Advances in Therapeutic Drug Monitoring and Pharmacokinetic Researches of Oxazolidinone Antibacterial Agents in the Elderly Patients

Introduction

The global population is aging, leading to a growing number of elderly patients. Due to factors such as multimorbidity, polypharmacy, immunosenescence, and frailty, these patients face an increased risk of methicillin-resistant Staphylococcus aureus (MRSA) infection. This risk is particularly pronounced in those over 80 years of age, who frequently reside in healthcare settings; the common use of invasive devices in this population further elevates the infection risk.^1–3

Early administration of effective antibiotics is a prerequisite for successful infection treatment. Although vancomycin is the cornerstone of MRSA treatment, its potential nephrotoxicity limits its use in elderly patients, especially in very elderly patients.^4,5 Daptomycin is primarily reserved for MRSA bloodstream infections due to its hydrophilicity and susceptibility to inactivation by pulmonary surfactant. Tigecycline is effective against most G⁺ bacteria (including MRSA), Gram-negative bacteria, and atypical pathogens; however, its low blood concentration raises concerns regarding its efficacy and safety for Gram-positive bacterial infections.⁶ Although teicoplanin has efficacy comparable to vancomycin with a significantly lower adverse reaction rate,^7,8 its slow onset of antibacterial action hampers its widespread use.

Oxazolidinones are a class of synthetic antibacterial agents. They exert their effect by binding to the 23S rRNA of the bacterial 50S ribosomal subunit, thereby inhibiting the formation of the functional 70S initiation complex and arresting bacterial growth. This unique mechanism confers no cross-resistance with other common antibiotic classes, such as aminoglycosides or lincosamides.⁹ Linezolid, the first approved oxazolidinone, is used to treat infections caused by Gram-positive bacteria including MRSA, Mycobacterium tuberculosis, and vancomycin-resistant Enterococcus (VRE). It possesses demonstrated efficacy, generally mild and reversible side effects, and is widely used in the elderly population.¹⁰ Contezolid is a newer, orally-administered oxazolidinone indicated for infections caused by multidrug-resistant Gram-positive bacteria such as MRSA and VRE. Evidence suggests its antibacterial activity is comparable to or exceeds that of linezolid, making it a valuable alternative or sequential treatment option for patients at high risk of thrombocytopenia.¹¹ Tedizolid is also a new oxazolidinone antibacterial agent approved for the treatment of acute bacterial skin and skin structure infections.

Individualized Dosing Strategies for Antibacterial Agents

The distinct pathophysiology of the elderly population—including reduced hepatic and renal functional reserve, hypoproteinemia, and multiple comorbidities—alongside prevalent polypharmacy and its associated drug-drug interactions (DDIs), can significantly alter antibiotic pharmacokinetics. This often results in suboptimal or potentially toxic plasma drug concentrations under conventional dosing regimens.^12,13 Several age-related pathophysiological changes critically influence antibiotic PKs. Impaired hepatic or renal function reduces drug clearance, prolongs the half-life (t_1/2), and elevates plasma drug concentration. Conversely, enhanced renal function can accelerate clearance, lowering plasma concentration. Additionally, hypoproteinemia increases the free drug fraction and reduces the apparent volume of distribution (Vd). In states like sepsis, endothelial damage and increased capillary permeability expand the Vd. Furthermore, multiple organ dysfunction syndrome (MODS) alters antibiotic clearance and metabolism, leading to unpredictable concentration changes. Achieving an appropriate antibiotic dosage is therefore critical in elderly patients, as subtherapeutic plasma concentrations risk therapeutic failure, whereas supratherapeutic concentrations increase the risk of serious adverse drug reactions. Moreover, the reduced susceptibility of G⁺ bacteria to antimicrobial agents further complicates clinical management.¹⁴ In the evolving field of clinical pharmacology, individualized dosing strategies are central to optimizing therapeutic efficacy and minimizing adverse drug reactions. These strategies are founded on PK (describing a drug’s concentration-time profile in the body) and pharmacodynamic (PD, describing a drug’s effects on the body) principles. They generally fall into three categories: empirical dose regimens, therapeutic drug monitoring (TDM), and model-informed precision dosing (MIPD).

Empirical Dose Adjustment Strategy

The empirical dose adjustment strategy employs a one-size-fits-all approach, typically applying the standard dosage from the drug label or a fixed dosing regimen. For example, the prescribing information for linezolid recommends a fixed dose of 600 mg every 12 hours for all adults, irrespective of renal function, age, or gender. This strategy simplifies clinical dosing but overlooks relevant patient-specific variables. In specific populations, antibiotic pharmacokinetics can change significantly, leading to wide inter-individual variability in plasma drug concentration after identical doses.^13,15 The empirical dose approach is generally successful for drugs possessing a broad therapeutic window—characterized by a wide margin between effective and toxic concentrations.¹⁶ However, for drugs with a narrow therapeutic window and/or high pharmacokinetic/pharmacodynamic variability, individualized dose adjustment becomes necessary.

Therapeutic Drug Monitoring Strategy

TDM compensates for the limitations of empirical dose adjustment strategy and is indicated for drugs with narrow therapeutic windows, such as anti-infectives, chemotherapeutic agents, immunosuppressants, and some therapeutic antibodies. It is also widely used in populations with altered pharmacokinetics, including elderly and pediatric patients, as well as those with obesity or burns.¹⁶ The traditional TDM approach involves establishing a therapeutic exposure range—a target drug concentration window with a lower limit (minimum effective concentration) for efficacy and an upper limit (maximum tolerated concentration) for safety. Generally, the trough concentration (C_min) is typically selected for monitoring.¹⁷ For example, to balance efficacy against the risk of nephrotoxicity, the recommended C_min range for vancomycin is 10–20 mg/L.¹⁸ TDM concentrations are usually measured at steady state, achieved after 5–7 half-lives of continuous dosing. Although trough concentration monitoring remains the standard due to its stability and practicality, levels may be obtained at other specific times for particular indications, such as suspected toxicity.

Despite its advantages of simplicity and feasibility, the TDM approach has several limitations. First, the necessity for steady-state sampling at specific time points can delay dosage adjustments, potentially resulting in a failure to achieve the therapeutic target concentration promptly. Second, empirical dose adjustments based on a single concentration measurement are inadequate for drugs with nonlinear pharmacokinetics, such as the concentration- and/or time-dependent kinetics of rifampicin.¹⁹ Third, reliance on a single concentration (such as the C_min) to estimate overall drug exposure is suboptimal, as it ignores the complete concentration-time profile. The correlation between C_min and the area under the curve (AUC) is valid only under specific conditions, such as a consistent dosing interval and stable pharmacokinetics.¹⁹ Fourth, timing accuracy is critical in traditional TDM. Deviations in sampling or administration times from the protocol can compromise result interpretation, especially for drugs with a short half-life. Finally, traditional TDM considers any concentration within the therapeutic range as effective, which may not achieve optimal PK/PD target attainment.²⁰ A concentration near the range’s limit may still be deemed acceptable, even when the dosage is suboptimal. These limitations have motivated the development of more sophisticated and comprehensive individualized dosing strategies.

Model-Informed Precision Dosing Strategy

MIPD is an advanced quantitative approach that integrates mathematical and statistical models of drug behavior and disease with patient-specific demographic and clinical data to develop individualized dosing regimens. MIPD is widely recognized as a valuable tool for optimizing dosage strategies in both drug development and clinical practice.²¹ Compared to empirical dose adjustment and TDM strategies, MIPD represents a more advanced methodology for designing dosing regimens based on a patient’s physiological, pathological, and genetic profile, thereby enhancing treatment safety, efficacy, cost-effectiveness, and compliance.

The core of the MIPD strategy is the establishment of a population model. Commonly used models include the population pharmacokinetic (PopPK) model, PK/PD model, population PK/PD (Pop-PK/PD) model, physiologically based pharmacokinetic (PBPK) model, and artificial intelligence (AI). The PopPK model studies the processes of drug absorption, distribution, metabolism, and excretion across individuals to identify and quantify intrinsic and extrinsic factors influencing PK, such as age, gender, disease state, and drug-drug interactions. This analysis is crucial for dose selection, particularly for drugs with a narrow therapeutic range in specific populations like pediatric or critically ill patients.¹⁶ The MIPD workflow differs significantly from traditional TDM (Figure 1). Prior to the first dose, a population model can predict an initial regimen while incorporating multiple covariates simultaneously. By integrating patient-specific variables with the model’s parameter variability, MIPD can calculate and optimize the probability of achieving PK/PD targets prospectively.¹⁶

Figure 1 Comparison of the empirical dose adjustment strategy, TDM strategy and MIPD strategy. “×” represents “Not applicable”. Abbreviations: TDM, Therapeutic Drug Monitoring; MIPD, Model-informed precision dosing.

The MIPD strategy is now applied across numerous clinical fields. These include its use in special populations (critical, pediatric, and elderly patients) for anti-infective agents such as vancomycin, linezolid, beta-lactams, and antifungals, as well as in oncology for chemotherapeutic and targeted agents like cisplatin, paclitaxel, imatinib, and cetuximab.¹⁶ In summary, considerable progress has been made with MIPD, particularly in developing population PK models. The focus of scientific exploration has consequently shifted from merely developing new models with clinical datasets to actively utilizing and refining existing ones.

TDM and PK Studies of Oxazolidinone Antibacterial Agents in Elderly Patients

Linezolid, contezolid, and tedizolid are commonly used oxazolidinone antibacterial agents in clinical practice. This review therefore focuses primarily on TDM and pharmacokinetic studies of these three agents in the elderly population. Posizolid and Radezolid are both oxazolidinone antibiotics; however, the PK and TDM data for these drugs remain very limited. Sutezolid and ranbezolid, which are currently in clinical development, will not be discussed in this review.

Linezolid

Linezolid, the first approved oxazolidinone antibiotic, is a synthetic agent that inhibits bacterial protein synthesis by binding to the 23S rRNA of the 50S ribosomal subunit.¹⁰ It is clinically used to treat infections caused by Gram-positive bacteria, including VRE and MRSA.

Following the approval of linezolid, an early study by Sisson et al²² investigated the effects of age and gender on its PK. The trial administered a single 600 mg oral dose to healthy young (18–40 years) and elderly (60–65 years) adults of both sexes, using non-compartmental analysis to evaluate PK parameters. The authors concluded that neither age nor gender significantly affected linezolid PK and that no dose adjustment was necessary. However, with subsequent widespread clinical use, numerous studies have reported severe drug overexposure in elderly patients receiving the conventional dose.^13,23–26 Consequently, the latest Chinese expert consensus on linezolid recommends TDM for elderly patients to prevent overexposure.²⁷

A retrospective study found that C_min of linezolid in elderly patients exhibited 20-fold interindividual variability and were positively correlated with age and inversely correlated with renal function. The risk of supratherapeutic exposure to linezolid rose significantly in elderly patients older than 80 years with concurrent renal dysfunction.²⁴ In this study, although the linezolid C_min exceeded the previously recommended target value, most clinicians did not adjust the drug dosage based on the TDM results.²⁴ Cattaneo et al²⁶ analyzed 3250 plasma concentration samples and confirmed that age is a key factor influencing the linezolid C_min. For every 10-year increase in age, the C_min increased by approximately 30%. Cattaneo et al²⁶ recommended that TDM be performed during the first week of linezolid treatment in elderly patients (initiating from day 3) to enable early detection of supratherapeutic exposure. If TDM is unavailable, a dosage reduction should be considered for patients planned for long-term linezolid therapy, particularly those with a high risk of drug accumulation (eg, renal dysfunction or advanced age) and a low risk of treatment failure. Tinelli et al²⁵ studied elderly patients (≥ 70 years) receiving the conventional linezolid dose. They reported a median C_min of 13.0 mg/L (IQR: 11.9–16.0), which exceeded the therapeutic upper limit (8.0 mg/L). Xu et al²⁸ also reported that in elderly patients aged ≥ 85 years and 65–84 years receiving the conventional linezolid dose, median C_min was 13.60 mg/L (IQR: 7.28–21.00) and 7.55 mg/L (IQR: 4.32–12.65), respectively. The incidence of supratherapeutic exposure was 75% and 54.8%, respectively. Creatinine clearance (CrCl) was inversely correlated with C_min and positively correlated with age. A prospective, multicenter study analyzing 860 plasma concentration measurements from 313 elderly patients revealed substantial drug overexposure in this population. It reported a steady-state linezolid C_min of 26.1 mg/L—approximately 4 to 5 times higher than in non-elderly individuals. Over 90% of patients had supratherapeutic exposure (> 8 mg/L), and 38% had severe exposure (≥ 30 mg/L).¹³ Using a baseline age range of 65–80 years (where the median C_min was approximately 10 mg/L), the study found that for every 10-year increase in age, the median C_min increased by approximately 10 mg/L.¹³ Another study found that renal dysfunction significantly increased linezolid C_min in elderly patients and the associated risk of hematological toxicity. Consequently, a dosage reduction is recommended for elderly patients with renal insufficiency.²⁹ In a propensity score-matched study, the incidence of linezolid-related hematological adverse events in elderly patients did not differ significantly between groups with C_min < 8 mg/L and 8–14.5 mg/L. Thus, a revised TDM target range of 2–14.5 mg/L has been proposed for elderly patients.³⁰

While TDM has inherent limitations in ensuring precise drug dosing, MIPD offers a more refined approach via the development of population pharmacokinetic models. However, research applying MIPD to optimize linezolid dosing in the elderly remains scarce. To our knowledge, only two studies have developed population PK models for linezolid specifically in this population and have preliminarily simulated the dosage regimens, achieving MIPD.

In 2009, Abe et al²³ developed a PopPK model using 2539 plasma concentration samples from 455 patients (aged 18–98 years). Using nonlinear mixed-effects modeling (NONMEM), they described linezolid pharmacokinetics with a one-compartment model featuring first-order absorption and elimination. Their final model identified age as a significant covariate affecting clearance (CL). However, subsequent studies failed to confirm age as a key determinant of linezolid exposure,²² and the research focus shifted toward critically ill patients or those with renal dysfunction. This gap was specifically addressed by Li et al³¹ in 2024 through a retrospective analysis of TDM data from 120 elderly patients (210 plasma samples). They established a PopPK model, employing a one-compartment structure, and estimated a linezolid CL of 101.28 L/day and a volume of distribution (Vd) of 45.80 L in this cohort. Their analysis identified blood uric acid as a significant covariate for CL. Using this model for dose simulation, Li et al³¹ concluded that for a pathogen MIC of 2 mg/L, the standard regimen (600 mg q12h) achieved satisfactory target attainment in all elderly patients. However, they proposed that more precise regimens could mitigate overexposure risk: for patients with uric acid > 260 μmol/L, 300 mg q8h achieved a target attainment (PTA) > 80%, and for those with uric acid > 436 μmol/L, 300 mg q12h remained effective. As a retrospective study, the work by Li et al³¹ has inherent limitations. The sample size, in terms of both patient numbers and concentration data, was limited. Furthermore, the cohort’s age distribution was biased towards younger elderly individuals (mean age 70 years), limiting generalizability to older age groups. Most critically, the model was developed using only trough concentrations, lacking random or peak concentrations (C_max), which restricts the comprehensiveness of the PK analysis. Despite these limitations, Li et al provided the first actionable, covariate-guided strategy for dose adjustment of linezolid in elderly patients, marking a significant step toward precision dosing in this population.

In 2025, Liu et al³² prospectively addressed these gaps by constructing a PopPK model from 861 plasma samples (556 C_min, 305 C_max) from 232 patients. With a mean cohort age of 90.6 ± 11.6 years, this study specifically included the very elderly, compensating for the age-related limitation of the earlier work by Li et al.³¹ Using NONMEM software, a one-compartment model with first-order absorption and linear elimination was developed, identifying both age and estimated glomerular filtration rate (eGFR) as significant covariates affecting linezolid concentrations. Using the established PK/PD target of AUC/MIC >100 (with a corresponding C_min target of 2–8 mg/L), the model simulated target attainment probabilities. For pathogens with an MIC ≤ 1 mg/L, it recommended specific regimens: 300 mg twice daily for patients aged 65–80 years; 600 mg once daily for those aged 80–90 years with normal renal function; and 300 mg once daily for patients outside these subgroups. These regimens achieved a > 60% probability of C_min within the target range and a > 90% probability of attaining AUC/MIC > 100. Although Liu et al provided more precise, age-stratified dosing guidance, the emerging challenges of MIC creep and resistance necessitate further research to define optimal regimens against pathogens with higher MIC values.

Contezolid

Contezolid is a novel oral oxazolidinone antibacterial agent developed for treating multidrug-resistant Gram-positive bacterial infections. The MIC₅₀ and MIC₉₀ values of contezolid against MRSA are both 1 mg/L, which is half of that of linezolid. The MIC₅₀ and MIC₉₀ values of contezolid against methicillin-sensitive and -resistant coagulase-negative staphylococci are 1 mg/L, and the MIC₅₀ of Enterococcus is 1 mg/L and the MIC₉₀ is 1 or 2 mg/L. These values are similar to or lower than those of linezolid. In addition, contezolid shows good antibacterial activity against streptococci, with MIC₅₀ (0.5–1 mg/L) and MIC₉₀ (1 mg/L) being similar to or lower than those of linezolid, indicating that contezolid exhibits more effective antibacterial activity than linezolid.³³ It was approved in China in June 2021 for complicated skin and skin structure infections. Its antibacterial mechanism, similar to linezolid, involves binding to a unique site near the peptidyl transferase center of the bacterial 23S rRNA within the 50S ribosomal subunit.³³ A key potential advantage of contezolid is its improved safety profile, characterized by minimal bone marrow suppression and low monoamine oxidase (MAO) inhibitory activity.³³ The primary PK/PD index associated with its antibacterial efficacy is a free-drug area under the concentration-time curve to minimum inhibitory concentration ratio (fAUC/MIC) of ≥ 2.3.

As contezolid has only recently been approved for clinical use, TDM data are scarce and currentlylimited to case reports. Consequently, no established therapeutic target range exists. Ma et al³⁴ evaluated the safety of contezolid in a 90-year-old patient with multidrug-resistant tuberculosis and renal insufficiency. During treatment with a contezolid-containing regimen (400 mg twice daily), the patient’s hemoglobin decreased significantly, though the clinicians attributed this to causes other than contezolid. Trough concentrations and levels at 2, 4, 6, and 10 hours post-dose were 3.88 μg/mL, 6.32 μg/mL, 8.99 μg/mL, 3.14 μg/mL, and 1.27 μg/mL, respectively. The time to peak concentration (T_max) was approximately 6 hours, with a C_max of 8.99 μg/mL.

To date, the majority of PK studies on contezolid have been conducted by the team of Professor Zhang Jing at Huashan Hospital, both prior to and following the drug’s market approval. The studied populations have primarily comprised healthy adults and patients with skin and soft tissue infections. However, data are still lacking for key subgroups, including obese patients, pediatric populations, burn patients, and the elderly patients.

In non-elderly patients, contezolid is rapidly absorbed after oral administration, with a T_max of approximately 2 hours, a C_max of ~26.5 mg/L, a t_1/2 of 1.91 hours, a CL of 8.83 L/h, an apparent volume of distribution (Vd) of 24.5 L, and an AUC_0−∞ of 96.9 mg·h/L. Contezolid exhibits considerable food effects on its AUC and C_max. Administration with a high-fat diet increased C_max by 133.4% (42.25 vs 18.1 mg/L) and AUC_0-∞ by 112.3% (141.33 vs 66.57 mg·h/L), while significantly decreasing t_1/2 by 53.3%.^33,35 PK/PD analyses indicate that the PK of contezolid are best described by a two-compartment model with first-order elimination. Thus, food enhances the oral bioavailability of contezolid. Patient type is a significant covariate for the volume of distribution of the central compartment (Vc), but not for CL. Body weight was a significant covariate for both CL and Vc.^36,37 Mild renal impairment, hepatic function, and albumin levels have no significant impact on the pharmacokinetics of contezolid.^36–38 Monte Carlo simulations indicate that an 800 mg bid dosage regimen can achieve satisfactory efficacy against MRSA.^33,36,37 Multiple studies have shown that contezolid is not associated with significant hematological toxicity. The most commonly reported drug-related adverse events include nausea, vomiting, dizziness, rash, and headache, all of which are of mild to moderate intensity, transient, and resolve spontaneously without intervention.^35,39,40

In elderly patients, studies indicate that AUC_ss of contezolid is similar to that in non-elderly patients (difference < 10%) after weight adjustment, and therefore no dose adjustment is required in the population aged 18 to 74 years.³⁶ Liu et al⁴¹ investigated the pharmacokinetics and safety of contezolid in Chinese patients aged ≥ 80 years and evaluated dosing regimens based on PK/PD principles. The steady-state plasma concentration-time profile following multiple doses was simulated using non-parametric superposition analysis (WinNonlin) to derive the PK parameters. Their study included 13 patients and demonstrated rapid absorption and dose-dependent increases in C_max and AUC_0–t in this super-elderly population. The plasma concentration of contezolid peaked at 2–3 h post-dose. Both C_max and AUC_0-t exhibited dose-dependent increases across regimens (400 mg q24h, 400 mg q12h, and 800 mg q12h). At a dosage of 800 mg q12h, super-elderly patients demonstrated comparable C_max (20.32 vs 26.45 mg/L), AUC_0-t (97.80 vs 90.38 h·mg/L), and CL (9.08 vs 10.20 L/h) values to those of healthy adults, but had prolonged T_max (2.67 vs 0.57 h) and shorter t_1/2 values (2.33 vs 4.84 h). Based on the PK/PD target, although 400 mg q12h might be effective against many G⁺ pathogens, Liu et al⁴¹ recommended the 800 mg q12h regimen due to the significant inter-individual variability and greater disease severity observed in this frail population, as it is expected to achieve higher treatment success without compromising safety. Future PK studies of contezolid in the elderly should aim for larger sample sizes and more extensive concentration data to develop a more robust PopPK model for precise dose optimization.

Tedizolid

Tedizolid is an oxazolidinone antibiotic with high potency against Gram-positive bacteria and currently prescribed in bacterial skin and skin-structure infections.^42,43 Tedizolid is administered as tedizolid phosphate, which is rapidly hydrolyzed by plasma phosphatases into the free active moiety tedizolid, which then binds to the 50S subunit of the bacterial ribosome, thereby inhibiting protein synthesis.⁴⁴ In in vitro susceptibility studies, tedizolid exhibited activity against most G⁺ bacteria (MIC ≤ 0.5 mg/L), was four-fold more potent than linezolid, and has the potential to treat pathogens less susceptible to linezolid.^45,46 In the Phase 2 clinical study, tedizolid MIC values ranged from 0.12 to 0.5 mg/L for S. aureus (MIC₉₀ of 0.25 mg/L) and did not exceed 0.25 and 0.12 mg/Lfor Streptococcus agalactiae and Streptococcus pyogenes, respectively.⁴⁷ The efficacy of tedizolid is most significantly correlated with fAUC/MIC. A pharmacokinetic-pharmacodynamic model-based analysis of tedizolid against enterococci using the hollow-fibre infection model indicated that bacteriostasis was observed only at a higher dose of 1200 mg/day over 120 h, and an fAUC/MIC of 80 related to stasis over 120 h.⁴⁸ In neutropenic mice, an fAUC/MIC of ~50 and ~20 resulted in bacteriostasis in thigh and pulmonary infection models, respectively, at 24 h.^49,50

In non-elderly patients, the PK parameters of tedizolid include a volume of distribution of approximately 100 L, plasma protein binding of 70–90%, and a t_1/2 of about 11 h, which is approximately twice that of linezolid. Therefore, Tedizolid can be administered once daily.⁵¹ The oral bioavailability of tedizolid is approximately 91%, and its PK parameters are comparable following oral or intravenous administration. Consequently, no dose adjustment is required when switching between these routes of administration.^40,52 No dosage adjustment is required for patients with renal dysfunction or hepatic impairment.⁵³ The penetration of tedizolid into alveolar epithelial lining fluid and alveolar macrophages is approximately 40-fold and 20-fold higher, respectively, than the free drug concentration in plasma.⁵⁴ Following multiple-dose administration of 200 mg tedizolid once daily under fasted conditions, the mean C_max and AUC_0-24 were approximately 1.8 mg/L and 22.5 mg·h/L, respectively. The key pharmacokinetic parameters were: C_max, 1.8 mg/L; C_min, 0.4 mg/L; T_max, 3 h; CL, 7.16 L/h; and Vz/F, 108 L.⁵¹ After a single intravenous injection of 100–400 mg of tedizolid phosphate, the C_max of tedizolid (1.2–5.1 mg/L) and the AUC (17.4–58.7 mg·h/L) both showed a dose-dependent increase.⁴⁰ Tedizolid is primarily excreted in the feces (approximately 69%) as an inactive sulfate metabolite, with approximately 10% excreted in the urine.⁵⁵

In elderly patients, previously published population PK analyses demonstrated that age had no significant effect on tedizolid plasma exposure.⁵⁶ Similarly, this analysis indicated that dose adjustment was not required based on sex, race, body weight, BMI, or renal or hepatic function.⁵⁶ Negishi et al⁵⁷ reported two cases (a 79-year-old and a 73-year-old female, cases 1 and 2) treated with tedizolid for osteoarthritis caused by Staphylococcus aureus. Treatment with a once-daily intravenous infusion of 200 mg tedizolid phosphate was successful. In case 1, synovial fluid and plasma tedizolid concentrations were 2.1 mg/L and 1.6 mg/L, respectively, yielding a synovial fluid-to-plasma concentration ratio of 130%. In case 2, the corresponding concentrations were 2.9 mg/L and 3.3 mg/L, with a ratio of 88%. These findings indicate that tedizolid penetrates effectively into bone and joint tissues. In an open-label Phase 1 study, 14 elderly (≥ 65 years) and 14 younger control (18–45 years) subjects each received a single oral dose of tedizolid phosphate 200 mg.⁵⁸ The PK parameters of tedizolid after a single dose were similar in both age groups. The t_1/2 of tedizolid was similar between groups: 12.3 h in the elderly group and 11.8 h in younger controls.⁵⁸ The data show greater variability of AUC_0-∞ and C_max parameters in the elderly group. Geometric mean ratios (elderly/younger controls) and corresponding 90% confidence intervals were: C_max, 1.091 (0.917–1.297); AUC_0-∞, 1.132 (0.954–1.343), suggesting similar plasma exposure between the groups.⁵⁸ The findings support that no dose adjustment is necessary in elderly patients. Tedizolid was well tolerated. A single mild adverse event was reported in an elderly subject, and no participants discontinued due to an adverse event.⁵⁸

Conclusion

Timely, accurate, and effective antibiotic therapy is the cornerstone of successful infection treatment in elderly patients. Given their frailty and complex pathophysiology, individualized and precise dosing strategies are imperative. In this context, TDM serves as the foundational tool, the development of PopPK models is the essential methodological process, and the ultimate goal is achieving MIPD. Demonstrating the benefit of MIPD in clinical trials presents unique challenges, characterized by an abundance of retrospective data but a paucity of prospective studies. Nonetheless, MIPD offers a valuable roadmap for clinicians navigating complex cases, and the dosing strategies it informs will continue to be refined and validated through clinical practice.