Impact on Antibiotic Resistance, Therapeutic Success, and Control of Side Effects in Therapeutic Drug Monitoring (TDM) of Daptomycin: A Scoping Review

Antimicrobial resistance (AR) is a problem that threatens the search for adequate safe and effective antibiotic therapy against multi-resistant bacteria like methicillin-resistant Staphylococcus aureus (MRSA), and vancomycin-resistant Enterococci (VRE) and Clostridium difficile, among others. Daptomycin is the treatment of choice for some infections caused by Gram-positive bacteria, indicated most of the time in patients with special clinical conditions where its high pharmacokinetic variability (PK) does not allow adequate plasma concentrations to be reached. The objective of this review is to describe the data available about the type of therapeutic drug monitoring (TDM) method used and described so far in hospitalized patients with daptomycin and to describe its impact on therapeutic success, suppression of bacterial resistance, and control of side effects. The need to create worldwide strategies for the appropriate use of antibiotics is clear, and one of these is the performance of therapeutic drug monitoring (TDM). TDM helps to achieve a dose adjustment and obtain a favorable clinical outcome for patients by measuring plasma concentrations of an administered drug, making a rational interpretation guided by a predefined concentration range, and, thus, adjusting dosages individually.


Introduction
The World Health Organization (WHO) has reviewed in detail the increase in antimicrobial resistance (AR), which represents a threat to health worldwide [1]. According to the report on AR, this problem is among the top 10 public health threats and is related to the inappropriate use of antibiotics [2]. Due to the great spread of multi-resistant (MDR) and pan-resistant bacteria that have acquired various multi-resistance mechanisms, these are compromising the ability of antibiotics to control infection and produce a favorable clinical outcome for patients [3].
Due to this situation, the WHO has classified MDR bacteria into two different groups according to the priority regarding antimicrobial therapy and the development of new antibiotics [4]. A list of antibiotic resistant bacteria was reported, describing some Grampositive bacteria such as Methicillin-resistant Staphylococcus aureus (MRSA) and vancomycinresistant Enterococci (VRE) and Clostridium difficile. These microorganisms comprise 7 of the 18 urgent and serious AR-related threats described by the United States Centers for Disease Control and Prevention (CDC) [5], and they are one of the main risk factors associated with in-hospital mortality [6][7][8]. For this reason, it has been necessary to develop strategies that allow an early diagnosis, focusing on the identification of the causative microorganism and initiating a timely and adequate anti-infective treatment to reduce the risk of mortality and increase rates of therapeutic success [7,8]. Infections caused by Gram-positive bacteria are resistant to multiple antibiotics [9], and despite their frequency, there are few studies that report the best management practices for these infections, for which the WHO has created campaigns focused on the research and development of new antibiotics [1]. Currently, there are two antibiotics approved by the US Food and Drug Administration (FDA) for the treatment of MRSA bacteremia and endocarditis: vancomycin and daptomycin [10].
Daptomycin is categorized as one of the latest antibiotics developed for the management of serious infections caused by multi-resistant germs, especially Gram-positive bacteria. Additionally, it has been shown that despite low doses, it could develop severe side effects, which is why performing therapeutic drug monitoring (TDM) would be ideal to control complications and maintain doses within therapeutic ranges.

Structure and Mechanism of Action of Daptomycin
Daptomycin is a cyclic lipopeptide antibiotic that is structurally and functionally related to cationic antimicrobial peptides produced by the innate immune system. The daptomycin molecule consists of a cyclic polypeptide nucleus (tridecapeptide) of 13 amino acids, six of which are non-proteinogenic: D-Asn, ornithine (Orn), D-Ala, D-Ser, (2S, 3R)methylglutamate (MeGlu), and kynurenine (Kyn) [11]. The 10 terminal carbon residues form a closed macrocyclic ring via an ester bond and an exocyclic side chain of 3 amino acids with a terminal tryptophan (Thr) linked to a decanoic acid residue [12], and it contains an altered sequence of the N-terminal decanoyl fatty acid lethal chain [13].
Regarding its mechanism of action, daptomycin is a calcium-dependent antibiotic (CDA), which results in membrane depolarization and loss of intracellular components, such as K + , Mg 2+ , and ATP [14], which is attractive by not causing bacterial lysis [15]. The groups responsible for this activity are the core macrocycle (binding of an ester bridge) and the group containing tsushimycin (amphomycin, laspartomycin, and several others). Likewise, these groups share the mechanism of action, which consists of binding and sequestering a constituent of the bacterial membrane (undecaprenol phosphate), which is important in the transport of coenzymes and in the assembly and translocation of peptidoglycan precursors in the plasma membrane [11].

Pharmacokinetic and Pharmacodynamic Considerations
Daptomycin exhibits the following pharmacokinetic/pharmacodynamic (PK/PD) characteristics: (1) hydrophilic drug [16,17]; (2) high binding to plasma proteins (92-94%); (3) small volume of distribution (Vd) (0.1 L/kg); (4) renal elimination [6,16]; (5) elimination half-life (V 1/2 ) of 8 to 9 h; and (6) post-antibiotic effect up to 6.8 h [17,18]. This antibiotic is used mainly for the management of bacteremia, complicated skin and soft tissue infections, and endocarditis secondary to Gram-positive bacteria [8,15,18]. The PK/PD index allows us to analyze the relationship between dose and effect, taking into account plasma concentration as an important variable when relating drug exposure with the minimum inhibitory concentration (MIC) of the pathogen. Based on this, antimicrobials are classified by the following PK/PD indices that describe their efficacy: (1) time-dependent-the drug concentration remains above the MIC in a dose interval (fT > MIC); (2) concentrationdependent-the maximum concentration peak remains above the MIC (C max /MIC); and (3) area under the curve-the concentration and time remain above the MIC for at least 24 h (AUC 0-24 /MIC) [6,7,19]. The bactericidal effect of daptomycin is associated with an AUC/MIC > or equal to 200 [7], but recent studies have shown greater therapeutic efficacy with AUC/MIC levels > 666 [6,7,20] and a C max /MIC between 12-94 to obtain an optimal bacteriostatic effect [7] and suppression of bacterial resistance [19]. Therapeutic efficacy is directly related to optimal serum concentrations [19,20], which are expected to be obtained by means of a standard dosage schedule.
When we face patients with special clinical conditions (sepsis, obesity, chronic kidney disease, renal replacement therapy (RRT), and hypoalbuminemia), it is not so feasible to obtain adequate plasma levels because they present pathophysiological changes altering the PK of medications, leading to a variable exposure and obtaining sub or supraoptimal concentrations despite receiving the recommended doses [7,19,21,22]. Therefore, it is essential to optimize the use of antibiotics in these types of patients, performing individual dosage regimens to maximize efficacy, minimize toxicity, and achieve PK/PD goals [7,8,16,19]. A method that can contribute to the rational individualization of pharmacological treatments and the evolution of personalized medicine [23,24] is therapeutic drug monitoring (TDM), which involves the following: (1) the measurement of plasma concentrations of some drugs or in different biological fluids (plasma, serum, urine, saliva, etc.) of patients [7]; (2) dose individualization based on circulating plasma exposure, targeting a predefined concentration range [24]; and (3) maintaining blood levels within the therapeutic window to achieve PK/PD objectives and thus increase the probability of achieving therapeutic success and reduce the risk of toxicity and development of bacterial resistance [8,19,25,26].
TDM is a method that allows the plasma concentrations of an administered drug to be measured, and then a rational interpretation can be made, guided by a predefined concentration range, and thus the doses can be adjusted individually [21,24]. Initially, TDM was used only to reduce the risk of toxicity of some specific medications, especially those with a narrow therapeutic index (NTI) [6,26,27]; however, taking into account the possible changes that a drug may undergo in plasma concentration after administration and its close relationship with pharmacological effects, it is considered that it can also help to achieve PK/PD goals and thus improve the therapeutic efficacy of many other drugs, such as antibiotics [6,25,26].
TDM allows to one differentiate the clinical symptoms and signs secondary to toxicity due to overdose, compared with the clinical condition that can be easily confused [24]. However, the rational interpretation of TDM and the consequent dose adjustment require knowledge of the following: (1) availability of a precise and selective bioanalytical assay with a fast response time; (2) defined target concentration range to obtain drug response; (3) understanding of the PK characteristics of the measured drug; (4) susceptibility of the causative bacterial pathogen [7,19,25]; (5) PK/PD variabilities of each patient according to their clinical condition; and (6) suspected drug interactions and side effects [23].
Despite the fact that TDM was initially used in drugs with NTI in order to reduce the risk of toxicity, it is considered that there is the possibility of a new use and approach given to the increase of multidrug-resistant germs associated with serious infections, which increasingly present limitation in therapeutic options. The objective of this review is to describe the data available about the type of TDM method used and described in hospitalized patients with daptomycin and to describe its impact on therapeutic success, suppression of bacterial resistance, and control of side effects.

Results
Initial database searches yielded 578 unique articles, of which after refining the search according to the exclusion criteria, 55 studies were reviewed in their entirety, 16 were excluded, and 39 met the inclusion criteria ( Figure 1).

Therapeutic Monitoring Methods
Publication dates ranged from 2008 to 2020, and various types of methods for TDM in hospitalized daptomycin patients were described. Among the most common bioanalytical methods we found was the use of liquid chromatography-tandem mass spectrometry (LC-MS/MS) [16,22,25,29,33,37,42,46], followed by high performance liquid chromatography (HPLC) [8,18,23,28,30,41,47], ultrahigh pressure liquid chromatography-tandem mass spectrometry method (UHPLC-MS/MS) [38,39,43,44], high performance liquid chromatography with ultraviolet detection (HPLC-UV) [17,38], dual use of high performance liquid chromatography with ultraviolet detection (HPLC-UV), and liquid chromatographytandem mass spectrometry (LC-MS/MS) [6,7]. Other methods were also found, such as ultrahigh-performance liquid chromatography equipped with a photodiode array (UHPLC-PDA) [32,49], Bayesian estimation [21], and liquid chromatography using a core-layer octadecylsilyl microparticle coupled to tandem mass spectrometry [20]. Regarding clinical methods, dosing protocols were described [50], as were Monte Carlo simulations [43], and population PK models [46]. Additionally, there were five studies that described the importance of performing TDM in hospitalized patients with daptomycin to achieve therapeutic success, control of side effects, and control of bacterial resistance [19,27,32,34,49]. Table 2 summarizes the types of TDM methods found for daptomycin. It is a new option and a good alternative for the treatment of serious Gram-positive infections in critically ill patients.

Parameter Results
No. of publications per year It was found that the average C min and C max described by the TDM methods was 13.16 mg/L (7,41,45,46,49) and~66.6 mg/L [8,16,42,46,50], respectively. The AUC/MIC results were variable depending on the administered dose. For doses of 6 mg/kg/day and 8 mg/kg/day, there was evidence of an average value of AUC/MIC of~642.69 and 788.85, respectively, levels higher than those recommended to obtain therapeutic efficacy. This shows us that patients with severe infections who received doses of 8 mg/kg/day have higher values of C max and AUC/MIC compared to those who received doses of 6 mg/kg/day, having a greater probability of therapeutic success [19].
It should be noted that the blood samples studied in the different articles were taken from populations that were in different clinical conditions, but these results showed us in detail that the different bioanalytical methods used to perform TDM in patients hospitalized with daptomycin helped to optimize treatment and achieve therapeutic success in patients with Gram-positive bacterial infections.

Bacterial Resistance
Very little is known about the frequency of occurrence of Gram-positive bacteria resistant to daptomycin. However, over the years, some reports have appeared related to microorganisms such as Staphylococcus aureus, Enterococcus faecium, and Enterococcus faecalis. This resistance occurs mainly in the context of prolonged treatment and infections with a high bacterial load, but it can occur in the presence of previous exposure to daptomycin. It seems that resistance both in Staphylococcus spp. and Enterococcus spp. is mediated by adaptations to cell wall homeostasis and membrane phospholipid metabolism [3,51].
During the analysis of the articles, none of them showed development of bacterial resistance to daptomycin, but yet there was a need to increase the dose in those patients with bacteremia and persistent infections by Gram-positive bacteria. A case report describes a patient with bacteremia that persisted with positive blood cultures 14 days after starting treatment with daptomycin, which is why he required dose adjustment to up 14 mg/kg/day to achieve PK/PD goals and therapeutic efficacy [27].

Therapeutic Success and Control of Side Effects
It was possible to show that most of the methods described reached levels of AUC/MIC and C max /MIC, reaching daptomycin PK/PD goals [8,19,40,[44][45][46]49] with doses of 6-8 mg/kg/day [17,23,42]. Additionally, it was found that for those bacteremia or persistent infections, the dose needed to be increased >8 mg/kg/day, related to an increase in the levels of C min [18], but without development of side effects [17,18,22,46,51]. The C min > 24.3 mg/L, has been associated with an elevation of creatine kinase (CPK) of up to 30 times [6,7,27], being the main marker of toxicity at the muscle level due to the use of daptomycin [35]. Patients with special clinical conditions, mentioned previously, require dose adjustment of daptomycin, since an increase in half-life could be evidenced (V 1/2 ) as well as a decreased in renal clearance (CL), leading to an increase in plasma concentrations, and therefore, a high risk of developing side effects associated with elevated CPK [21,23,32]. One study showed an increase in CPK in approximately 43-64% of the study population, without subsequent complications [50]; therefore, daptomycin is an antibiotic candidate for TDM, especially for those patients with special clinical conditions due to its intra-and inter-individual variability of their PK/PD [18,48].

Discussion
Most of the articles selected within this review describe a significant benefit in terms of performing TDM for hospitalized patients with daptomycin, especially those with special clinical conditions (obesity, chronic kidney disease, hypoalbuminemia, renal replacement therapy). TDM studies have been carried out in this type of population because they present alterations in their PK, ignoring the behavior of the drug, and as a consequence presenting a change in plasma concentrations with a high risk of presenting therapeutic failure or toxicity [6,17,18,22,35,36,52]. The interest in this group of patients is based on the great burden of infection presented by Gram-positive bacteria as the causative agent, being closely related to an increase in mortality [6,15]. Hematoncological patients, for example, have resistance rates to methicillin of approximately 70% to 80%, with VRE being responsible for up to 41.1% of all Gram-positive bacteremia [17]. In hemodialysis patients, MRSA is the main infectious agent [46], being responsible for almost 30% of all deaths [15,49].
According to what has been reported in the literature, daptomycin is used for the treatment of serious infections caused by Gram-positive bacteria, especially for those strains that present resistance to the usual therapeutic options [8,17,49]. However, reports of daptomycin resistance towards strains of S. aureus and Enterococcus spp. have been associated with a mutation in the vraS and pitA genes that generates alterations in three glycerophosphoryl diester phosphodiesterase proteins (GdpD), (LiaF, GdpD, and Cls) and additionally, a greater voltage difference across the cytoplasmic membrane, reducing binding to its site of action [52,53].
It is important to note that daptomycin undergoes significant changes in its PK/PD in populations with special clinical conditions [47], being associated with a variability of serum levels despite receiving the standard dose [6][7][8]18]. In this type of population, it is suggested to increase the dose up to >8 mg/kg/day if they present serious infections, and the performance of TDM is of great support to be able to optimize management, guarantee therapeutic efficacy, and decrease risks of side effects and bacterial resistance [17,18,23]. However, despite the recommendations in favor of the use of TDM in patients with daptomycin, controversy is evidenced by positions where it is recommended that TDM is not necessary for dose adjustment given that the PK/PD changes of daptomycin are minimal. In addition, there were others who maintained an impartial position for not being able to recommend or contraindicate TDM for patients with daptomycin use [6,15].
Daptomycin and linezolid are among the last available options for the treatment of resistant Gram-positive infections [54,55]. In the treatment of Staphylococcus aureus bacteremia, vancomycin TDM has been part of the standard of care [56]; this is in consideration of its NTI. Daptomycin is not different, and the use of high doses of daptomycin is increasingly needed in scenarios such as endocarditis [57], and these dosages are frequently accompanied by marked elevations of CPK, especially in critically ill patients or patients with chronic kidney disease [58]. In clinical practice, it is common that CPK elevation leads to treatment withdrawal with daptomycin. TDM would make the event less frequent, but additionally, in cases where toxicity occurs, TDM would facilitate dosage adjustment and eventually allow continuity of a drug that may be the last therapeutic option in many clinical settings [59].
Different bioanalytical methods have been developed and published for the detection and quantification of daptomycin in plasma. Despite finding great variability in the techniques and the populations studied, all methods are suitable for pharmacokinetic studies and performance of daptomycin TDM [27,32]. However, it should be taken into account that the routine implementation of TDM requires a change in clinical practice, as well as a monetary investment for human, scientific, and technological talent; therefore, a prior evaluation of the technique should be made for each institution and its population [21].
As with all reviews, this study had limitations. First, the articles found were few and with low quality of evidence. Second, the populations were very different between the methods used for TDM, probably leading to results with a wide range. The few studies found and the heterogeneity in study design and population are major limitations of this review, as it is difficult to compile and compare results from a small collection samples with potential sampling bias.

Search Strategy
In November 2020, we chose to conduct a scoping review of the literature to provide an overview of the information available on therapeutic drug monitoring in hospitalized patients with daptomycin use. A research protocol was designed, which was approved by the research subcommittee of the Faculty of Medicine of the University of La Sabana, which was developed under the guidelines of the Joanna Briggs Institute for Panoramic Reviews [60].
We performed a bibliographic search through the following databases: PubMed, EMBASE, Web of Science, and Scopus. We used key terms without restriction of date or language. Keywords searches included drug monitoring, therapeutic drug monitoring, and daptomycin. Supplementary Material Table S1 shows the search strategies that were used for each of the databases. Additionally, a literature search was performed in Open Gray System information on Gray Literature in Europe (http://www.opengrey.eu (accessed on 15 January 2021)), without results. Figure 1 summarizes the selection process that was carried out. Once the final references were obtained, they were classified in EndNoteX9 software by eliminating duplicates. Through the Rayyan QCRI platform (https://rayyan.qcri.org (accessed on 15 January 2021)), COR and LGP independently applied the study inclusion criteria from the titles and abstracts to later obtain the full texts of the articles for review. Discrepancies of the included studies were resolved through discussion and consultation with the co-authors.

Inclusion and Exclusion Criteria
Articles were included if they described aspects related to daptomycin TDM in hospitalized patients regardless of its indication, those that described clinical and bioanalytical methods of monitoring, control of its side effects, bacterial resistance, and/or therapeutic success. Exclusion criteria were based on studies that spoke of patients with outpatient medical management and therapeutic monitoring of antibiotics other than daptomycin.

Graphing the Data
Once we reviewed the articles and considered them eligible, we summarized the main research results of each study and organized them in a graph using the following titles: monitoring method, population (n), objective, type of study, bioanalytical and clinical results, and conclusions (Table 1).

Collecting, Summarizing, and Reporting the Results
From Table 1, the researchers (COR and LGP) summarized the results corresponding to each of the research objectives, organized them thematically, and described and discussed them in detail. Specifically, the findings of the study characteristics, including type of clinical or bioanalytical method used for drug monitoring, year of publication, type of study, and PK/PD values, were noted, and we summarized the results of the thematic analysis in a tabular format (Table 2) corresponding to the research objectives as described here.

Conclusions
The need to create worldwide strategies for the appropriate use of antibiotics is clear, and one of these is the performance of therapeutic drug monitoring (TDM). This type of method brings great benefits, especially to those patients with special clinical conditions. In our study, it was possible to show that performing TDM helps us find certain benefits, such as (1) maintaining plasma levels within the therapeutic range; (2) adjusting the dose in a timely manner, based on PK/PD goals; and (3) controlling side effects and the development of bacterial resistance. However, given the variability in the different published methods, the difficulty of implementing several of these (the need for financial, scientific, and human resources), and the scarcity of evidence, more studies are requiredprobably controlled clinical trials (CCT)-to establish a clear therapeutic range, adequately documenting the clinical impact on the patients studied in order to develop a rapid, accurate, and clinically validated monitoring model that can be established for the routine treatment of those patients with serious infections, and which can also contribute to the evolution of personalized medicine.
Due to the aforementioned implications, such as an NTI in some indications, the clinical impact on infections with few treatment options, and little research, we consider that daptomycin is a molecule that should be investigated further in order to achieve TDM methods that will be commercially available.