use 2 g/6 h	(66, 67, 73)
Ertapenem		1 g/24 h IV		Consider 2 g/24 h if MIC >0.25–0.5 mg/mL	(66, 67, 74, 75)
Imipenem/cilastatin		1 g/6 h IV		Meropenem is recommended for seizure risk	(66, 67)
Meropenem		2 g/8 h IV		–	(66, 67, 76)
Meropenem/vaborbactam		4 g/ 8 h IV		–	(66, 67)
Cotrimoxazole
Trimethoprim/sulfamethoxazole	ABW (C = 0.4) (limited evidence)	8–20 mg TMP/kg/day IV divided into several doses	Not recommended	Oral route <5 mg/kg/day suboptimal in obese	(52, 77, 78)
Fluoroquinolones
Ciprofloxacin	Maximum dose. Some authors recommend dosing according to ABW (C = 0.45)	400 mg/8 h IV 750 mg/12 h OR	Not recommended	–	(79–81)
Levofloxacin	Maximum dose. Some authors recommend dosing by IBW	750 mg/24 h OR-IV		Up to 1,000 mg/24 h if CrCl (IBW) >110 mL/min in G infections	(82, 83)
Phosphonic acid derivatives
Fosfomycin trometamol	TBW	3 g orally in a single dose 2 g orally every 48 h, two doses	Not recommended	–	(84–87)
Disodium fosfomycin		100–300 mg/kg/day IV divided into three to four doses (maximum dose 24 g/24 h)		Maximum dose: 8 g
Glycopeptides
Vancomycin	TBW	Loading dose: 20–25 mg/kg (max. 3 g) IV. Maintenance: 15–20 mg/kg/8–12 h (max. 4.5 g/24 h) IV dose 10–12.5 mg/kg/12 h if BMI ≥ 40 kg/m²	Always recommended	–	(88–91)
Teicoplanin		Loading dose: 12 mg/kg/12 h IV three doses Maintenance: 6–12 mg/kg/24 h IV		In deep infections, the use of 15 mg/kg has been described	(10, 92–94)
Lincosamides
Clindamycin	Unknown	900 mg/8 h IV	Not recommended	–	(95, 96)
Lipopeptides
Daptomycin	If BMI ≥ 30 kg/m² dose according to ABW (C = 0.4)	6–10 mg/kg/24 h IV	Not recommended	–	(97–99)
Lipoglycopeptides
Dalbavancin	Standard dosage	1,500 mg single dose IV	Not recommended	Alternative: 1,000 mg + 500 mg 1 week later	(100, 101)
Oritavancin		1,200 mg in 3 h single dose IV			(102)
Macrolides
Azithromycin	Unknown	No data available. Usual maximum dose: 500 mg/24 h OR-IV	Not recommended	–	(103)
Clarithromycin		Eradication of Helicobacter pylori: 500 mg/8 h OR-IV
Erythromycin		1 g/6 h IV
Nitroimidazole
Metronidazole	TBW	Loading dose: 15 mg/kg (max. 1 g) OR-IV Maintenance: 7.5 mg/kg (max. 500 mg) every 6–8 h OR-IV	Not recommended	–	(104–106)
Oxazolidinone
Linezolid	Standard dosage	600 mg/8–12 h OR-IV	Recommended if possible	If decreasing age, eGFR > 60 mL/min/1.73 m2, MIC ≥ 2mg/L is recommended to use 600 mg c/8 h concomitant with TDM.	(107, 108)
Polymyxins
Sodium colistimethate                                                                 (1 million IU = 30 mg colistin base)	IBW	Loading dose (sepsis, severe infection): Weight > 50 kg: 9 MUI; weight ≤ 50 kg: 6 MUI IV Maintenance dose: 4.5 MUI c/12 h (2.5–5 mg colistin base/kg/24 h divided into two doses) IV	Not recommended	Maximum dose: 360 mg colistin base /24 h	(109, 110)
Tetracyclines
Doxycycline	Standard dosage	Loading dose: 200 mg OR-IV Maintenance: 100–200 mg/24 h OR-IV	Not recommended	Max. 300 mg/24 h OR-IV	(111)
Tigecycline		Loading dose: 100 mg IV Maintenance: 50 mg/12 h IV		If infection with carbapenemase- producing bacteria: Loading dose: 200 mg IV Maintenance: 100 mg IV/12 h	(112–118)
Antifungals
Echinocandins
Anidulafungin	Standard dosage	Loading dose: 200 mg/24 h IV one dose Maintenance: 100 mg/24 h IV	Not recommended	–	(119–128)
Caspofungin		70 mg/24 h IV			(129–135)
Micafungin		Candida albicans: 200 mg/24 h IV (115–185 kg) 150 mg/24 h IV (<115 kg) Candida glabrata: 200 mg/24 h IV (<115 kg)		Max. 200 mg/24 h. Higher doses do not provide benefits.	(136–144)
Azole derivatives
Fluconazole	TBW	6–12 mg/kg/24 h IV	Not recommended	Maximum dose described: 1,600 mg/day	(145–147)
Isavuconazole	Standard dosage	Loading dose: isavuconazole base 200 mg/8 h six doses OR-IV Maintenance: isavuconazole base 200 mg/24 h OR-IV		–	(148–152)
Itraconazole		200 mg/12 h OR		–	(153, 154)
Posaconazole	Maximum dose	Loading dose: 300 mg OR-IV/12 h, two doses Maintenance: 300 mg OR-IV/24 h		If >120 kg, there may be a lower plasma exposure	(155–177)
Voriconazole	OR: Standard dosage IV: ABW (C = 0.4)	OR: Loading dose 400 mg/12 h, two doses Maintenance: 200 mg/12 h IV: Loading dose 6 mg/kg/12 h, two doses Maintenance: 4 mg/kg/12 h	Always recommended	–	(178–183)
Polyene
Liposomal amphotericin B	TBW	3–5 mg/kg/24 h IV	Not recommended	Maximum recommended per dose: 500 mg	(52, 153, 184–187)
Nucleoside analog
Flucytosine	IBW	25–40 mg/kg/6 h OR-IV	Not recommended	–	(52, 188)
Antiviral agents
Acyclovir	ABW (C = 0.4)	10–15 mg/kg/8 h IV	Not recommended	OR: not specified	(189–194)
Cidofovir	ABW (C = 0.4) No data available, extrapolation from acyclovir data	Loading dose: 5 mg/kg/7 days IV, two doses Maintenance: 3–5 mg/kg/14 days IV		–	(52)
Foscarnet		Consult dosage according to indication		–	(52, 195)
Ganciclovir		Treatment: 5 mg/kg/12 h IV Prophylaxis: 5 mg/kg/24 h IV		–	(196)
Valganciclovir	Standard dosage	Treatment: 900 mg/12 h OR Prophylaxis: 900 mg/24 h OR		–	(197)
Oseltamivir		75 mg/12 h OR		–	(198–200)
Antitubercular agents
Ethambutol	IBW	15–25 mg/kg OR-IV/24 h (max. 2.5 g/24 h)	Not recommended	Dosing on a TBW basis may increase toxicity	(201–204)
Isoniazid		5 mg/kg OR-IV/24 h (max. 300 mg OR-IV/24 h)			(204)
Pyrazinamide		20–30 mg/kg/24 h (max. 2,000 mg OR/24 h)			(204)
Rifampin	Standard dosage	600 mg OR-IV/12 h Tuberculosis: 600 mg OR-IV/24 h			(204, 205)

^a C, drug-specific correction factor; IV, intravenous; OR, oral; and TDM, therapeutic drug monitoring.

Antibiotics

Aminoglycosides

Aminoglycosides are hydrophilic antimicrobials with low V_d and whose elimination is mostly renal and proportional to glomerular filtration. They are concentration-dependent agents whose PK/PD target is C_max/MIC. In obese patients, V_d of hydrophilic agents is increased, and renal function is probably higher than in normal-weight population due to larger kidney size (206). These two factors will probably generate a decrease in the plasmatic antibiotic concentrations. However, since aminoglycoside doses are based on weight, using TBW would overestimate the dose, so the use of ABW is recommended with a 0.4 correction factor since it is estimated that 40% of the dose is distributed to adipose tissue (62, 63). The current recommendation is to use ABW for the calculation of the initial dose and guide the following doses with therapeutic drug monitoring (TDM). It is recommended to adjust the dose according to renal function, but it is not clear which equation for calculating renal clearance is the best. Some authors prioritize the use of the MDRD and CK-EPI or Salazar-Corcoran over Cockroft-Gault (CG) (62, 64, 65), but the evidence is not high, so CG continues to be widely used in clinical practice.

β-lactams

β-lactams are time-dependent antibiotics with renal elimination, and their target PK/PD is 100%ft > (MIC or 4×MIC in critically ill patients). There is much evidence of the high interindividual variability of β-lactams’ PK (207, 208). In obese patients, the increase in lean mass and the increase in Cl_r imply an increase in this variability, especially due to their hydrophilic nature (66). Different pharmacokinetic studies suggest a need for an increased dose of β-lactams in obese patients, mainly due to an increase in the V_d and inadequate tissue penetration, although evidence regarding decreased penetration in this population is still limited (67, 68, 72, 74, 75). However, many studies have failed to demonstrate the need for a dose increase in this population, obtaining similar results in obese and non-obese patients with the same dosing (71, 76, 209). As a general recommendation, it is suggested to start treatment with β-lactams at higher doses in obese patients with complicated infections, infections caused by microorganisms with high MICs, critically ill patients, or those whose Cl_r is increased [creatinine clearance (CrCl) > 100 mL/min]. It is important to consider the source of infection, with bone infections being the most difficult to treat in obese patients and requiring an increase in the dose (69).

A highly recommended way to intensify β-lactam treatment is to reduce the frequency of administration or to use extended or continuous infusions (207). In all these cases, it is recommended to perform TDM and to adjust future doses with the aim of reaching target concentrations but avoiding potentially toxic effects (208, 210).

Cotrimoxazole (sulfamethoxazole/trimethoprim)

Sulfamethoxazole/trimethoprim is lipophilic with a protein bound of 70% for sulfamethoxazole and 44% for trimethoprim and excreted primarily through the kidneys. The target PK/PD is not well defined, although the most used are C_max and AUC_0-24/MIC. Sulfamethoxazole/trimethoprim is usually dosed by weight with little evidence on the impact of overweight on its pharmacokinetics. The usual recommendation is to use AWB with a 0.4 correction factor (52). However, this recommendation is based on PK changes of sulfisoxazole (another sulfonamide antibiotic with similar PK properties to sulfamethoxazole) in morbidly obese patients undergoing intestinal bypass surgery (77). In this study, no differences in PK parameters were observed in obese patients, suggesting that an obese individual may require a dose like a normal-sized individual. In a more recent study, in which cotrimoxazole concentration was measured in patients with different weights, a reduction in drug concentration was observed using the same dose in obese patients, suggesting that higher doses should be used in overweight patients (78). Since no clinical data are available to support a reference dosing strategy, appropriate dosing should be determined on a case-by-case basis, monitoring for signs of clinical improvement and drug toxicity.

Fluoroquinolones

Fluoroquinolones are hydrophilic molecules, except levofloxacin, which has an intermediate lipophilic character (211). Clinical efficacy is related with AUC_0-24/MIC or C_max/MIC. There is little evidence on the dosing of fluoroquinolones such as levofloxacin or ciprofloxacin in obese patients. Data regarding the effects of obesity on V_d and Cl for ciprofloxacin are conflicting (79). However, the need to give higher doses in obese patients to ensure target tissue concentrations has been observed, suggesting dosing by ABW (using a correction factor of 0.45) (80). A recent study of PK changes of ciprofloxacin in obese patients showed no differences, recommending not to adjust routinely and assessing that higher doses may be necessary in difficult-to-access infections (81). A PK study conducted in obese patients treated with levofloxacin failed to demonstrate an increase in the Cl of levofloxacin in overweight patients, although a dose adjustment is suggested based on the CrCl estimated by the CG equation and IBW. In this work, the need to increase the dose to 1,000 mg every 24 h is recommended for patients with CrCl > 110 mL/min in Gram-negative infections (82). Some case series suggest the use of higher doses (1,000 mg every 12 h) in obese patients to achieve therapeutic objectives (83). Limited PK data for moxifloxacin suggest that adjustment for obesity is not necessary (212). Data for delafloxacin are limited to skin infections, although the data also suggest that no dose adjustment is necessary (213, 214).

Phosphonic acid derivatives

Fosfomycin is a small, hydrophilic antibiotic that has total renal elimination (84). Information on the pharmacokinetics of fosfomycin is scarce, both in obese and normal-weight patients, and the PK/PD target is still not well defined (85, 86). In a PK study conducted on obese versus non-obese patients treated with intravenous fosfomycin, a decrease in C_max, a decrease in AUC, and an increase in V_d were observed in obese patients. In addition, a decrease in tissue penetration was observed in the group of obese patients (84). However, it has not been possible to demonstrate the need to increase the dose of fosfomycin due to the condition of obese patients, although increasing the dose is suggested in obese patients with infections caused by pathogens with high MICs or with glomerular hyperfiltration (87).

Glycopeptides

Glycopeptides are hydrophilic agents predominantly cleared by renal elimination, whose PK/PD target is AUC_0-24/MIC (208). For vancomycin dosage, clinical guidelines recommend empiric dosing based on TBW and TDM at trough concentrations, which may not be optimal for obese and severely obese patients because an increase in the V_d of vancomycin with weight has been widely described (215, 216). However, the relationship between V_d and weight is not proportional. In addition, Cl is also increased in obese patients due to increased kidney size and increased blood flow. Some studies suggest a higher Cl in obese adolescent patients compared to adults, which is also higher in males than females, so higher doses could be necessary in this subgroup of patients (88). Alternative strategies were tested in some studies using ABW, obtaining promising results (89). However, the last vancomycin’s guidelines recommend using actual body weight-based loading doses of 20–25 mg/kg of body weight (using TBW), with consideration of capping doses at 3 g in obese patients with serious infections, followed by maintenance doses calculated by 15–20 mg/kg of body weight every 8–12 h (maximum 4.5 g/day) (90, 91).

Teicoplanin is dosed by weight in all indications. Generally, the use of maximum doses of teicoplanin is recommended in obese patients. Several dosing regimens have been published depending on the objective target and the type of infection (92). Currently, the most accepted dosage is three doses of 12 mg/kg of body weight every 12 h and a maintenance dose of 6–12 mg/kg of body weight per day, using TBW (10, 93). Some guidelines recommend TDM to guide maintenance dosing in obese patients (94).

Lincosamides

Clindamycin is a lipophilic molecule with mainly biliary elimination and high binding to plasma proteins (60%–90%). PK/PD target is fT > CMI (percentage of optimal time not established). There are no PK studies performed in adult obese patients. Clinical guidelines recommend the use of maximum doses in bone and skin and soft tissue infections (95). In a study conducted on obese children, dosing by weight was compared using TBW, normal fat mass , free fat mass, and LBW, supporting the dosing based on TBW for obese and nonobese children (96).

Lipopeptides

Daptomycin is a hydrophilic antibiotic with high protein binding (92%) and renal elimination (78%). The PK/PD target is AUC_0-24/MIC (97). The use of TBW, lean body mass, and ABW has been evaluated without reaching a clear conclusion (98). Obese patients treated with daptomycin (TBW) were found to have higher rates of creatine phosphokinase elevations and treatment discontinuation in a multicenter study compared to published data for primarily normal-weight patients. ABW may be used in place of TBW with concerns for toxicity, especially in the setting of indications for high-dose daptomycin (99).

Lipoglycopeptides

Dalbavancin is an antibiotic with an extended elimination half-life because of its exceptionally high protein binding (≥93%) and widespread tissue distribution. The PK/PD index established for dalbavancin is the free area under the dalbavancin concentration–time curve over minimum inhibitory concentration (AUC_0-24/MIC). The usual posology of dalbavancin is a once-weekly infusion (1,500 mg as a single dose or 1,000 mg on day 0 followed by 500 mg on day 7) (100). The effect of obesity was studied in a subgroup analysis of a phase III clinical trial, and it was demonstrated that no changes are needed (101). In a retrospective registry study in patients treated with oritavancin (median BMI 31.4 kg/m²), a high clinical success rate of 88.1% was achieved in skin and soft-tissue infections and complicated Gram-positive infections (102). No subgroup analysis was performed in obese patients, so different dosage recommendations cannot be made for this population.

Macrolides

Macrolides are lipophilic antibiotics whose PK/PD target is AUC_0-24/MIC. Dosing strategies for macrolides such as azithromycin, clarithromycin, or erythromycin have not been studied in the obese population. However, some studies revealed good treatment results in the cohort of obese patients with treatment at standard doses (103).

Nitroimidazole

Metronidazole is a concentration-dependent antibiotic whose PK/PD target is AUC_0-24/MIC. There is not much evidence on the need for dose adjustment of metronidazole in obese patients. In some studies, a decrease in plasma concentration and an increase in V_d were observed in obese patients, leading to failure to reach the PK/PD target in these patients (104). However, clinical guidelines currently state that there is insufficient data to support the use of higher doses in obese patients to date (105, 106).

Oxazolidinone

Linezolid is a time-dependent antibiotic, and the goal of effectiveness is AUC_0-24/MIC or C_min. V_d and CL could be increased in overweight and obese patients. For this reason, it seems to have a higher risk of treatment failure using the usual doses. The risk is higher with decreasing age, eGFR ≥ 60 mL/min/1.73 m² and MIC values ≥ 2 mg/L. In these cases, higher doses of linezolid such as 600 mg every 8 h, concomitant with TDM, may be considered (107, 108).

Polymyxins

Colistin methanesulfonate is the prodrug of colistin (polymyxin E) with a rapid and concentration-dependent bactericidal effect. The PK/PD index that best describes its efficacy is AUC_0–24/MIC. There are limited data comparing the pharmacokinetics of colistin in obese and normal-weight patients. However, some studies suggest that there is a significant risk of nephrotoxicity with colistin in obese patients, so dosing based on IBW may be recommended, with a maximum daily dose of 360 mg of colistin base or 12 MU of colistimethate (109, 110).

Tetracyclines

Tetracyclines are highly lipophilic antibiotics, so changes in their disposition are expected at extremely high body weights. Nevertheless, there are limited data evaluating their clinical outcomes in obese patients. The PK/PD target in this group is AUC_0-24/MIC (112, 113). The recommended dose for doxycycline in obese patients does not vary from that used in patients with normal weight (111). Tigecycline has a large V_d (approximately 7–10 L/kg), resulting in widespread tissue distribution and very low plasma drug concentrations (112). In addition, tigecycline exhibits non-linear plasma protein binding over therapeutic drug concentrations, being the major route of elimination for its unchanged excretion in the feces, which accounts for 59% of the dose (114). Tigecycline is an antibiotic with bacteriostatic and post-antibiotic activity. In obese patients, standard doses are recommended (an initial loading dose of 100 mg followed by a maintenance dose of 50 mg/12 h) (115). However, for resistant Gram-negative bacteria, higher doses may be considered regardless of the patient’s weight (200 mg loading dose, followed by 100 mg every 12 h) (116–118).

Antifungals

Echinocandins

They bind strongly to proteins (97%–99%), leading to lower drug concentrations in serum and tissues (217). They are concentration-dependent antifungals whose PK/PD index is associated with their AUC_0-24/MIC ratio (218). Accumulating evidence suggests that obese patients treated with echinocandins have reduced exposure due to changes in pharmacokinetics (219). A recent systematic review carried out by Alsowaida et al. (220) has collected all the studies published to date on the exposure of obese patients to echinocandins. Out of a total of 25 studies, 17 studies reported lower echinocandin exposures in overweight and obese subjects compared to normal-weight subjects based on PK/PD targets (119–124, 129–133, 136–142). In contrast, eight studies have also been published that endorse no differences in echinocandin exposure in overweight and obese subjects compared with normal-weight subjects (125–128, 134, 135, 143, 144). Therefore, and due to the lack of high-quality evidence, consensus on recommendations for echinocandins in obese patients is the use of standard doses (220).

Azole derivatives

Azole derivatives are weak bases, mainly lipophilic, with limited water solubility, apart from fluconazole, which is more hydrophilic than other antifungal azoles (145). Regarding their PK/PD index, AUC_0-24/MIC correlates with effectiveness against invasive fungal infections (221). Itraconazole, voriconazole, and posaconazole require solubilizers to prepare oral solutions and intravenous dosage forms due to their lipophilicity (222–226). Fluconazole differs from these drugs by its high bioavailability, low protein binding, and minimal hepatic metabolism, resulting in dose-dependent linear pharmacokinetics (145). As obese patients are less likely to achieve the dose/MIC and AUC_0-24/MIC ratios, fluconazole should be dosed based on TBW (146). Doses of up to 1,600 mg/day for 2 weeks have been described, but there are no data to support higher dosing of obese patients (147). Regarding isavuconazole, intravenous and oral formulations produce similar pharmacokinetics, although it has not been uniformly studied in obese patients (148). To date, it is not possible to recommend dose adjustment of isavuconazole in the obese population since data obtained on the effect of body weight and/or BMI on pharmacokinetics are not consistent (149–152).

Further studies are needed to determine the optimal dosing regimen of itraconazole in the obese population, so the recommendation for these patients is the standard dosage of 200 mg of itraconazole every 12 h (153, 154). The pharmacokinetics of posaconazole have not been studied directly in obese patients in any of its different dosage forms. However, contradictory results have been found in studies that sought to correlate body size descriptors (in kilograms, BMI, or BSA) as a covariate that may affect posaconazole concentrations (155–177). Therefore, it is not possible to recommend a change in posaconazole dosage based on weight. TDM studies showed that voriconazole plasma concentrations were significantly higher in patients receiving TBW doses, within the reference range when ABW is used, and below the range in IBW (178–182). No differences were found when voriconazole was dosed orally (183).

Polyenes

Amphotericin B exhibits non-linear kinetics resulting in large increases in serum concentrations relative to dose escalation (52, 184). To date, there are insufficient data from which definitive dosing recommendations for most amphotericin B formulations can be established, although for liposomal amphotericin B, ABW or TBW dose may be used depending on the severity of the infection (153, 185). Recent studies proposed the use of fixed doses of amphotericin B in obese patients since body size had no effect on clearance, showing that TBW dosing might lead to an increased risk of toxicity. Wasmann et al. (186) recommended the use of 3 or 5 mg/kg of body weight/dose, limiting the dose to a maximum weight of 100 kg, resulting in a fixed dose of 300 or 500 mg, respectively. However, Nix et al. (187) express their concern about the extrapolation of these findings resulting from the simulation of 10,000 subjects with BW ranging from 60 to 180 kg. In this sense, these authors state that further studies are needed to identify the most appropriate liposomal amphotericin B dosing strategy for obese patients.

Nucleoside analog

The pharmacokinetics of flucytosine in obesity have only been described in a case report of a morbidly obese female with extrameningeal cryptococcal disease treated with 0.3–0.5 mg/kg of body weight/day using IBW (188). In the absence of reliable clinical data, administration of flucytosine using ABW in obese patients may be prudent for initial dosing in life-threatening fungal infections, whereas for non-life-threatening infections, dosing based on IBW may be sufficient.

Antivirals

Acyclovir is poorly bound to plasma proteins (~15%) and widely penetrates tissues and body fluids, including cerebrospinal fluid. Excretion occurs primarily by glomerular filtration and tubular secretion. Acyclovir dosing is conventionally weight based, which poses a risk of overdosage in obese people if TBW is used, leading to the development of crystalluria and an acyclovir-induced acute kidney injury (189–192). The evidence available so far recommends the dosing of acyclovir in obese patients by ABW (193, 194).

The pharmacokinetics of cidofovir in obesity have not been studied, so there is currently no published literature. PK values in non-obese patients suggest limited distribution in adipose tissue; therefore, ABW appears to be the most appropriate strategy for cidofovir dosing in obese patients (52).

Dosing recommendation for foscarnet in obese patients is using ABW (52, 195). Ganciclovir hardly binds to plasma proteins and its elimination is mostly renal. Ganciclovir dosage is based on body weight, which results in an increased risk of toxicity when subsequent high doses are administered in overweight or obese patients. Using ABW dose could help reduce this risk, although a recent study has concluded that ganciclovir ABW dosing did not result in a decrease in neutropenia or treatment efficacy compared to TBW dosing (196). On the other hand, for its prodrug valganciclovir, fixed doses of 900 mg/24 h are used for prophylaxis and 900 mg/12 h for treatment (197). In the case of oseltamivir, different studies concluded that a dose modification is likely to be unnecessary in obese patients (198–200).

Antitubercular agents

Little information is available on the dosing of antitubercular agents in obese patients, although it is known that the toxicity of these drugs can be increased if they are dosed according to TBW (227). Optimal microbiocidal efficacy of anti-tuberculosis drugs is related to AUC/MIC and, in the case of ethambutol, the PK/PD target is C_max/MIC, with drug resistance linked to fT > MIC (228, 229). Data published to date suggest that ethambutol, isoniazid, and pyrazinamide should be dosed by IBW in obese patients (201–204), while rifampin is recommended to be dosed at a flat dose of 600 mg/12 h (204, 205).

CONCLUSIONS

The present work compiles the information currently available on the dosage of antibiotics, antifungals, antivirals, and antituberculosis drugs in this population. There is currently scant and sometimes contradictory information in scientific literature on the dosing of antimicrobials in obese patients. More studies in obese patients are still needed to establish antimicrobial dosing better adapted to their characteristics, allowing therapeutic objectives to be achieved with a lower risk of adverse effects.

Biographies

Teresa Rodríguez-Jato is an established researcher, who completed her studies in Pharmacy at the University of Santiago de Compostela in 2001. Subsequently, she accessed the Specialized Health Training at the Hospital Clínico de Santiago de Compostela, completing this training in 2007. Since 2013, she develops her research and care work in the area of critical patients, abdominal transplant unit and pharmaceutical care in infectious diseases at the Hospital de Santiago de Compostela. In addition, she is part of the antimicrobial stewardship program of the aforementioned hospital, playing an important role in the optimization of anti-infective therapy in the center.

Anxo Fernández-Ferreiro is an established researcher who completed his studies in Pharmacy at the University of Santiago de Compostela in 2008. Subsequently, he accessed the Specialized Health Training at the Hospital Clínico de Santiago de Compostela, completing this training in 2014. He received his Doctor of Pharmacy degree in 2015, focused on the development of anti-infective ophthalmic formulations. Since that time, he has developed an important research and care work, through the research contracts Río Hortega (2016-2018) and subsequently Juan Rodés (2019-present) at the Health Research Institute of Santiago de Compostela. His research focuses on the field of personalized medicine, with special interest in the individualized dosing of anti-infectives in the last 5 years.