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

Background: Owing to its low risk of adverse effects, teicoplanin has been extensively used in patients with infections caused by MRSA. To promote the better management of patients receiving teicoplanin, we have updated the guidelines for therapeutic drug monitoring (TDM).Methods: The guidelines were developed by a committee following the methodology handbook published by the Japanese Medical Information Distribution Service. Nine clinical questions were selected. The committee conducted a systematic review and meta-analysis to establish evidence-based recommendations for the target trough concentration (C min ). An initial electronic database search returned 515 articles, and 97 articles qualified for a full review. Four and five studies were included for the efficacy evaluation of cut-off C min values of 15 and 20 mg/L, respectively.Results: Compared with C min , 15 mg/L, a target C min value of 15-30 mg/L resulted in increased clinical efficacy in patients with non-complicated MRSA infections (OR = 2.68; 95% CI = 1.14-6.32) without an increase in adverse effects. Although there was insufficient evidence, target C min values of 20-40 mg/L were suggested in patients with complicated or serious MRSA infections. A 3 day loading regimen followed by maintenance treatment according to renal function was recommended to achieve the target trough concentrations. Because of the prolonged half-life of teicoplanin, measurement of the C min value on Day 4 before reaching steady state was recommended.Conclusions:The new guideline recommendations indicate the target C min value for TDM and the dosage regimen to achieve this concentration and suggest practices for specific subpopulations.

# Introduction
Teicoplanin, a glycopeptide antibiotic, has been extensively evaluated as a treatment for infections caused by Gram-positive bacteria including MRSA. [bib_ref] A critical review of the dosage of teicoplanin in Europe and the..., Wilson [/bib_ref] Comparative studies versus vancomycin have revealed that teicoplanin is equally effective but better tolerated with lower risks of adverse events. [bib_ref] The comparative efficacy and safety of teicoplanin and vancomycin, Wood [/bib_ref] [bib_ref] Teicoplanin versus vancomycin for proven or suspected infection, Cavalcanti [/bib_ref] In a systematic review, there was significantly less nephrotoxicity [relative risk (RR) = 0.44; 95% CI = 0.32-0.61] and red man syndrome (RR = 0.21; 95% CI = 0.08-0.54) with teicoplanin than with vancomycin. [bib_ref] Comparative efficacy and safety of vancomycin versus teicoplanin: systematic review and meta-analysis, Svetitsky [/bib_ref] Teicoplanin strongly binds to plasma albumin and it has an extremely long elimination half-life ranging from 83 to 163 h. [bib_ref] Teicoplanin pharmacokinetics in healthy volunteers after administration of intravenous loading and maintenance..., Outman [/bib_ref] [bib_ref] Comparative pharmacokinetics of teicoplanin and vancomycin, Harding [/bib_ref] [bib_ref] Clinical pharmacokinetics of teicoplanin, Wilson [/bib_ref] Consistent with these pharmacokinetic (PK) characteristics, wide variations and fluctuations of concentrations are expected when administering fixed-dose regimens. [bib_ref] Teicoplanin therapeutic drug monitoring in critically ill patients: a retrospective study emphasizing..., Pea [/bib_ref] [bib_ref] The use and therapeutic drug monitoring of teicoplanin in the UK, Darley [/bib_ref] Therapeutic drug monitoring (TDM) is useful during teicoplanin treatment as anti-MRSA therapy to ensure that adequate drug concentrations are achieved. Individualization of teicoplanin treatment based on TDM and dose adjustment may be a useful strategy in antimicrobial stewardship programmes. The current clinical practice guideline was established by an evaluation of the scientific data concerning serum teicoplanin monitoring to provide recommendations regarding teicoplanin treatment to healthcare providers. Herein, a systematic review, meta-analysis and clinical study of the evidence-based recommendations have been conducted. 12-14

# Methods
The previous clinical practice guidelines for the TDM of teicoplanin were reviewed by a clinical practice guideline committee consisting of nine experts in the field of TDM convened by the Japanese Society of Chemotherapy (JSC) and the Japanese Society of Therapeutic Drug Monitoring (JSTDM). [bib_ref] Revised guidelines for therapeutic drug monitoring of antimicrobials, Takesue [/bib_ref] The guidelines were based on the 'Minds Manual for Guideline Development 2017' established by the Medical Information Network Distribution Service (Minds) in Japan.Initially, the committee agreed on the nine clinical questions (CQs) and the main issues to be discussed in each question, followed by a complete review of original articles and guidelines related to every CQ identified through general databases (i.e. MEDLINE, Embase and Cochrane Library). Ichushi-Web was used to search Japanese-language literature and websites. In addition, systematic reviews of the CQs were performed by several committee members to assess the current evidence, and recommendations were formulated. In the Minds classification, recommendations are made based on the certainty of evidence (strong certainty; moderate certainty; conditional certainty; and lack of certainty) for efficacy estimation to support the recommendations. Because randomized controlled trials (RCTs) are rarely performed on the practice of TDM because of its nature, the content of some of the recommendations was difficult to explain using the aforementioned terms; thus, recommendations for each CQ were made using the modified Minds classification (grades I, II, III-A, III-B, III-C and IV; see [fig_ref] Table 1: Grading system for ranking recommendations and evidence levels adopted in the guidelines... [/fig_ref].
We searched electronic databases for clinical studies published through to 30 June 2020 using a combined MeSH heading and text search strategy with the following terms: 'teicoplanin'; 'targocid'; 'teichomycin' and 'drug monitoring'. We also manually checked the reference lists of relevant original papers and reviews, screened articles in the PubMed 'related citations' section and restricted the search to human studies. We excluded studies if the data were generated from simulated patients or PK models rather than real patients. Our initial search returned 515 articles. After screening the titles and abstracts, 97 articles qualified for a full review. For the target trough concentration (CQs 4 and 5), four trials assessing clinical success (n = 299) 12, [bib_ref] Effective use of teicoplanin for MRSA infections in surgical patients, Arakawa [/bib_ref] [bib_ref] High-dose regimen to achieve novel target trough concentration in teicoplanin, Ueda [/bib_ref] [bib_ref] Enhanced loading regimen of teicoplanin is necessary to achieve therapeutic pharmacokinetics levels..., Ueda [/bib_ref] and three studies assessing adverse effects (n = 546) 17-19 at a cut-off value of 15 mg/L, and five trials assessing clinical success (n = 136) 12,20-23 and four studies assessing adverse effects (n = 702) 12,21,24,25 at a cut-off value of 20 mg/L were included for meta-analysis. For dosage regimens according to target trough concentrations in patients with normal renal function and those with decreased renal function (CQs 6 and 7), 14 studies were included in the analysis. 12, [bib_ref] High-dose regimen to achieve novel target trough concentration in teicoplanin, Ueda [/bib_ref] [bib_ref] Enhanced loading regimen of teicoplanin is necessary to achieve therapeutic pharmacokinetics levels..., Ueda [/bib_ref] [bib_ref] Development of teicoplanin loading regimen that rapidly achieves target serum concentrations in..., Nakamura [/bib_ref] [bib_ref] Development of initial loading procedure for teicoplanin in critically ill patients with..., Matsumoto [/bib_ref] [bib_ref] Optimal teicoplanin loading regimen to rapidly achieve target trough plasma concentration in..., Li [/bib_ref] [bib_ref] Loading dose required to achieve rapid therapeutic teicoplanin trough plasma concentration in..., Wang [/bib_ref] [bib_ref] Teicoplanin use in adult patients with haematological malignancy: exploring relationships between dose,..., Byrne [/bib_ref] [bib_ref] Variability in trough total and unbound teicoplanin concentrations and achievement of therapeutic..., Byrne [/bib_ref] [bib_ref] Loading regimen required to rapidly achieve therapeutic trough plasma concentration of teicoplanin..., Seki [/bib_ref] [bib_ref] Clinical efficacy of high dose treatment with teicoplanin (TEIC) against MRSA infections..., Ueda [/bib_ref] [bib_ref] Retrospective study of teicoplanin loading regimen that rapidly achieves target 15-30 g/mL..., Kato [/bib_ref] [bib_ref] Evaluating the optimal dose of teicoplanin with therapeutic drug monitoring: not too..., Kim [/bib_ref] [bib_ref] Teicoplanin in patients with acute leukaemia and febrile neutropenia: a special population..., Pea [/bib_ref] For dosage regimens in patients with continuous venovenous haemodiafiltration (CVVHDF), seven studies were selected (CQ 9). 14, [bib_ref] Teicoplanin pharmacokinetics in critically ill patients on continuous veno-venous hemofiltration, Bellmann [/bib_ref] [bib_ref] Therapeutic drug monitoring-guided high teicoplanin dosage regimen required to treat a hypoalbuminemic..., Pea [/bib_ref] [bib_ref] High variability of teicoplanin concentration in patients with continuous venovenous hemodiafiltration, Lim [/bib_ref] [bib_ref] Pharmacokinetics of teicoplanin in critically ill patients undergoing continuous hemodiafiltration, Yagasaki [/bib_ref] [bib_ref] Teicoplanin pharmacokinetics and dosage recommendations in chronic hemodialysis patients and in patients..., Wolter [/bib_ref] [bib_ref] Proposal of a pharmacokinetically optimized dosage regimen of antibiotics in patients receiving..., Yamamoto [/bib_ref] The draft guidelines in the executive summary were uploaded to the home pages of JSC and JSTDM. External public comments were obtained between 2 June 2021 and 2 July 2021, and revisions were performed if necessary. The Japanese version of the guidelines was approved by the JSC and JSTDM Board of Directors and published in the Japanese Journal of Chemotherapy in June 2021. All members of the clinical practice guideline committee complied with the JSC policy on conflict of interest, which requires disclosure of any financial or other interests that might be construed as constituting an actual, potential or apparent conflict. Potential conflicts of interest are listed in the Acknowledgements section. At 5 year intervals, the committee will determine the need for revisions to the guidelines. CQ 1. What are the recommended pharmacokinetic/pharmacodynamic (PD) parameters for TDM for teicoplanin?
Executive summary (a) The AUC/MIC is the key PK/PD parameter for teicoplanin. [bib_ref] Basic pharmacodynamics of antibacterials with clinical applications to the use of -lactams,..., Craig [/bib_ref] [bib_ref] Pharmacokinetic/pharmacodynamic evaluation of teicoplanin against Staphylococcus aureus in a murine thigh infection..., Watanabe [/bib_ref] Because AUC estimation software is unavailable in many institutions, the trough concentration is recommended as a surrogate marker in clinical settings (II). 8,45-49 (b) Model-informed precision dosing (MIPD) is a promising tool to inform individualized rational dosing of antibiotics. However, compared with vancomycin, the evidence to support a recommendation for an MIPD approach is sparser for teicoplanin.

## Literature review
Matsumoto et al. [bib_ref] Pharmacokinetic/pharmacodynamic analysis of teicoplanin in patients with MRSA infections, Matsumoto [/bib_ref] reported that the treatment success rate for teicoplanin was 87% in patients achieving AUC/MIC  900. Ramos-Martin et al. [bib_ref] Pharmacodynamics of teicoplanin against MRSA, Ramos-Martin [/bib_ref] demonstrated that an AUC/MIC value of 610.4 for an MRSA strain with an MIC value of 0.5 mg/L was needed for bactericidal efficacy, and a higher exposure threshold was needed to suppress the emergence of resistance. In evaluation of the AUC alone, a cut-off value ranging from 700 to 800 mgh/L of teicoplanin was required. [bib_ref] Population pharmacokinetics of teicoplanin and attainment of pharmacokinetic/pharmacodynamic targets in adult patients..., Byrne [/bib_ref] [bib_ref] An initial dosing method for teicoplanin based on the area under the..., Kanazawa [/bib_ref] [bib_ref] Exploration of optimal teicoplanin dosage based on pharmacokinetic parameters for the treatment..., Hagihara [/bib_ref] Similarly to vancomycin, the trough level of teicoplanin may be a suboptimal surrogate for the AUC value for overall drug exposure, and AUC-based dosing may be ideal.
Recently, MIPD has emerged as an integrative approach that uses mathematical models to predict personalized dosing beyond a specific approach or technique. There is increasing research on the use of MIPD software to streamline the TDM process, which can increase the accuracy of dose individualization. [bib_ref] From therapeutic drug monitoring to model-informed precision dosing for antibiotics, Wicha [/bib_ref] A population model can be used before administration of the first dose to predict a dosing regimen that maximizes the likelihood of meeting the AUC targets for an individual patient. When drug concentrations (trough only, or both peak and trough levels) can be measured, these can be used to derive the AUC value using Bayesian estimation. Because of the reasonably long half-life of teicoplanin, conventional TDM is performed on [bib_ref] Prospective validation of a model-informed precision dosing tool for vancomycin in intensive..., Heine [/bib_ref] [bib_ref] Performance of area under the concentration-time curve estimations of vancomycin with limited..., Oda [/bib_ref] A recent systematic review and meta-analysis has shown that, compared with trough-guided dosing, AUC-guided dosing showed the potential for decreasing nephrotoxicity with vancomycin treatment. [bib_ref] The monitoring of vancomycin: a systematic review and meta-analyses of area under..., Tsutsuura [/bib_ref] Several investigators have attempted to develop AUC-based models to explore the probability of target attainment for teicoplanin dosage regimens. [bib_ref] Pharmacokinetic/pharmacodynamic analysis of teicoplanin in patients with MRSA infections, Matsumoto [/bib_ref] [bib_ref] An initial dosing method for teicoplanin based on the area under the..., Kanazawa [/bib_ref] Because of the low rate of adverse effects, 4 even with trough-guided dosing, the need for AUC-guided dosing should be discussed before the introduction of the MIPD approach in adult patients who are treated with teicoplanin. The number of reported population PK models of teicoplanin in infants and children is increasing. [bib_ref] Pharmacodynamics of teicoplanin against MRSA, Ramos-Martin [/bib_ref] [bib_ref] Tools for the individualized therapy of teicoplanin for neonates and children, Ramos-Martin [/bib_ref] [bib_ref] Population pharmacokinetics of teicoplanin in preterm and term neonates: is it time..., Kontou [/bib_ref] Ramos-Martin et al. [bib_ref] Tools for the individualized therapy of teicoplanin for neonates and children, Ramos-Martin [/bib_ref] have developed the teicoplanin dose optimization software 'cartridge' for neonates and children, using a teicoplanin multiple-model Bayesian adaptive dosing controller. However, adequate model validation and re-evaluation of existing workflows is scarce. Further clinical studies are required to ensure that the MIPD approach for teicoplanin is applicable in a clinical setting.

## Cq 2. what are the candidates for tdm in teicoplanin therapy?
Executive summary (a) The primary purpose of TDM is to improve the clinical efficacy of teicoplanin treatment (II). [bib_ref] Teicoplanin monotherapy of serious infections caused by Gram-positive bacteria: a re-evaluation of..., Davey [/bib_ref] [bib_ref] Pharmacokinetics and pharmacodynamics of sequential intravenous and subcutaneous teicoplanin in critically ill..., Barbot [/bib_ref] However, TDM should also be considered to prevent adverse effects in patients receiving larger loading doses of teicoplanin. (b) Owing to the poor prediction of serum concentrations of teicoplanin, TDM should be scheduled in patients with serious infections, acute or chronic renal dysfunction, obesity or low body weight, burn infections or hypoalbuminaemia, [bib_ref] Variability in protein binding of teicoplanin and achievement of therapeutic drug monitoring..., Roberts [/bib_ref] [bib_ref] Albumin concentration significantly impacts on free teicoplanin plasma concentrations in noncritically ill..., Brink [/bib_ref] [bib_ref] The effects of hypoalbuminaemia on optimizing antibacterial dosing in critically ill patients, Ulldemolins [/bib_ref] as well as in paediatric populations [bib_ref] Population pharmacokinetics of teicoplanin in children, Ramos-Martin [/bib_ref] [bib_ref] Teicoplanin pharmacokinetics in pediatric patients, Dufort [/bib_ref] [bib_ref] Teicoplanin pharmacokinetics in critically ill paediatric patients, Sanchez [/bib_ref] (I). (c) In patients who poorly respond to teicoplanin or experience adverse effects, TDM should be conducted to evaluate the need for dose adjustment (III-A).

## Literature review
The previous recommended trough concentration to achieve clinical efficacy was 10 mg/L, which is considerably lower than the concentration causing adverse effects (thrombocytopenia, 40 mg/L; nephrotoxicity, 60 mg/L). [bib_ref] Teicoplanin-induced thrombocytopenia, Veldman [/bib_ref] [bib_ref] Teicoplanin nephrotoxicity: first case report, Frye [/bib_ref] Therefore, routine TDM has not been mandatory in patients receiving standard-dose teicoplanin. Rather than to prevent adverse effects, TDM has been performed mainly to confirm the achievement of the trough concentration for clinical efficacy. [bib_ref] Population pharmacokinetics of teicoplanin in preterm and term neonates: is it time..., Kontou [/bib_ref] [bib_ref] Teicoplanin monotherapy of serious infections caused by Gram-positive bacteria: a re-evaluation of..., Davey [/bib_ref] However, to treat serious or complicated MRSA infections, trough concentrations ranging from 20 to 40 mg/L are recommended, and several authors have suggested an enhanced loading-dose regimen to achieve the target concentrations. 12, [bib_ref] High-dose regimen to achieve novel target trough concentration in teicoplanin, Ueda [/bib_ref] [bib_ref] Enhanced loading regimen of teicoplanin is necessary to achieve therapeutic pharmacokinetics levels..., Ueda [/bib_ref] [bib_ref] Development of teicoplanin loading regimen that rapidly achieves target serum concentrations in..., Nakamura [/bib_ref] [bib_ref] Development of initial loading procedure for teicoplanin in critically ill patients with..., Matsumoto [/bib_ref] [bib_ref] Optimal teicoplanin loading regimen to rapidly achieve target trough plasma concentration in..., Li [/bib_ref] [bib_ref] Loading dose required to achieve rapid therapeutic teicoplanin trough plasma concentration in..., Wang [/bib_ref] [bib_ref] Teicoplanin use in adult patients with haematological malignancy: exploring relationships between dose,..., Byrne [/bib_ref] [bib_ref] Variability in trough total and unbound teicoplanin concentrations and achievement of therapeutic..., Byrne [/bib_ref] [bib_ref] Loading regimen required to rapidly achieve therapeutic trough plasma concentration of teicoplanin..., Seki [/bib_ref] [bib_ref] Clinical efficacy of high dose treatment with teicoplanin (TEIC) against MRSA infections..., Ueda [/bib_ref] [bib_ref] Retrospective study of teicoplanin loading regimen that rapidly achieves target 15-30 g/mL..., Kato [/bib_ref] [bib_ref] Evaluating the optimal dose of teicoplanin with therapeutic drug monitoring: not too..., Kim [/bib_ref] [bib_ref] Teicoplanin in patients with acute leukaemia and febrile neutropenia: a special population..., Pea [/bib_ref] For these patients, TDM should be planned to either increase the clinical efficacy or prevent possible adverse effects.
The clearance of teicoplanin is greater in paediatric patients than in adult patients. Ramos-Martin et al. [bib_ref] Population pharmacokinetics of teicoplanin in children, Ramos-Martin [/bib_ref] reported that the rate of achieving the initial trough concentration of 10 mg/L was 44.9% in patients weighing 25 kg and 60.5% in patients weighing 10 kg. Similarly, only 55.6% of paediatric patients with febrile neutropenia and only 11% of infant patients with serious infections achieved a trough concentration exceeding 10 mg/L. [bib_ref] Teicoplanin pharmacokinetics in pediatric patients, Dufort [/bib_ref] [bib_ref] Teicoplanin pharmacokinetics in critically ill paediatric patients, Sanchez [/bib_ref] In addition, because of the diverse range of PK values in paediatric patients, there were significant differences in trough concentrations between individuals. The free fraction rate of highly protein-binding antimicrobial agents, such as teicoplanin, is increased, and low trough concentrations have been demonstrated in patients with hypoalbuminaemia. [bib_ref] Variability in protein binding of teicoplanin and achievement of therapeutic drug monitoring..., Roberts [/bib_ref] [bib_ref] Albumin concentration significantly impacts on free teicoplanin plasma concentrations in noncritically ill..., Brink [/bib_ref] [bib_ref] The effects of hypoalbuminaemia on optimizing antibacterial dosing in critically ill patients, Ulldemolins [/bib_ref] For this reason, alteration of the target trough concentration according to the level of hypoalbuminaemia is required (see .

## Cq 3. when should initial tdm be performed?
Executive summary (a) In general, blood samples are obtained at steady state.
Because of its prolonged half-life, teicoplanin requires a long time to reach steady state. 7,72 Therefore, the trough concentration on Day 4 before reaching steady state is recommended as a surrogate measure (II), and the target trough concentration is determined as the concentration on Day 4. If TDM is performed on Day 3 for any reason, blood sampling should be performed later than 18 h after the predose in patients who were administered teicoplanin twice daily for 2 days. 72 (b) TDM on Day 4 is an evaluation of the loading dose for the initial 3 days, and follow-up TDM is conducted to evaluate the maintenance dose. Follow-up TDM should be considered within 7 days after the initial TDM in patients with renal dysfunction and those with serious infections who require high target trough concentrations exceeding 20 mg/L (III-A). 48

## Literature review
The elimination of teicoplanin is triexponential, with half-lives of 0.4-1.0 h in the  phase, 6.6-38 h in the  phase and 83-182 h in the  phase. [bib_ref] Clinical pharmacokinetics of teicoplanin, Wilson [/bib_ref] In contrast, the half-lives of vancomycin are 0.12, 0.5-1.5 and 3-11 h for the ,  and  phases, respectively. [bib_ref] streptogramins (quinupristin-dalfopristin), lipopeptides (daptomycin), and lipoglycopeptides (telavancin), Murray [/bib_ref] Compared with vancomycin, a prolonged half-life has been demonstrated for teicoplanin, especially in the  phase. Because the time to reach a steady state is four to five half-lives if the drug is given at regular intervals, 74 the steady state is reached only slowly; 93% of the concentration at steady state is obtained after 14 days of repeated administration. [bib_ref] Clinical pharmacokinetics of teicoplanin, Wilson [/bib_ref] In clinical settings, early PK evaluation is mandatory to achieve the target concentration with dose adjustment, and it is recommended to perform TDM on Day 4 before steady state is reached. [bib_ref] Teicoplanin therapeutic drug monitoring in critically ill patients: a retrospective study emphasizing..., Pea [/bib_ref] [bib_ref] Teicoplanin monotherapy of serious infections caused by Gram-positive bacteria: a re-evaluation of..., Davey [/bib_ref] [bib_ref] Pharmacokinetics and pharmacodynamics of sequential intravenous and subcutaneous teicoplanin in critically ill..., Barbot [/bib_ref] The trough concentration on Day 4 has been generally used in clinical studies. [bib_ref] Teicoplanin pharmacokinetics in healthy volunteers after administration of intravenous loading and maintenance..., Outman [/bib_ref] [bib_ref] Teicoplanin therapeutic drug monitoring in critically ill patients: a retrospective study emphasizing..., Pea [/bib_ref] [bib_ref] Guidelines for the prophylaxis and treatment of methicillin-resistant Staphylococcus aureus (MRSA) infections..., Gemmell [/bib_ref] [bib_ref] Analyses of teicoplanin concentrations from 1994 to 2006 from a UK assay..., Tobin [/bib_ref] [bib_ref] Development of new software (Ver. 2.0) based on the Bayesian estimation utilized..., Niwa [/bib_ref] [bib_ref] Therapeutic drug monitoring survey of anti-MRSA agents in Japan, Kobayashi [/bib_ref] [bib_ref] Teicoplanin therapy for Staphylococcus aureus septicaemia: relationship between pre-dose Review serum concentrations..., Harding [/bib_ref] [bib_ref] Teicoplanin monotherapy of serious infections caused by Gram-positive bacteria: a re-evaluation of..., Davey [/bib_ref] [bib_ref] Recommendations to achieve rapid therapeutic teicoplanin plasma concentrations in adult hospitalised patients..., Brink [/bib_ref] However, in a Japanese multicentre surveillance study on the use of TDM in clinical practice conducted by the previous antibiotic TDM guideline committee, only 46.3% of institutions adopted Day 4 TDM, with some institutions selecting Day 3 TDM. [bib_ref] Therapeutic drug monitoring survey of anti-MRSA agents in Japan, Kobayashi [/bib_ref] In patients who received three doses of teicoplanin at Review 12 h intervals, the rate of achievement of the target trough level was 17% on Day 3 and 38% on Day 4. [bib_ref] Variability in trough total and unbound teicoplanin concentrations and achievement of therapeutic..., Byrne [/bib_ref] In addition, TDM on Day 3 should be assessed carefully in patients receiving loading doses via q12h administration for 2 days. Because TDM in the morning on Day 3 (12 h after the pre-dose) has a risk for over-estimation of the trough concentration, administration on Day 3 should be delayed until 18 h after the pre-dose. [bib_ref] Pharmacokinetics of teicoplanin in man after intravenous administration, Traina [/bib_ref] CQ 4. What is the target trough concentration in TDM for non-complicated MRSA infections?
Executive summary Traditionally, it has been reported that concentrations of 10 mg/L need to be achieved for the successful treatment of all MRSA infections. [bib_ref] Guidelines for the prophylaxis and treatment of methicillin-resistant Staphylococcus aureus (MRSA) infections..., Gemmell [/bib_ref] [bib_ref] Analyses of teicoplanin concentrations from 1994 to 2006 from a UK assay..., Tobin [/bib_ref] Wang et al. [bib_ref] Factors on trough teicoplanin levels, associations between levels, efficacy and safety in..., Wang [/bib_ref] identified teicoplanin trough concentrations of 10-20 mg/L as the therapeutic range with optimum clinical efficacy and safety. Because teicoplanin is better tolerated than vancomycin, the therapeutic range of teicoplanin has been gradually increased to higher concentrations. [bib_ref] High-dose regimen to achieve novel target trough concentration in teicoplanin, Ueda [/bib_ref] [bib_ref] Loading regimen required to rapidly achieve therapeutic trough plasma concentration of teicoplanin..., Seki [/bib_ref] [bib_ref] Teicoplanin in patients with acute leukaemia and febrile neutropenia: a special population..., Pea [/bib_ref] [bib_ref] Recommendations to achieve rapid therapeutic teicoplanin plasma concentrations in adult hospitalised patients..., Brink [/bib_ref] [bib_ref] Development of teicoplanin dosage guidelines for patients treated within an outpatient parenteral..., Lamont [/bib_ref] [bib_ref] Steady-state trough serum and epithelial lining fluid concentrations of teicoplanin 12 mg/kg..., Mimoz [/bib_ref] [bib_ref] Evaluation of teicoplanin dosing designs to achieve a new target trough concentration, Ueda [/bib_ref] In a large 13 year retrospective study in the UK, the median trough teicoplanin concentration was found to have increased from 14.5 to 21.8 mg/L for all types of infections. [bib_ref] Analyses of teicoplanin concentrations from 1994 to 2006 from a UK assay..., Tobin [/bib_ref] In Japanese clinical research, an average trough concentration of 16.3 mg/L was likely to be associated with a better treatment success rate than a concentration of 9.4 mg/L in a cohort mainly containing patients with pneumonia. [bib_ref] Clinical efficacy of high dose treatment with teicoplanin (TEIC) against MRSA infections..., Ueda [/bib_ref] Ueda et al. [bib_ref] High-dose regimen to achieve novel target trough concentration in teicoplanin, Ueda [/bib_ref] reported that in patients with normal renal function, a trough concentration of 15 mg/L was associated with a higher clinical response rate at the end of treatment than a concentration of ,15 mg/L (85.0% versus 66.7%; P = 0.014). Additionally, this group demonstrated that a trough concentration of 15 mg/L was an independent factor for clinical success in patients with renal dysfunction before the treatment (adjusted OR = 4.20; 95% CI = 1. . [bib_ref] Enhanced loading regimen of teicoplanin is necessary to achieve therapeutic pharmacokinetics levels..., Ueda [/bib_ref] In patients with renal dysfunction who had maximal trough concentrations of 15-30 mg/L during therapy, the rates of nephrotoxicity and hepatotoxicity were 13.1% and 2.6%, respectively, and these rates were not significantly higher than those in patients with concentrations of ,15 mg/L. [bib_ref] Enhanced loading regimen of teicoplanin is necessary to achieve therapeutic pharmacokinetics levels..., Ueda [/bib_ref] CQ 5. What is the target trough concentration in TDM for difficult-to-treat complicated MRSA infections?
Executive summary

## Literature review
In a systematic review and meta-analysis conducted by committee [fig_ref] Table 1: Grading system for ranking recommendations and evidence levels adopted in the guidelines... [/fig_ref] between patients with trough concentrations of 20 mg/L and those with concentrations of ,20 mg/L. In conclusion, further clinical trials are needed to indicate the required target trough concentration to increase treatment success in patients with complicated infections caused by MRSA. However, this meta-analysis confirmed the safety of target trough concentrations of 20 mg/L. Several studies have illustrated that trough concentrations of ,20 mg/L produced significantly higher rates of failure than those of 20 mg/L for serious infections, including severe infections, 36,49,80-83 endocarditis 1,7,84-86 and bone and joint infections. [bib_ref] Teicoplanin in the treatment of bone and joint infections. Teicoplanin Bone and..., Lefrock [/bib_ref] [bib_ref] Teicoplanin levels in bone and joint infections: are standard doses subtherapeutic?, Matthews [/bib_ref] An open study revealed that in patients with staphylococcal endocarditis, 6 of 10 treatments failed when the serum trough concentrations were ,20 mg/L, whereas only 1 of 11 treatments failed when the trough concentrations were .20 mg/L (P = 0.04). [bib_ref] A critical review of the dosage of teicoplanin in Europe and the..., Wilson [/bib_ref] Byrne et al. reported that the target trough concentration of teicoplanin should be 20 mg/L to achieve high clinical efficacy rates in patients with haematological malignancy and CoNS central line-associated bloodstream infection. [bib_ref] Variability in trough total and unbound teicoplanin concentrations and achievement of therapeutic..., Byrne [/bib_ref] A clinical study conducted by a committee member has demonstrated that a trough concentration of 20 mg/L was an independent factor for an early clinical response to teicoplanin therapy for the treatment of bacteraemia/complicated MRSA infections (OR = 3.95; 95% CI = 1.25-12.53). Concerning the adverse effects of teicoplanin, thrombocytopenia was observed at trough concentrations of 40 mg/L 71 and nephrotoxicity was reported at trough concentrations of 60 mg/L. [bib_ref] Teicoplanin monotherapy of serious infections caused by Gram-positive bacteria: a re-evaluation of..., Davey [/bib_ref] Wilson et al. [bib_ref] A critical review of the dosage of teicoplanin in Europe and the..., Wilson [/bib_ref] demonstrated that a high-loadingdose regimen of teicoplanin to maintain trough concentrations of 40-60 mg/L led to a higher incidence of adverse events, such as thrombocytopenia and fever, than a standard regimen in patients with staphylococcal endocarditis. A previous clinical practice TDM guideline committee conducted a Japanese Review multicentre retrospective study on the safety and efficacy of teicoplanin at target trough concentrations of 20 mg/L. [bib_ref] Clinical efficacy and safety of teicoplanin with a target trough concentration over..., Takakura [/bib_ref] In total, 199 patients were included the study, and the clinical success rate was 70.9% and the nephrotoxicity rate was 8.3%, indicating that the target trough concentration range was clinically appropriate. A post hoc analysis of this study by revealed that the rates of nephrotoxicity in patients with teicoplanin trough concentrations of ,20 and 20-40 mg/L were 7.2% and 8.1%, respectively, and those of hepatotoxicity were 3.0% and 1.5%, respectively, with no significant differences between the groups. CQ 6. How can the dosage regimen of teicoplanin be optimized to achieve the target trough concentration?
Executive summary (a) An initial 3 day actual body weight-based loading dose regimen and subsequent maintenance dose regimen are suggested separately in these guidelines [fig_ref] Table 2: Dosage regimen of teicoplanin to achieve the target trough concentration in patients... [/fig_ref]. (b) To achieve a trough concentration of 15-30 mg/L, five doses of 10 mg/kg or four doses of 12 mg/kg within the initial 3 days are recommended (II). (c) To achieve a trough concentration of 20-40 mg/L, five doses of 12 mg/kg within the initial 3 days are recommended (II). (d) A maintenance dose of 6-6.7 mg/kg once daily is recommended to sustain a trough concentration of 15-30 mg/L (II). Because there are limited data on the maintenance dose needed to sustain a trough concentration of 20 mg/L, a higher dose than the recommended maintenance dose might be considered (III-A). Early follow-up TDM should be performed to confirm a trough concentration of 20 mg/L, irrespective of dose adjustment.

## Literature review
A loading dose is a high dose of a drug that may be given at the initiation of treatment. Although it requires four to five half-lives to reach a steady state,the concentration obtained by the loading dose is closer to the eventual steady state concentration, which suggests that the therapeutic effect will happen more rapidly. Because of the extremely long half-life, a loading dose for 2 to 3 days is essential during teicoplanin therapy to achieve an early optimal concentration. A summary of the systematic review of high-loading-dose regimens of teicoplanin with a dose of 10-12 mg/kg or 600-800 mg to achieve trough levels of 15 or 20 mg/L, which was recommended by this guideline, is provided in [fig_ref] Table 2: Dosage regimen of teicoplanin to achieve the target trough concentration in patients... [/fig_ref]. Once the optimal concentrations are achieved, a lower maintenance dose regimen can be started.
Dosage regimen to achieve a target trough concentration of 15-30 mg/L Previously, three doses of 400 mg q12h have been recommended to achieve a trough concentration of 10 mg/L. [bib_ref] Clinical efficacy of high dose treatment with teicoplanin (TEIC) against MRSA infections..., Ueda [/bib_ref] [bib_ref] Recommendations to achieve rapid therapeutic teicoplanin plasma concentrations in adult hospitalised patients..., Brink [/bib_ref] Even with a standard dosage of 400 mg q12h, five times, the trough concentration remained at 10-15 mg/L. [bib_ref] Teicoplanin pharmacokinetics in healthy volunteers after administration of intravenous loading and maintenance..., Outman [/bib_ref] Dosage regimen to achieve a target trough concentration of 20-40 mg/L Although a trough concentration of 20 mg/L has been recommended in the treatment of complicated MRSA infections, limited data regarding the dosage regimen needed to achieve this target range are available. [bib_ref] Teicoplanin use in adult patients with haematological malignancy: exploring relationships between dose,..., Byrne [/bib_ref] Kim et al. [bib_ref] Evaluating the optimal dose of teicoplanin with therapeutic drug monitoring: not too..., Kim [/bib_ref] reported that a loading dose of three doses of 9 mg/kg q12h could achieve a trough concentration of 20 mg/L within 10 days and improve the clinical outcome of teicoplanin treatment. However, the relatively There are limited data on the maintenance dose needed to sustain a trough concentration of 20 mg/L. Therefore, an increase in the suggested maintenance dose (6.7 mg/kg) might be considered even in patients who achieved the target trough concentration after receiving the loading dose for the initial 3 days. Early follow-up TDM (e.g. prior to the 4th or 5th maintenance dose) should be performed to confirm a trough concentration of 20 mg/L after the start of maintenance therapy irrespective of dose adjustment.
Review high daily maintenance dose (mean 11.3 mg/kg) had a significant impact on this result, and high trough concentrations were observed, especially in patients measured on Days 7-10. In general, three to five doses of teicoplanin 12 mg/kg q12h is suggested for the early achievement of trough concentrations 20 mg/L. A simulation study has indicated that a loading regimen of five doses of 12 mg/kg at 12 h intervals would be needed to ensure a high likelihood of achieving the target trough concentration of 20 mg/L within 72 h. [bib_ref] Population pharmacokinetics of total and unbound teicoplanin concentrations and dosing simulations in..., Byrne [/bib_ref] demonstrated in a clinical study that a trough concentration of 20 mg/L was achieved in 75% of patients receiving five doses of 12 mg/kg q12h within 3 days, compared with 41% for a regimen of five doses of 10 mg/kg within 3 days. Possibly because of a high incidence of hypoalbuminaemia in the study population, Mimoz et al. [bib_ref] Steady-state trough serum and epithelial lining fluid concentrations of teicoplanin 12 mg/kg..., Mimoz [/bib_ref] reported an achievement rate of 31% for a target concentration of 20 mg/L with the same loading dose regimen (five doses of 12 mg/kg q12h within 3 days).

## Maintenance dose
Once an effective concentration of teicoplanin is achieved within the first 72 h using an adequate loading dose regimen, the target concentration must be maintained over time. In general, 6 26 or 6.7 mg/kg 12 q24h has been used as the maintenance dose in patients with normal renal function. However, a higher maintenance dose might be required to sustain a trough level of 20 mg/L that was obtained with an enhanced loading dose regimen. Although the trough levels from follow-up TDM were not available, Li et al. [bib_ref] Optimal teicoplanin loading regimen to rapidly achieve target trough plasma concentration in..., Li [/bib_ref] used 800 mg q24h following three doses of 800 mg q12h. Tsai et al. [bib_ref] Impact of teicoplanin maintenance dose and MIC values on the clinical outcomes..., Tsai [/bib_ref] reported that patients in the high-dose maintenance regimen (6 mg/kg q12h) group had a statistically significant favourable outcome at the end of treatment after appropriate propensity score matching. CQ 7. How can the dosage regimen of teicoplanin be optimized to achieve the target trough concentration in patients with renal dysfunction?
Executive summary (a) Dose adjustment based on actual body weight and estimated glomerular filtration rate (mL/min/1.73 m 2 ) is recommended in patients with reduced renal function. A nomogram is presented in [fig_ref] Table 3: Nomogram of the teicoplanin regimen in patients with renal dysfunction [/fig_ref]. (b) A loading dose for the initial 3 days is still recommended in patients with reduced renal function [bib_ref] Teicoplanin therapeutic drug monitoring in critically ill patients: a retrospective study emphasizing..., Pea [/bib_ref] [bib_ref] Enhanced loading regimen of teicoplanin is necessary to achieve therapeutic pharmacokinetics levels..., Ueda [/bib_ref] [bib_ref] Development of teicoplanin loading regimen that rapidly achieves target serum concentrations in..., Nakamura [/bib_ref] [bib_ref] Recommendations to achieve rapid therapeutic teicoplanin plasma concentrations in adult hospitalised patients..., Brink [/bib_ref] [bib_ref] Recommended initial loading dose of teicoplanin, established by therapeutic drug monitoring, and..., Sato [/bib_ref] [bib_ref] Determination of the distribution volume that can be used to calculate the..., Wada [/bib_ref] [bib_ref] Concentration of teicoplanin in the serum of adults with end stage chronic..., Mercatello [/bib_ref] [bib_ref] Teicoplanin pharmacokinetics in patients with chronic renal failure, Bonati [/bib_ref] , although the dosage should be adjusted according to the patient's degree of renal function (II). 89 (c) Substantial impact on renal function should be considered in the subsequent maintenance dosing of teicoplanin, and maintenance doses should be adjusted by reducing the amount of each dose, increasing the interval between doses, or both. [bib_ref] Pharmacokinetics of teicoplanin in renal failure, Falcoz [/bib_ref] [bib_ref] Significance of individual adjustment of initial loading dosage of teicoplanin based on..., Niwa [/bib_ref] However, further studies are needed to establish a better maintenance dose regimen than is currently suggested in patients with renal dysfunction (III-A). (d) Maintenance doses should be optimized by follow-up TDM in patients with reduced renal function.

## Review
In general, a loading dose is administered in hydrophilic antibiotics to compensate for the increased volume of distribution during the first day of sepsis. [bib_ref] The influence of acute kidney injury on antimicrobial dosing in critically ill..., Blot [/bib_ref] Therefore, an initial dose reduction is not recommended, irrespective of the patient's renal function.
After the loading dose, the maintenance dose was reduced in patients with renal dysfunction. In contrast, because of the extremely long half-life, 7 a loading dose for 2-3 days is mandatory for all patients on teicoplanin to achieve the optimal concentration more rapidly. Because of the longer administration of the loading dose than that of other antibiotics, the impact of drug clearance should be considered for the loading dose regimen before reducing the maintenance dose in patients with renal dysfunction.
Byrne et al. [bib_ref] Population pharmacokinetics of total and unbound teicoplanin concentrations and dosing simulations in..., Byrne [/bib_ref] reported that a loading dose of five doses of 12 mg/kg q12h was needed to attain a target trough concentration of 20 mg/L in patients with creatinine clearance (CL CR ) of 70 mL/min, whereas for patients with CL CR values of 20-40 mL/ min, each dose could be reduced to 10 mg/kg. In a simulation study, [bib_ref] Simplified dosing regimens of teicoplanin for patient groups stratified by renal function..., Yamada [/bib_ref] patients with normal renal function and mild renal dysfunction showed a trough concentration of 15 mg/L following six doses of 400 mg for an initial 3 days. However, patients with moderate and severe renal dysfunction achieved the target trough concentration following five doses of 400 mg for 3 days. In a clinical study, reported that trough concentrations can be obtained with a reduced loading dose regimen in patients with reduced renal function at similar levels to those with normal renal function. Although Byrne et al. [bib_ref] Population pharmacokinetics of total and unbound teicoplanin concentrations and dosing simulations in..., Byrne [/bib_ref] suggested an increased dose of five doses of 18 mg/kg q12h for patients with a CL CR value of 130 mL/min, a recommended dosing regimen for the initial 3 days in patients with sepsis and augmented renal clearance has not been able to be established in this guideline.
PK analysis of a loading dose for 3 days was the primary endpoint in most studies, 12,19 and the maintenance dose suggested in these guidelines is based on the regimen adopted in these studies. The maintenance dose should be evaluated by follow-up TDM in patients who achieved the target trough concentration during initial TDM following the loading dose, and the appropriateness of suggested maintenance dose should be verified via clinical research. In a simulation study, 4 mg/kg q24h in patients with a CL CR value of 40 mL/min, and 2 mg/kg q24h in patients with a CL CR value of 20 mL/min were suggested to achieve a trough concentration of 20 mg/L. [bib_ref] Population pharmacokinetics of total and unbound teicoplanin concentrations and dosing simulations in..., Byrne [/bib_ref] CQ 8. What are the recommendations for performing TDM in patients with hypoalbuminaemia?
Executive summary (a) Teicoplanin is highly bound to serum albumin, and therefore patients with hypoalbuminaemia have higher unbound fractions of teicoplanin. An increase in the unbound fraction may result in an increased volume of distribution and clearance of teicoplanin, which can lead to reduced total teicoplanin concentrations (II). 12,99 (b) Although total concentration is decreased in patients with hypoalbuminaemia, the concentration of the unbound drug, which is responsible for efficacy and safety, remains unchanged. Alternatively, only the concentration of the bound fraction is decreased. Therefore, adjustment of the recommended loading dose regimen is not necessary for patients with hypoalbuminaemia (III-C). (c) The target trough teicoplanin concentration might be lowered in patients with hypoalbuminaemia, depending on the degree of hypoalbuminaemia, compared with patients without hypoalbuminaemia (III-A). 89

## Literature review
Teicoplanin is highly protein bound (.90%), and therefore the unbound fraction of teicoplanin is higher in patients with hypoalbuminaemia, which is relatively common in patients in ICUs (correlation coefficient = 0.6; P , 0.001), than in patients without hypoalbuminaemia. [bib_ref] Variability in trough total and unbound teicoplanin concentrations and achievement of therapeutic..., Byrne [/bib_ref] Even if the total trough teicoplanin concentration is decreased in patients with hypoalbuminaemia, the concentration of unbound drug, which is responsible for the efficacy and side effects of the drug, will remain unchanged. Byrne et al. [bib_ref] Population pharmacokinetics of total and unbound teicoplanin concentrations and dosing simulations in..., Byrne [/bib_ref] developed a nomogram to estimate the unbound concentration of teicoplanin from the measured total trough teicoplanin and serum albumin concentrations. In patients with normal serum albumin concentrations (3.4-3.6 g/dL), the estimated unbound concentration of teicoplanin for patients with total teicoplanin concentrations of 20 mg/L was 1.2-1.3 mg/L. To attain the corresponding unbound teicoplanin concentrations in patients with moderate (2.4-2.6 g/dL) and severe hypoalbuminaemia (1.4-1.6 g/dL), the nomogram indicated that total serum concentrations of 15 and 10 mg/L, respectively, will be sufficient. CQ 9. What is the recommended dosing regimen to achieve the target trough concentration for CVVHDF?
Executive summary (a) For the initial 3 days, a loading dose of teicoplanin 10 mg/kg twice on Day 1 and once on Days 2 and 3 is suggested to attain a target trough concentration of 15-30 mg/L (III-A). 14,37-42 (b) A loading dose of 12 mg/kg twice on Day 1 and once on Days 2 and 3 is suggested to attain a target trough concentration of 20-40 mg/L (III-A). 14 (c) Five doses of 12 mg/kg within the initial 3 days might be considered in patients receiving CVVHDF with a high flow rate (III-A). 37 Review (d) Although additional study is required, subsequent maintenance doses of 3-3.3 mg/kg once daily might be considered (III-B). [bib_ref] Enhanced loading dose of teicoplanin for three days is required to achieve..., Ueda [/bib_ref] [bib_ref] Teicoplanin pharmacokinetics in critically ill patients on continuous veno-venous hemofiltration, Bellmann [/bib_ref] [bib_ref] Teicoplanin pharmacokinetics and dosage recommendations in chronic hemodialysis patients and in patients..., Wolter [/bib_ref] [bib_ref] Proposal of a pharmacokinetically optimized dosage regimen of antibiotics in patients receiving..., Yamamoto [/bib_ref] An increased maintenance dose is required in patients receiving CVVHDF with a high flow rate (III-A). 37

## Literature review
Although teicoplanin was previously considered to be nondialysable by CVVHDF because of its high protein binding, subsequent analysis has revealed that CVVHDF removes a considerable amount of teicoplanin. In an in vitro adsorption study, Shiraishi et al. [bib_ref] Elimination of teicoplanin by adsorption to the filter membrane during haemodiafiltration: screening..., Shiraishi [/bib_ref] reported that teicoplanin was significantly and predominantly adsorbed by polymethyl methacrylate membranes. Another study found that an average of 19.3% of the teicoplanin was removed in a 3.5 h dialysis session using a high-flux polysulfone membrane. [bib_ref] Single-dose pharmacokinetics of teicoplanin during hemodialysis therapy using high-flux polysulfone membranes, Thalhammer [/bib_ref] For patients in Western countries, Wolter et al. [bib_ref] Teicoplanin pharmacokinetics and dosage recommendations in chronic hemodialysis patients and in patients..., Wolter [/bib_ref] suggested a teicoplanin loading dose of 800 mg once on Day 1, followed by 400 mg once daily on Days 2 and 3, and a maintenance dose of 400 mg every 48-72 h for the treatment of patients undergoing CVVHDF. Bellmann et al. [bib_ref] Teicoplanin pharmacokinetics in critically ill patients on continuous veno-venous hemofiltration, Bellmann [/bib_ref] reported that a loading dose of 1200 mg once on Day 1, followed by 400 mg once on Days 2 and 3, with a maintenance dose of 600-1800 mg daily was required to achieve a target trough concentration of 15-25 mg/L in critically ill patients undergoing CVVHDF with a blood flow rate of 35 mL/kg/h (2445 mL/h). However, the blood flow rate of CVVHDF in Japan is set at 800 mL/h, which is lower than that in Western countries. Ueda et al. 14 used a high-dose regimen (four doses of 10 mg/ kg) and an enhanced regimen (four doses of 12 mg/kg) for the initial 3 days in patients undergoing CVVHDF at 20 mL/kg/h. The same maintenance dose (3.3 mg/kg once daily) was used. The proportion of patients achieving concentrations of 15 and 20 mg/L were 50.0% and 8.3%, respectively, for the highdose regimen and 88.2% and 52.9%, respectively, for the enhanced regimen. Nakamura et al. [bib_ref] Development of teicoplanin loading regimen that rapidly achieves target serum concentrations in..., Nakamura [/bib_ref] reported that a loading dose of four doses of 12 mg/kg q12h enabled 68.4% of patients undergoing continuous renal replacement therapy using a polymethyl methacrylate membrane to attain a serum concentration of 15-30 mg/L on Day 3.

## Limitations of the guidelines
These guidelines have several limitations. First, no RCT to determine the target trough concentration of teicoplanin required to obtain clinical efficacy was included. Second, because routine follow-up TDM after the start of the maintenance dosing was not conducted in most studies, the suggested maintenance doses in these guidelines should be verified by additional studies. Third, although performing TDM on Day 4 is recommended, earlier TDM (e.g. on Day 3) was performed in some studies included in the systematic review. There is a risk of incorrect estimation of trough level in patients with TDM on Day 3, as mentioned in CQ 3. Finally, AUC-based dosing using Bayesian estimations should be considered for teicoplanin in future guidelines.
[table] Table 1: Grading system for ranking recommendations and evidence levels adopted in the guidelines PK for the use of MIPD in clinical practice. [/table]
[table] Table 2: Dosage regimen of teicoplanin to achieve the target trough concentration in patients with normal renal function (eGFR  [/table]
[table] Table 3: Nomogram of the teicoplanin regimen in patients with renal dysfunction [/table]