Target Therapeutic Ranges of Anti-MRSA Drugs, Linezolid, Tedizolid and Daptomycin, and the Necessity of TDM

Abstract

The target therapeutic ranges of vancomycin, teicoplanin, and arbekacin have been determined, and therapeutic drug monitoring (TDM) is performed in clinical practice. However, TDM is not obligatory for daptomycin, linezolid, or tedizolid. In this study, we examined whether TDM will be necessary for these 3 drugs in the future. There was no significant difference in therapeutic effects on acute bacterial skin and skin structure infection between linezolid and tedizolid by meta-analysis. Concerning the therapeutic effects on pneumonia, the rate of effectiveness after treatment with tedizolid was significantly lower than with linezolid. With respect to safety, the incidences of gastrointestinal adverse events and blood/lymphatic system disorders related to tedizolid were significantly lower than those related to linezolid. Linezolid exhibits potent therapeutic effects on pneumonia, but the appearance of adverse reactions is indicated as a problem. There was a dose-dependent decrease in the platelet count, and the target trough concentration (C_trough) was estimated to be 4–6 or 2–7 µg/mL in accordance with the patient’s condition. The efficacy of linezolid may be obtained while minimizing the appearance of adverse reactions by performing TDM. The target therapeutic range of tedizolid cannot be achieved in immunocompromised or severe patients. Therefore, we concluded that TDM was unnecessary, considering step-down therapy with oral drugs, use in non-severe patients, and high-level safety. Concerning daptomycin, high-dose administration is necessary to achieve an area under the curve (AUC) of ≥666 as an index of efficacy. To secure its safety, C_trough (<20 µg/mL) monitoring is important. Therefore, TDM is necessary.

1. INTRODUCTION

In Japan, 6 drugs for methicillin-resistant Staphylococcus aureus (MRSA) infection are commercially available as of April 2022. Concerning vancomycin, teicoplanin, and arbekacin, therapeutic drug monitoring (TDM) is recommended, and clinical practice guidelines were published for each drug.^1–4) The therapeutic ranges of these drugs are presented in Table 1. The therapeutic ranges were established based on pharmacokinetics and pharmacodynamics analyses. Several studies indicated that the efficacy and safety of vancomycin were correlated with the area under the curve/minimum inhibitory concentration (AUC/MIC) and AUC, respectively.^5–7) Its target therapeutic range was established as an AUC of 400–600 µg*h/mL based on a systematic review and meta-analyses.⁸⁾ It was reported that the efficacy and safety of teicoplanin were correlated with the AUC/MIC and peak concentration (C_peak)/MIC through in vivo pharmacokinetics/pharmacodynamics (PK/PD) analyses.⁹⁾ Some clinical studies showed that an AUC of ≥750 µg*h/mL¹⁰⁾ and AUC/MIC of ≥900¹¹⁾ were correlated with bactericidal effects. However, few studies have evaluated the efficacy or safety of teicoplanin on the basis of AUC; these should be examined in the future. In clinical practice, TDM is performed based on the trough concentration (C_trough). The relationship of C_trough with efficacy and safety is being investigated. The target therapeutic range of teicoplanin was established as a C_trough of 15–30 µg/mL based on a systematic review and meta-analyses.¹²⁾ In addition, a C_trough of 20–40 µg/mL is recommended for patients with complicated MRSA infections such as septic arthritis, osteomyelitis, and endocarditis.^13,14)

Table 1. Target Therapeutic Ranges of Vancomycin, Teicoplanin, and Arbekacin

Anti-MRSA drugs	Target therapeutic ranges
Vancomycin	AUC 400–600 µg*h/mL
Teicoplanin	Ctrough 15–30 µg/mL, in complicated infections 20–40 µg/mL
Arbekacin	Cpeak ≥15 µg/mL, Ctrough <1–2 µg/mL

A study indicated that ≥80% of MRSA-infected patients responded to arbekacin when the C_peak/MIC value was ≥8.¹⁵⁾ According to surveys in Japan, the MIC₉₀ of arbekacin for MRSA was 2 µg/mL.^16,17) Therefore, a C_peak of ≥15 µg/mL is targeted as the therapeutic range. On the other hand, a systematic review and meta-analyses showed that the incidence of acute kidney injury was low when the C_trough was <2 µg/mL.¹⁸⁾ In addition, it was indicated that the incidences of nephropathy at trough concentrations of 1, 2, and 5 µg/mL were 2.5, 5.2, and 13.1%, respectively.¹⁹⁾ A C_trough of <1–2 µg/mL is recommended.

Thus, the target therapeutic ranges of vancomycin, teicoplanin, and arbekacin have been determined, and TDM is performed in clinical practice. However, TDM is not obligatory for daptomycin, linezolid, or tedizolid. In this study, we examined whether TDM will be necessary for these 3 drugs in the future. In addition, we investigated the target therapeutic ranges of these drugs.

2. THE EFFICACY AND SAFETY OF LINEZOLID VERSUS TEDIZOLID

Oxazolidinone antimicrobial drugs include linezolid and tedizolid. To examine differences between the two drugs, a systematic review and meta-analyses regarding their efficacy and safety were conducted. We performed a literature search in 4 electronic databases: PubMed, Web of Science, The Cochrane Library, and ClinicalTrials.gov on May 28, 2020. As search terms, we selected “Gram-positive bacteria,” “Staphylococcus aureus,” “methicillin-resistant Staphylococcus aureus,” “acute bacterial skin and skin structure infection,” “skin and soft tissue infection,” “pneumonia,” “tedizolid,” “linezolid,” and 19 other terms (Supplementary Table S1). The criteria for article screening/selection included comparative studies in which tedizolid or linezolid was administered to patients with Gram-positive bacterial infection, and the efficacy and safety were evaluated. Two persons independently conducted all work operations from article extraction until analysis. When the results differed, a third person evaluated them. Only academic articles written in English were adopted, and the year of publication was not limited. The extracted data were analyzed using the Review Manager for Windows (RevMan, Version 5.4.1, Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2020), and forest plots were prepared. We used the Mantel–Haenszel, random-effects model to calculate the risk ratios (RRs) and 95% confidence intervals (95% CIs). Between-study heterogeneity was quantified using the I² statistics.

Overall, 391 articles were extracted. Finally, we used 5 randomized controlled trials and 1 prospective observational study (total: 6 studies) for meta-analysis^20–25) (Fig. 1, Table 2). With respect to the efficacy, when comparing the rate of effectiveness after treatment among patients with Gram-positive bacterial infection, there was no significant difference between tedizolid and linezolid (RR = 0.97, 95%CI = 0.94–1.01, p = 0.10, Fig. 2A). A subgroup analysis involving subjects with acute bacterial skin and skin structure infection (ABSSSI) alone also showed that there was no significant difference between the two drugs (RR = 0.98, 95%CI = 0.94–1.02, p = 0.28, Fig. 2B). Their effects on pneumonia were investigated only in 1 randomized controlled trial. It was indicated that the rate of effectiveness after treatment with tedizolid was significantly lower than with linezolid (RR = 0.88, 95%CI = 0.78–0.99, p = 0.04, Fig. 2C). In addition, subgroup analyses with respect to bacterial strains were conducted. There were no significant differences in the rates of effectiveness for Gram-positive bacteria, S. aureus, methicillin-susceptible S. aureus (MSSA), MRSA, Streptococcus anginosus, and Streptococcus pyogenes between the two groups (Figs. 3A–F). Therefore, it was shown that the efficacy of tedizolid was similar to that of linezolid in patients with ABSSSI, and that linezolid was more effective than tedizolid in those with pneumonia.

Table 2. Characteristics of the Included Studies in the Present Meta-analyses

Study	Design	Period	Target infection	Number of patients		Dosage regimen
				TZD	LZD	TZD	LZD
Prokocimer 2013	Randomized, double-blind, multicenter, multinational, non-inferior trial	2010–2011	ABSSSI	332	335	Oral 200 mg daily, 6 d	Oral 600 mg twice daily, 10 d
Moran 2014	Randomized, double-blind, multicenter, multinational, non-inferior trial	2011–2013	ABSSSI	332	334	Intravenous 200 mg daily, 6 d with optional step-down	Intravenous 600 mg twice daily, 10 d with optional step-down
Mikamo 2018	Prospective, randomized, open-label, multicenter trial	2013–2016	ABSSSI	84	41	Intravenous/oral 200 mg daily, 6 d	Intravenous/oral 600 mg twice daily, 10 d
Bayer 2019	Open-label, prospective, multi-center, non-interventional, observational, parallel cohort study	2016–2018	ABSSSI	86	22	Intravenous/oral 200 mg daily	Intravenous/oral 600 mg twice daily
Lv 2019	Randomized, double-blind, multicenter, non-inferior trial	2014–2016	ABSSSI	300	298	Intravenous/oral 200 mg daily, 6 d	Intravenous/oral 600 mg twice daily, 10 d
Wunderink 2019	Randomized, double-blind, multicenter, multinational, non-inferior trial	2014–2018	Pneumonia	366	360	Intravenous 200 mg daily, 6 or 14 d for concurrent bacteremia	Intravenous 600 mg twice daily, 10 or 14 d for concurrent bacteremia

TZD: tedizolid, LZD: linezolid, ABSSSI: acute bacterial skin and skin structure infection.

Fig. 1. Flow Chart of Selection Process in the Meta-analyses

Fig. 2. Forest Plot Comparing Efficacy between Tedizolid (TZD) and Linezolid (LZD) among Patients with Gram-Positive Bacteria Infection (Including Suspected Patients)

(A) All infection, (B) acute bacterial skin and skin structure infection (ABSSSI), and (C) pneumonia.

Fig. 3. Forest Plot of Subgroup Analyses Comparing Efficacy between Tedizolid (TZD) and Linezolid (LZD) among Patients with Gram-Positive Bacteria Infection Stratified by Strains

(A) Gram-positive bacteria, (B) Staphylococcus aureus, (C) methicillin-susceptible Staphylococcus aureus (MSSA), (D) methicillin-resistant Staphylococcus aureus (MRSA), (E) Streptococcus anginosus, and (F) Streptococcus pyogenes.

Next, to evaluate the safety of these drugs, subgroup analyses regarding gastrointestinal adverse events and blood/lymphatic system disorders were conducted. The incidence of gastrointestinal adverse events related to tedizolid was significantly lower than that related to linezolid (RR = 0.75, 95%CI = 0.60–0.94, p = 0.01, Fig. 4A). With respect to symptoms, the incidences of nausea and diarrhea related to tedizolid were significantly lower than those related to linezolid (RR = 0.72, 95%CI = 0.54–0.96, Fig. 4B and p = 0.03, RR = 0.72, 95%CI = 0.54–0.97, p = 0.03, Fig. 4D). The incidence of blood and lymphatic system disorders related to tedizolid was significantly lower than that related to linezolid (RR = 0.58, 95%CI = 0.36–0.94, p = 0.03, Fig. 5A). With respect to symptoms, the incidences of decreases in the platelet and neutrophil counts related to tedizolid were significantly lower than those related to linezolid (RR = 0.57, 95%CI = 0.39–0.82, p = 0.003, Fig. 5C and RR = 0.38, 95%CI = 0.18–0.77, p = 0.008, Fig. 5D). Therefore, it was shown that tedizolid was safer than linezolid.

Fig. 4. Forest Plot Comparing the Rate of Gastrointestinal Adverse Events between Tedizolid (TZD) and Linezolid (LZD)

(A) All, (B) nausea, (C) vomiting, (D) diarrhea, and (E) constipation.

Fig. 5. Forest Plot Comparing the Rate of Blood and Lymphatic System Disorders between Tedizolid (TZD) and Linezolid (LZD)

(A) All, (B) anemia, (C) platelet count decrease, and (D) neutrophil count decrease.

3. THERAPEUTIC RANGE OF LINEZOLID AND NECESSITY OF TDM

The above meta-analysis indicated that linezolid was more effective than tedizolid in patients with pneumonia (Fig. 2C). Kato et al. clarified that linezolid was significantly more effective than vancomycin in patients with proven-MRSA-related pneumonia through a meta-analysis.²⁶⁾ Therefore, linezolid is a key drug for MRSA pneumonia. On the other hand, the incidence of adverse reactions was significantly higher (Figs. 4, 5). In particular, the incidence of a decrease in the platelet count is reportedly 8 to 68%.²⁷⁾ Concerning the route of linezolid excretion, it is described in the package inserts that 30% of the dose is excreted in urine as an unchanged compound, and that 40 and 10% of the remainder are excreted in urine as PNU-142586 and PNU-142300, respectively, through non-enzymatic oxidation reactions. With respect to the dosage and administration in adults, 600 mg/session of linezolid should be administered twice a day regardless of liver/kidney functions. However, a study indicated that the incidence of a decrease in the platelet count in patients with renal dysfunction was significantly higher than in those with normal kidney function, and that a creatinine clearance of <60 mL/min was a risk factor for a decrease in the platelet count.²⁸⁾ In addition, it was reported that linezolid clearance was correlated with creatinine clearance, and that there was a decrease in the platelet count in high-C_trough or -AUC patients.²⁹⁾ Briefly, a linezolid-related decrease in the platelet count is dose-dependent; if its threshold becomes clear, linezolid may be used while avoiding a decrease in the platelet count.

Several studies reported the target therapeutic range of linezolid. In 3 studies presenting the median C_trough based on the presence or absence of a decrease in the platelet count, the median C_trough values in patients with a decrease in the platelet count were 12.9 (n = 6), 8.8 (n = 31), and 20.4 (n = 21) µg/mL, respectively. In those without such a decrease, the values were 4.2 (n = 72), 2.9 (n = 39), and 4.9 (n = 31) µg/mL, respectively.^30–32) Four studies presented the threshold of C_trough at which there was a decrease in the platelet count; the values were 6.5 (n = 35), 7.5 (n = 30), 7.9 (n = 84), and 8.2 (n = 44) µg/mL, respectively.^27,33–35) Based on these results, its upper limit may be 6 to 7 µg/mL. Concerning the efficacy, an AUC of ≥160–200 µg*h/mL is required in the case of MIC₉₀ = 2 µg/mL³⁶⁾ when adopting a target PK/PD parameter value of linezolid, that is, an AUC/MIC of ≥80–100, as an index. Based on this, the target C_trough was determined. Pea et al. targeted a C_trough of ≥2 µg/mL to achieve an AUC of ≥160 µg*h/mL.³⁷⁾ Matsumoto et al. targeted a C_trough of ≥3.6 µg/mL to achieve an AUC of ≥200 µg*h/mL.²⁷⁾ Therefore, from the viewpoint of efficacy and safety, 2–7 µg/mL is recommended as the therapeutic range of linezolid in accordance with the patient’s condition, targeting a C_trough of 4–6 µg/mL. Considering the dose for achieving this target C_trough based on the results of pharmacokinetics analysis involving a Japanese population,²⁷⁾ it is estimated that a dose for patients with a creatinine clearance of 30, 60, or 90 mL/min may be 1200 mg/d on the first day, and that maintenance doses may be 600, 800, and 1000 mg/d, respectively.

Few studies have examined the relationship between the appearance of a decrease in the platelet count and AUC. Boak et al. reported that the mean AUC in the presence of a decrease in the platelet count was 243 (n = 10) µg*h/mL, whereas that in the absence of such a decrease was 213 (n = 28) µg*h /mL.³⁸⁾ Pea et al. indicated that the threshold for a decrease in the platelet count was 281 (n = 35) µg*h /mL.³³⁾ Both the number of reports and that of patients are still small, and future examination is necessary to determine the target AUC.

Linezolid is a first-choice drug for MRSA-related pneumonia, but adverse reactions frequently appear; therefore, administration is discontinued in many cases. On the other hand, the relationship between the appearance of adverse reactions and C_trough has been demonstrated through clinical studies. A target C_trough can be determined, as described above. Therefore, TDM may become obligatory for linezolid in the future, and C_trough-guided monitoring may be conducted.

4. THERAPEUTIC RANGE OF TEDIZOLID AND NECESSITY OF TDM

It was shown that the efficacy of tedizolid for ABSSSI was similar to that of linezolid (Fig. 2B), and that the incidence of adverse reactions related to tedizolid was lower than that related to linezolid (Figs. 4, 5). Concerning the target PK/PD parameter value of tedizolid, in vivo PK/PD studies with murine neutropenic thigh infection or pneumonia models indicated that unbound fraction (f) AUC/MIC values to obtain bacteriostatic effects were approximately 50 and 20, respectively.^39,40) In a clinical study, the AUC_24 h after oral administration was 20.7 µg*h/mL, and the AUC_24 h after intravenous administration was 24.4 µg*h/mL.⁴¹⁾ As the protein binding ratio of tedizolid is approximately 80%, the fAUC values are 4.1 and 4.9 µg*h/mL, respectively. The MIC₉₀ of tedizolid is 0.25 µg/mL,³⁶⁾ and the fAUC/MIC was calculated as 16.4 and 19.6, respectively; the target PK/PD parameter value cannot be achieved. Briefly, sufficient effects may not be obtained in immunocompromised patients. This may be the reason why the efficacy rate of tedizolid for pneumonia was significantly lower than that of linezolid (Fig. 2C). On the other hand, an in vivo PK/PD study was conducted using immunocompetent mice. The target PK/PD parameter value was low, indicating that it can be achieved at a standard dose.⁴²⁾ Usually, in vivo PK/PD studies are conducted using a murine neutropenic thigh infection model. A dosage at which the target PK/PD parameter value obtained in the study can be achieved is recommended. Therefore, drugs other than tedizolid should be used in immunocompromised or severe patients, and the use of tedizolid is recommended when performing step-down therapy with oral drugs in immunocompetent patients with a stable condition. Actually, according to a study investigating reasons for the use of tedizolid, switch therapy related to the appearance of adverse reactions to pretreatment or drug interactions accounted for 92%.⁴²⁾ In addition, the study indicated the appearance of nausea and vomiting in 3 of 51 patients treated with tedizolid for a long period (median: 29 d), demonstrating that this drug is highly safe.⁴³⁾

Infectious endocarditis and osteomyelitis are representative diseases requiring long-term administration. Chan et al. examined the effects of anti-MRSA drugs using a rabbit model of aortic valve endocarditis caused by MRSA.⁴⁴⁾ Tedizolid was significantly less effective than daptomycin, and there was no significant difference in comparison with vancomycin. Using a rat endocarditis model, Singh et al. compared the efficacy between a group in which monotherapy with tedizolid or daptomycin was performed for 5 d and a group in which tedizolid was administered for 2 d as step-down therapy after monotherapy with daptomycin for 3 d.⁴⁵⁾ The efficacy of treatment with tedizolid for 5 d was similar to that in the non-treated group. However, treatment with daptomycin for 5 d and step-down therapy were significantly more effective than the absence of treatment. Briefly, as an initial drug, tedizolid may not be effective for infectious endocarditis, but it may be useful for step-down therapy. On the other hand, Smith et al. examined the effects of monotherapy with daptomycin and combination therapy with daptomycin and tedizolid using an in vitro model of simulated endocardial vegetations.⁴⁶⁾ Interestingly, combination therapy with daptomycin and tedizolid was significantly less effective than monotherapy with daptomycin. In other words, the simultaneous administration of daptomycin and tedizolid is not recommended. Park et al. indicated that monotherapy with tedizolid was significantly more effective than the absence of treatment using a rat MRSA foreign-body-associated osteomyelitis model.⁴⁷⁾ However, it is necessary to establish further evidence for the clinical application of tedizolid as a drug for infectious endocarditis or osteomyelitis.

Based on previous evidence, tedizolid may be used in non-severe patients in whom immunity is maintained, and this drug is highly safe; therefore, TDM may be unnecessary.

5. THERAPEUTIC RANGE OF DAPTOMYCIN AND NECESSITY OF TDM

The urinary unchanged compound excretion rate of daptomycin is approximately 70%, and its protein binding ratio is approximately 90%. The volume of distribution is 0.1 L/kg in healthy adults and 0.16 L/kg in patients with infection. In an in vivo PK/PD study of daptomycin, target PK/PD parameter values for S. aureus were calculated using a murine neutropenic thigh infection models. It was indicated that the total concentration AUC/MIC and C_peak/MIC were ≥666 and ≥129, respectively, when establishing the f value as 10%, with an fAUC/MIC of ≥66.6 and fC_peak/MIC of ≥12.9.⁴⁸⁾ Falcone et al. investigated 35 patients with Gram-positive coccal infection, and reported that an AUC/MIC of <666 was a risk factor for failure in treatment.⁴⁹⁾ They demonstrated the usefulness of achieving an AUC/MIC of ≥666 in clinical practice. Galar et al. evaluated the relationship between the therapeutic effects of daptomycin and C_peak or C_trough in 63 patients, and reported that a C_trough of <3.18 µg/mL significantly reduced the therapeutic effects.⁵⁰⁾ The usefulness of C_peak must be further examined in the future. A survey in Japan from 2018 until 2019 showed that the MIC₉₀ of daptomycin was 1 µg/mL.⁵¹⁾ Therefore, when the MIC is 1 µg/mL, the target AUC is ≥666 µg*h/mL as an index of efficacy.

On the other hand, a representative adverse reaction to daptomycin is an increase in the creatine phosphokinase (CPK) level. Bhavnani et al. reported that the risk of the CPK level reaching >5 × upper limit of normal (ULN) significantly increased at a C_trough of ≥24.3 µg/mL.⁵²⁾ Yamada et al. indicated that the risk of the CPK level exceeding the ULN significantly increased at a C_trough of ≥19.5 µg/mL.⁵³⁾ Risk factors for an increase in the CPK level related to daptomycin include combination therapy with statins (especially fat-soluble statins), combination therapy with antihistamines, obesity, a history of rhabdomyolysis, and being African American in addition to C_trough.^54–61) Samura et al. retrospectively investigated the influence of the estimated blood concentration of daptomycin and other risk factors, and estimated the probability of an increase in the CPK level. According to their study, the probability of an increase in the CPK level was approximately 15% when daptomycin was combined with a statin or antihistamine in a setting of 10 ≤ C_trough < 20 µg/mL, or when the C_trough was ≥20 µg/mL. It was approximately 45% when daptomycin was combined with a statin or antihistamine at a C_trough of ≥20 µg/mL.⁵⁶⁾ Therefore, a C_trough of ≥20 µg/mL is a risk factor for an increase in the CPK level. Even when the C_trough is <20 µg/mL, the possibility that combination therapy with statins or antihistamines may increase the CPK level must be considered.

It was reported that once-a-day administration at 6 mg/kg decreased the probability that an AUC of ≥666 µg*h/mL may be achieved.^49,62,63) Therefore, to achieve an AUC of ≥666 µg*h/mL, high-dose once-a-day administration at 8–10 mg/kg is necessary. However, Lai et al. investigated the safety of administration at a daily dose of <8 or ≥8 mg/kg in 61 patients treated with daptomycin. They reported that there was no patient with a CPK level of >1000 IU/L in the <8 mg/kg group, whereas the rate of such patients was 16.7% in the ≥8 mg/kg group, being significantly higher.⁶⁴⁾ Moise et al. compared the therapeutic effects on MRSA infection between patients with a CLcr of 30–50 mL/min and those with a value of <30 mL/min, and indicated that a CLcr of <30 mL/min was a significant risk factor for an increase in the mortality rate,⁶⁵⁾ suggesting that a dose of 6 mg/kg administered every two days is insufficient for patients with a CLcr of <30 mL/min. Samura et al. conducted population pharmacokinetics analysis involving 25 patients aged ≥65 years, and indicated that an AUC of ≥666 µg*h/mL could not be achieved by every-two-days administration at 6 mg/kg to patients with an eGFRcys of <30 mL/min.⁶⁶⁾ In patients with severe renal impairment (especially elderly patients), the dose should be determined in reference to the dosing nomogram proposed by Samura et al. However, it must be considered that high-dose administration may increase the CPK level.

From the viewpoint of efficacy, high-dose administration is necessary to achieve an AUC of ≥666 µg*h/mL. In this case, daptomycin may be safely used by maintaining its blood concentration so that the C_trough may be <20 µg/mL. However, when daptomycin is combined with statins or antihistamines, the CPK level may increase even in a setting of 10 ≤ C_trough < 20 µg/mL; for combination therapy with these drugs, the use of other drugs should be considered. Falcone et al. evaluated pharmacokinetic parameters in patients with severe infection, and clarified that there were daptomycin-treated patients with augmented renal clearance (ARC).⁶⁷⁾ Cojutti et al. conducted population pharmacokinetics analysis involving patients with hematological malignancies, and reported that ARC was noted especially in patients with acute myelocytic leukemia.⁶⁸⁾ Therefore, ARC may decrease the blood concentration of daptomycin in patients with severe infection or hematological malignancies, and the AUC should be evaluated. To secure the efficacy and safety of daptomycin, TDM may be useful.

Considering the future of TDM, for drugs with a high protein binding ratio, measurement of non-protein-binding drug concentrations is ideal. Grégoire et al. measured the total concentration of daptomycin and non-protein-binding drug concentration in severe infection patients with renal dysfunction, and reported that the AUC reduced with an increase in the f value, whereas there was no influence on the fAUC.⁶⁹⁾ Samura et al. indicated that there was a negative correlation between the f value and serum albumin level, whereas the former was positively correlated with the blood urea nitrogen and fasting blood glucose levels.⁶⁶⁾ Briefly, the total-concentration-based AUC is not correlated with the fAUC in some cases. When performing TDM for daptomycin, non-protein-binding drug concentrations should be measured. In the future, a simple method of measuring non-protein-binding drug concentrations should be developed.

6. CONCLUSION

We investigated the therapeutic ranges of 3 drugs for which TDM is not obligatory among anti-MRSA drugs and the necessity of TDM. It was shown that linezolid could be safely used by performing TDM based on the C_trough. Concerning tedizolid, we concluded that TDM was unnecessary, considering that this drug is used for step-down therapy with oral drugs or in non-severe patients, and that it is highly safe. Concerning daptomycin, high-dose administration is necessary to achieve a target PK/PD parameter value. In addition, to secure the safety, C_trough monitoring is important; therefore, TDM is necessary.

For the future realization of TDM for linezolid and daptomycin, it is necessary to establish a simple method of measuring blood drug concentrations and pharmacokinetics-analyzing software that facilitates administration planning.

Conflict of Interest

K. Matsumoto received Grant support from Meiji Seika Pharma Co., Ltd. and Sumitomo Pharma Co., Ltd., and payment for lectures from Meiji Seika Pharma Co. The other authors have no conflict of interest to declare.

Supplementary Materials

This article contains supplementary materials.

REFERENCES

• 1) Matsumoto K, Takesue Y, Ohmagari N, Mochizuki T, Mikamo H, Seki M, Takakura S, Tokimatsu I, Takahashi Y, Kasahara K, Okada K, Igarashi M, Kobayashi M, Hamada Y, Kimura M, Nishi Y, Tanigawara Y, Kimura T. Practice guidelines for therapeutic drug monitoring of vancomycin: a consensus review of the Japanese Society of Chemotherapy and the Japanese Society of Therapeutic Drug Monitoring. J. Infect. Chemother., 19, 365–380 (2013).
• 2) Matsumoto K, Oda K, Shoji K, Hanai Y, Takahashi Y, Fujii S, Hamada Y, Kimura T, Mayumi T, Ueda T, Nakajima K, Takesue Y. Clinical practice guideline for therapeutic drug monitoring of vancomycin in the framework of model-informed precision dosing: a consensus review by the Japanese Society of Chemotherapy and the Japanese Society of Therapeutic Drug Monitoring. Pharmaceutics, 14, 489 (2022).
• 3) Hanai Y, Takahashi Y, Niwa T, Mayumi T, Hamada Y, Kimura T, Matsumoto K, Fujii S, Takesue Y. Clinical practice guidelines for therapeutic drug monitoring of teicoplanin: a consensus review by the Japanese Society of Chemotherapy and the Japanese Society of Therapeutic Drug Monitoring. J. Antimicrob. Chemother., 77, 869–879 (2022).
• 4) Okada K, Kimura T, Mikamo H, Kasahara K, Seki M, Takakura S, Tokimatsu I, Ohmagari N, Takahashi Y, Matsumoto K, Igarashi M, Kobayashi M, Hamada Y, Mochizuki T, Kimura M, Nishi Y, Tanigawara Y, Takesue Y. Clinical practice guidelines for therapeutic drug monitoring of arbekacin: a consensus review of the Japanese Society of Chemotherapy and the Japanese Society of Therapeutic Drug Monitoring. J. Infect. Chemother., 20, 1–5 (2014).
• 5) Rybak MJ. The pharmacokinetic and pharmacodynamic properties of vancomycin. Clin. Infect. Dis., 42 (Suppl. 1), S35–S39 (2006).
• 6) Pais GM, Avedissian SN, O’Donnell JN, Rhodes NJ, Lodise TP, Prozialeck WC, Lamar PC, Cluff C, Gulati A, Fitzgerald JC, Downes KJ, Zuppa AF, Scheetz MH. comparative performance of urinary biomarkers for vancomycin-induced kidney injury according to timeline of injury. Antimicrob. Agents Chemother., 63, e00079-19 (2019).
• 7) Avedissian SN, Pais GM, O’Donnell JN, Lodise TP, Liu J, Prozialeck WC, Joshi MD, Lamar PC, Becher L, Gulati A, Hope W, Scheetz MH. Twenty-four hour pharmacokinetic relationships for intravenous vancomycin and novel urinary biomarkers of acute kidney injury in a rat model. J. Antimicrob. Chemother., 74, 2326–2334 (2019).
• 8) Tsutsuura M, Moriyama H, Kojima N, Mizukami Y, Tashiro S, Osa S, Enoki Y, Taguchi K, Oda K, Fujii S, Takahashi Y, Hamada Y, Kimura T, Takesue Y, Matsumoto K. The monitoring of vancomycin: a systematic review and meta-analyses of area under the concentration-time curve-guided dosing and trough-guided dosing. BMC Infect. Dis., 21, 153 (2021).
• 9) Watanabe E, Matsumoto K, Ikawa K, Yokoyama Y, Shigemi A, Enoki Y, Umezaki Y, Nakamura K, Ueno K, Terazono H, Morikawa N, Takeda Y. Pharmacokinetic/pharmacodynamic evaluation of teicoplanin against Staphylococcus aureus in murine thigh infection model. J. Glob. Antimicrob. Resist., 24, 83–87 (2021).
• 10) Kanazawa N, Matsumoto K, Ikawa K, Fukamizu T, Shigemi A, Yaji K, Shimodozono Y, Morikawa N, Takeda Y, Yamada K. An initial dosing method for teicoplanin based on the area under the serum concentration time curve required for MRSA eradication. J. Infect. Chemother., 17, 297–300 (2011).
• 11) Matsumoto K, Watanabe E, Kanazawa N, Fukamizu T, Shigemi A, Yokoyama Y, Ikawa K, Morikawa N, Takeda Y. Pharmacokinetic/pharmacodynamic analysis of teicoplanin in patients with MRSA infections. Clin. Pharmacol., 8, 15–18 (2016).
• 12) Hanai Y, Takahashi Y, Niwa T, Mayumi T, Hamada Y, Kimura T, Matsumoto K, Fujii S, Takesue Y. Optimal trough concentration of teicoplanin for the treatment of methicillin-resistant Staphylococcus aureus infection: a systematic review and meta-analysis. J. Clin. Pharm. Ther., 46, 622–632 (2021).
• 13) Wilson AP. Clinical pharmacokinetics of teicoplanin. Clin. Pharmacokinet., 39, 167–183 (2000).
• 14) Gemmell CG, Edwards DI, Fraise AP, Gould FK, Ridgway GL, Warren RE. Guidelines for the pro-phylaxis and treatment of methicillin-resistant Staphylococcus aureus (MRSA) infections in the UK. J. Antimicrob. Chemother., 57, 589–608 (2006).
• 15) Aikawa N, Kohno S, Kaku M, Watanabe A, Yamaguchi K, Tanigawara Y. An open clinical study of arbekacin 200 mg q.d.in patients infected with methicillin-resistant Staphylococcus aureus (MRSA)—A clinical pharmacology study. Jpn. J. Chemother., 56, 299–312 (2008).
• 16) Hanaki H, Cui L, Ikeda-Dantsuji Y, et al. Antibiotic susceptibility survey of blood–borne MRSA isolates in Japan from 2008 through 2011. J. Infect. Chemother., 20, 527–534 (2014).
• 17) Yanagihara K, Matsumoto T, Tokimatsu I, et al. Nationwide surveillance of bacterial respiratory pathogens conducted by the surveillance committee of japanese society of chemotherapy, the japanese association for infectious diseases, and the japanese society for clinical microbiology in 2016: general view of the pathogens’ antibacterial susceptibility. J. Infect. Chemother., 26, 873–881 (2020).
• 18) Oda K, Fujii S, Yamamoto T, Mayumi T, Takesue Y. Evaluation of once-daily dosing and target concentrations in therapeutic drug monitoring for arbekacin: a meta-analysis. J. Infect. Chemother., 27, 26–31 (2021).
• 19) Sato R, Tanigawara Y, Kaku M, Aikawa N, Shimizu K. Pharmacokinetic-pharmacodynamic relationship of arbekacin for treatment of patients infected with methicillin-resistant Staphylococcus aureus. Antimicrob. Agents Chemother., 50, 3763–3769 (2006).
• 20) Prokocimer P, De Anda C, Fang E, Mehra P, Das A. Tedizolid phosphate vs. linezolid for treatment of acute bacterial skin and skin structure infections: the ESTABLISH-1 randomized trial. JAMA, 309, 559–569 (2013).
• 21) Moran GJ, Fang E, Corey GR, Das AF, De Anda C, Prokocimer P. Tedizolid for 6 days versus linezolid for 10 days for acute bacterial skin and skin-structure infections (ESTABLISH-2): a randomised, double-blind, phase 3, non-inferiority trial. Lancet Infect. Dis., 14, 696–705 (2014).
• 22) Mikamo H, Takesue Y, Iwamoto Y, Tanigawa T, Kato M, Tanimura Y, Kohno S. Efficacy, safety and pharmacokinetics of tedizolid versus linezolid in patients with skin and soft tissue infections in Japan—results of a randomised, multicentre phase 3 study. J. Infect. Chemother., 24, 434–442 (2018).
• 23) Lv X, Alder J, Li L, O’Riordan W, Rybak MJ, Ye H, Zhang R, Zhang Z, Zhu X, Wilcox MH. Efficacy and safety of tedizolid phosphate versus linezolid in a randomized phase 3 trial in patients with acute bacterial skin and skin structure infection. Antimicrob. Agents Chemother., 63, e02252-18 (2019).
• 24) “Bayer 2019: Sivextro in acute bacterial skin and skin structure infection (ABSSSI) in hospitalized patients. A global observational study (DART). NCT02991131.”: ‹https://clinicaltrials.gov/ct2/show/study/NCT02991131?term=Bayer%E3%80%80linezolid&draw=2&rank=2›, accessed 30 October, 2022.
• 25) “Wunderink 2019: Tedizolid phosphate (TR-701 FA, MK-1986) vs. linezolid for the treatment of nosocomial pneumonia (MK-1986-002). NCT02019420.”: ‹https://clinicaltrials.gov/ct2/show/NCT02019420?cond=linezolid++tedizolid&draw=2&rank=2›, accessed 30 October, 2022.
• 26) Kato H, Hagihara M, Asai N, Shibata Y, Koizumi Y, Yamagishi Y, Mikamo H. Meta-analysis of vancomycin versus linezolid in pneumonia with proven methicillin-resistant Staphylococcus aureus. J. Glob. Antimicrob. Resist., 24, 98–105 (2021).
• 27) Matsumoto K, Shigemi A, Takeshita A, Watanabe E, Yokoyama Y, Ikawa K, Morikawa N, Takeda Y. Analysis of thrombocytopenic effects and population pharmacokinetics of linezolid: a dosage strategy according to the trough concentration target and renal function in adult patients. Int. J. Antimicrob. Agents, 44, 242–247 (2014).
• 28) Matsumoto K, Takeda Y, Takeshita A, Fukunaga N, Shigemi A, Yaji K, Shimodozono Y, Yamada K, Ikawa K, Morikawa N. Renal function as a predictor of linezolid-induced thrombocytopenia. Int. J. Antimicrob. Agents, 33, 98–99 (2009).
• 29) Matsumoto K, Takeshita A, Ikawa K, Shigemi A, Yaji K, Shimodozono Y, Morikawa N, Takeda Y, Yamada K. Higher linezolid exposure and higher frequency of thrombocytopenia in patients with renal dysfunction. Int. J. Antimicrob. Agents, 36, 179–181 (2010).
• 30) Morata L, Cuesta M, Rojas JF, Rodriguez S, Brunet M, Casals G, Cobos N, Hernandez C, Martínez JA, Mensa J, Soriano A. Risk factors for a low linezolid trough plasma concentration in acute infections. Antimicrob. Agents Chemother., 57, 1913–1917 (2013).
• 31) Dong HY, Xie J, Chen LH, Wang TT, Zhao YR, Dong YL. Therapeutic drug monitoring and receiver operating characteristic curve prediction may reduce the development of linezolid-associated thrombocytopenia in critically ill patients. Eur. J. Clin. Microbiol. Infect. Dis., 33, 1029–1035 (2014).
• 32) Luque S, Muñoz-Bermudez R, Echeverría-Esnal D, Sorli L, Campillo N, Martínez-Casanova J, González-Colominas E, Álvarez-Lerma F, Horcajada JP, Grau S, Roberts JA. Linezolid dosing in patients with liver cirrhosis: standard dosing risk toxicity. Ther. Drug Monit., 41, 732–739 (2019).
• 33) Pea F, Viale P, Cojutti P, Del Pin B, Zamparini E, Furlanut M. Therapeutic drug monitoring may improve safety outcomes of long-term treatment with linezolid in adult patients. J. Antimicrob. Chemother., 67, 2034–2042 (2012).
• 34) Nukui Y, Hatakeyama S, Okamoto K, Yamamoto T, Hisaka A, Suzuki H, Yata N, Yotsuyanagi H, Moriya K. High plasma linezolid concentration and impaired renal function affect development of linezolid-induced thrombocytopenia. J. Antimicrob. Chemother., 68, 2128–2133 (2013).
• 35) Fang J, Chen C, Wu Y, Zhang M, Zhang Y, Shi G, Yao Y, Chen H, Bian X. Does the conventional dosage of linezolid necessitate therapeutic drug monitoring?—experience from a prospective observational study. Ann. Transl. Med., 8, 493 (2020).
• 36) Carvalhaes CG, Sader HS, Rhomberg PR, Mendes RE. Tedizolid activity against a multicentre worldwide collection of Staphylococcus aureus and Streptococcus pneumoniae recovered from patients with pneumonia (2017-2019). Int. J. Infect. Dis., 107, 92–100 (2021).
• 37) Pea F, Furlanut M, Cojutti P, Cristini F, Zamparini E, Franceschi L, Viale P. Therapeutic drug monitoring of linezolid: a retrospective monocentric analysis. Antimicrob. Agents Chemother., 54, 4605–4610 (2010).
• 38) Boak LM, Rayner CR, Grayson ML, Paterson DL, Spelman D, Khumra S, Capitano B, Forrest A, Li J, Nation RL, Bulitta JB. Clinical population pharmacokinetics and toxicodynamics of linezolid. Antimicrob. Agents Chemother., 58, 2334–2343 (2014).
• 39) Louie A, Liu W, Kulawy R, Drusano GL. In vivo pharmacodynamics of torezolid phosphate (TR-701), a new oxazolidinone antibiotic, against methicillin-susceptible and methicillin-resistant Staphylococcus aureus strains in a mouse thigh infection model. Antimicrob. Agents Chemother., 55, 3453–3460 (2011).
• 40) Abdelraouf K, Nicolau DP. Comparative in vivo efficacies of tedizolid in neutropenic versus immunocompetent murine Streptococcus pneumoniae lung infection models. Antimicrob. Agents Chemother., 61, e01957–e16 (2016).
• 41) Mikamo H, Takesue Y, Iwamoto Y, Tanigawa T, Kato M, Tanimura Y, Kohno S. Efficacy, safety and pharmacokinetics of tedizolid versus linezolid in patients with skin and soft tissue infections in Japan —results of a randomised, multicentre phase 3 study. J. Infect. Chemother., 24, 434–442 (2018).
• 42) Drusano GL, Liu W, Kulawy R, Louie A. Impact of granulocytes on the antimicrobial effect of tedizolid in a mouse thigh infection model. Antimicrob. Agents Chemother., 55, 5300–5305 (2011).
• 43) Benavent E, Morata L, Escrihuela-Vidal F, Reynaga EA, Soldevila L, Albiach L, Pedro-Botet ML, Padullés A, Soriano A, Murillo O. long-term use of tedizolid in osteoarticular infections: benefits among oxazolidinone drugs. Antibiotics (Basel), 10, 53 (2021).
• 44) Chan LC, Basuino L, Dip EC, Chambers HF. Comparative efficacies of tedizolid phosphate, vancomycin, and daptomycin in a rabbit model of methicillin-resistant Staphylococcus aureus endocarditis. Antimicrob. Agents Chemother., 59, 3252–3256 (2015).
• 45) Singh KV, Arias CA, Murray BE. tedizolid as step-down therapy following daptomycin versus continuation of daptomycin against enterococci and methicillin- and vancomycin-resistant Staphylococcus aureus in a rat endocarditis model. Antimicrob. Agents Chemother., 64, e02303-19 (2020).
• 46) Smith JR, Yim J, Rice S, Stamper K, Kebriaei R, Rybak MJ. combination of tedizolid and daptomycin against methicillin-resistant Staphylococcus aureus in an in vitro model of simulated endocardial vegetations. Antimicrob. Agents Chemother., 62, e00101-18 (2018).
• 47) Park KH, Greenwood-Quaintance KE, Mandrekar J, Patel R. Activity of tedizolid in methicillin-resistant Staphylococcus aureus experimental foreign body-associated osteomyelitis. Antimicrob. Agents Chemother., 60, 6568–6572 (2016).
• 48) Safdar N, Andes D, Craig WA. In vivo pharmacodynamic activity of daptomycin. Antimicrob. Agents Chemother., 48, 63–68 (2004).
• 49) Falcone M, Russo A, Cassetta MI, Lappa A, Tritapepe L, d’Ettorre G, Fallani S, Novelli A, Venditti M. Variability of pharmacokinetic parameters in patients receiving different dosages of daptomycin: is therapeutic drug monitoring necessary? J. Infect. Chemother., 19, 732–739 (2013).
• 50) Galar A, Muñoz P, Valerio M, Cercenado E, García-González X, Burillo A, Sánchez-Somolinos M, Juárez M, Verde E, Bouza E. Current use of daptomycin and systematic therapeutic drug monitoring: clinical experience in a tertiary care institution. Int. J. Antimicrob. Agents, 53, 40–48 (2019).
• 51) Ueda T, Takesue Y, Matsumoto T, et al. Change in antimicrobial susceptibility of pathogens isolated from surgical site infections over the past decade in Japanese nation-wide surveillance study. J. Infect. Chemother., 27, 931–939 (2021).
• 52) Bhavnani SM, Rubino CM, Ambrose PG, Drusano GL. Daptomycin exposure and the probability of elevations in the creatine phosphokinase level: data from a randomized trial of patients with bacteremia and endocarditis. Clin. Infect. Dis., 50, 1568–1574 (2010).
• 53) Yamada T, Ooi Y, Oda K, Shibata Y, Kawanishi F, Suzuki K, Nishihara M, Nakano T, Yoshida M, Uchida T, Katsumata T, Ukimura A. Observational study to determine the optimal dose of daptomycin based on pharmacokinetic/pharmacodynamic analysis. J. Infect. Chemother., 26, 379–384 (2020).
• 54) Dare RK, Tewell C, Harris B, Wright PW, Van Driest SL, Farber-Eger E, Nelson GE, Talbot TR. Effect of statin coadministration on the risk of daptomycin-associated myopathy. Clin. Infect. Dis., 67, 1356–1363 (2018).
• 55) Samura M, Takada K, Hirose N, Kurata T, Nagumo F, Koshioka S, Ishii J, Uchida M, Inoue J, Enoki Y, Taguchi K, Tanikawa K, Matsumoto K. Incidence of elevated creatine phosphokinase between daptomycin alone and concomitant daptomycin and statins: A systematic review and meta-analysis. Br. J. Clin. Pharmacol., 88, 1985–1998 (2022).
• 56) Samura M, Hirose N, Kurata T, Takada K, Nagumo F, Koshioka S, Ishii J, Uchida M, Inoue J, Enoki Y, Taguchi K, Higashita R, Kunika N, Tanikawa K, Matsumoto K. Identification of Risk Factors for Daptomycin-associated creatine phosphokinase elevation and development of a risk prediction model for incidence probability. Open Forum Infect. Dis., 8, ofab568 (2021).
• 57) Imai S, Kashiwagi H, Sato Y, Miyai T, Sugawara M, Takekuma Y. Factors affecting creatine phosphokinase elevation during daptomycin therapy using a combination of machine learning and conventional methods. Br. J. Clin. Pharmacol., 88, 1211–1222 (2022).
• 58) Yamada T, Mitsuboshi S, Suzuki K, Nishihara M, Uchiyama K. Risk of muscle toxicity events for daptomycin with and without statins: analysis of the Japanese Adverse Event Report database. Basic Clin. Pharmacol. Toxicol., 129, 268–272 (2021).
• 59) Chuma M, Nakamoto A, Bando T, Niimura T, Kondo Y, Hamano H, Okada N, Asada M, Zamami Y, Takechi K, Goda M, Miyata K, Yagi K, Yoshioka T, Izawa-Ishizawa Y, Yanagawa H, Tasaki Y, Ishizawa K. Association between statin use and daptomycin-related musculoskeletal adverse events: a mixed approach combining a meta-analysis and a disproportionality analysis. Clin. Infect. Dis., 1, ciac128 (2022).
• 60) Bland CM, Bookstaver PB, Lu ZK, Dunn BL, Rumley KF. Musculoskeletal safety outcomes of patients receiving daptomycin with HMG-CoA reductase inhibitors. Antimicrob. Agents Chemother., 58, 5726–5731 (2014).
• 61) Lehman B, Neuner EA, Heh V, Isada C. A Retrospective multisite case-control series of concomitant use of daptomycin and statins and the effect on creatine phosphokinase. Open Forum Infect. Dis., 6, ofz444 (2019).
• 62) Urakami T, Hamada Y, Oka Y, Okinaka T, Yamakuchi H, Magarifuchi H, Aoki Y. Clinical pharmacokinetic and pharmacodynamic analysis of daptomycin and the necessity of high-dose regimen in Japanese adult patients. J. Infect. Chemother., 25, 437–443 (2019).
• 63) Canut A, Isla A, Betriu C, Gascón AR. Pharmacokinetic-pharmacodynamic evaluation of daptomycin, tigecycline, and linezolid versus vancomycin for the treatment of MRSA infections in four western European countries. Eur. J. Clin. Microbiol. Infect. Dis., 31, 2227–2235 (2012).
• 64) Lai CC, Sheng WH, Wang JT, Cheng A, Chuang YC, Chen YC, Chang SC. Safety and efficacy of high-dose daptomycin as salvage therapy for severe gram-positive bacterial sepsis in hospitalized adult patients. BMC Infect. Dis., 13, 66 (2013).
• 65) Moise PA, Amodio-Groton M, Rashid M, Lamp KC, Hoffman-Roberts HL, Sakoulas G, Yoon MJ, Schweitzer S, Rastogi A. Multicenter evaluation of the clinical outcomes of daptomycin with and without concomitant β-lactams in patients with Staphylococcus aureus bacteremia and mild to moderate renal impairment. Antimicrob. Agents Chemother., 57, 1192–1200 (2013).
• 66) Samura M, Takada K, Yamamoto R, Ito H, Nagumo F, Uchida M, Kurata T, Koshioka S, Enoki Y, Taguchi K, Higashita R, Kunika N, Tanikawa K, Matsumoto K. Population pharmacokinetic analysis and dosing optimization based on unbound daptomycin concentration and cystatin C in nonobese elderly patients with hypoalbuminemia and chronic kidney disease. Pharm. Res., 38, 1041–1055 (2021).
• 67) Falcone M, Russo A, Venditti M, Novelli A, Pai MP. Considerations for higher doses of daptomycin in critically ill patients with methicillin-resistant Staphylococcus aureus bacteremia. Clin. Infect. Dis., 57, 1568–1576 (2013).
• 68) Cojutti PG, Candoni A, Ramos-Martin V, Lazzarotto D, Zannier ME, Fanin R, Hope W, Pea F. Population pharmacokinetics and dosing considerations for the use of daptomycin in adult patients with haematological malignancies. J. Antimicrob. Chemother., 72, 2342–2350 (2017).
• 69) Grégoire N, Marchand S, Ferrandière M, Lasocki S, Seguin P, Vourc’h M, Barbaz M, Gaillard T, Launey Y, Asehnoune K, Couet W, Mimoz O. Population pharmacokinetics of daptomycin in critically ill patients with various degrees of renal impairment. J. Antimicrob. Chemother., 74, 117–125 (2019).