Therapeutic drug monitoring of antibiotics in critically ill patients

C H A P T E R

8 Therapeutic drug monitoring of antibiotics in critically ill patients Dagmar Horna,*, Christoph Klaasa, Manfred Fobkerb, Robin Köckc,d, Christian Lanckohrd a

Department of Pharmacy, University Hospital Muenster, Muenster, Germany; bLaboratory Medicine, University Hospital Muenster, Muenster, Germany; cInstitute of Hygiene, DRK Kliniken Berlin, Berlin, Germany; dInstitute of Hygiene, University Hospital Muenster, Muenster, Germany *Corresponding author. E-mail: [email protected]

Abstract The basic principle of therapeutic drug monitoring (TDM) is the quantification of drug concentrations in body fluids, mostly from venous blood samples, for optimizing drug dosage, improving clinical outcome, and minimizing toxicity. TDM was traditionally applied to a small number of drugs only, which possess a narrow therapeutic index. This means that for these drugs the window for either safety or toxicity is exceptionally small, and therapeutic ranges of drug concentrations have been defined. Hence, TDM was hitherto mainly offered for early-generation antiepileptics, mood stabilizers and antipsychotics, immunosuppressants, specific anticancer agents, and other, often older drugs like digoxin and theophylline. For antibiotic therapy, TDM was mainly used in clinical routine to monitor vancomycin and aminoglycosides, substances known to have a narrow therapeutic range. However, as antimicrobial multidrug-resistant pathogens, such as carbapenemaseproducing enterobacteria or Acinetibacter spp., are globally emerging limiting the availability of effective antibiotics, there is an urgent need to optimize dosing of anti-infectives. Especially in the early phase of antibiotic therapy, it is essential to optimize antibiotic dosages to reduce the bacterial inoculum at the infection site and also minimize the risk for promoting resistance. In today’s context, TDM of antibiotics in critically ill patients is not only used for limiting toxicity but in particular to guard against clinically inadequate concentrations and minimizing the risk of the development of resistance.

8.1 Introduction The basic principle of therapeutic drug monitoring (TDM) is the quantification of drug concentrations in body fluids, mostly from venous blood samples, for optimizing drug dosage, improving clinical outcome, and minimizing toxicity [1,2]. TDM was traditionally applied to a small number of drugs only, which possess a narrow therapeutic index [1,2]. This means

Methods of Therapeutic Drug Monitoring including Pharmacogenetics https://doi.org/10.1016/B978-0-444-64066-6.00008-3

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that for these drugs the window for either safety or toxicity is exceptionally small, and therapeutic ranges of drug concentrations have been defined [1]. Hence, TDM was hitherto mainly offered for early-generation antiepileptics, mood stabilizers and antipsychotics, immunosuppressants, specific anticancer agents, and other, often older drugs like digoxin and theophylline [2]. For antibiotic therapy, TDM was mainly used in clinical routine to monitor vancomycin and aminoglycosides, substances known to have a narrow therapeutic range [3]. However, as antimicrobial multidrug-resistant pathogens, such as carbapenemaseproducing enterobacteria or Acinetobacter spp., are globally emerging and limiting the availability of effective antibiotics, there is an urgent need to optimize dosing of anti-infectives. Moreover, the aging population challenges clinicians due to an increase of renal impairment and other chronic diseases, which influence pharmacokinetics (PK) of antibiotics and might compromise both treatment safety and success [4]. Critically ill patients often suffer from severe infections. In a large 1-day point prevalence study including 13,796 patients admitted to intensive care units (ICUs) from 75 countries, Vincent et al. showed that 51% of patients were considered infected and 71% were receiving antibiotics [5]. Infection was independently associated with an increased risk of death in the ICU (25% vs. 11%, respectively; P < .001) and in hospital (33% vs. 15%, respectively; P < .001) [5]. Infections due to gram-negative organisms are as common as infections due to gram-positive bacteria [5]. In some cases the infection is polymicrobial [6]. As a high proportion of infections in ICU is of nosocomial origin [7,8], there is an increasing incidence of infections caused by antibiotic-resistant pathogens [7]. Owing to this raising bacterial resistance in common pathogens and uncertainties regarding optimal dosage in unclear PK, antibiotic therapy in critically ill patients confronts clinicians with enormous challenges. Especially in the early phase of antibiotic therapy, it is essential to optimize antibiotic dosages to reduce the bacterial inoculum at the infection site and also minimize the risk for promoting resistance. In today’s context, TDM of antibiotics in critically ill patients is not only used for limiting toxicity but in particular to guard against clinically inadequate concentrations and minimizing the risk of the development of resistance [3].

8.2 Aspects of pathophysiological changes in critically ill and their impact on antibiotic concentrations A significant body of literature elaborates the special PK of antibiotic dosing in critically ill patients [9e14]. In this paragraph, we will concentrate on some important aspects, which are known to have a significant effect on drug concentrations. Hypoalbuminemia is a common finding in critically ill patients, with reported incidences as high as 40%e50% [10]. Hypoalbuminemia can decrease the extent of antibacterial compounds bound to albumin, which in consequence increases the unbound fraction of the drug, rendering it available for distribution and clearance (CL) from the plasma [10]. Thus, hypoalbuminemia is able to increase the volume of distribution (Vd) and CL of moderately to highly protein-bound antibiotics [10,12]. As a consequence, these antibiotics are at high risk for missing the targeted concentrations. In severely infected critically ill patients, a systemic inflammatory response syndrome may lead to an extreme fluid extravasation into interstitial space due to endothelial damage and capillary leakage [2,12]. The resultant intravascular volume depletion is often treated with substantial amounts of fluid infusion, further changing the volume status of the whole body [12]. In sum, these alterations can lead to a significantly higher Vd, especially for

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hydrophilic antibiotics such as aminoglycosides, glycopeptides, beta-lactam antibiotics, and linezolid [12]. Secondary to this, plasma concentrations of these antibiotics can be markedly decreased and lower than expected [2]. As many antibiotics are cleared via renal excretion, their concentrations can be profoundly affected by changes in kidney function [12]. Some ICU patients develop augmented renal CL (creatinine CL of at least 130 mL/min) resulting in increased glomerular filtration and a higher CL of renally cleared antibiotics (aminoglycosides, beta-lactams, and glycopeptides). Again, a higher risk for low serum concentrations and underdosing is the consequence [12]. In contrast, other critically ill patients have an impaired renal function, which increases the risk for elevated serum concentrations and accumulation of renally excreted substances. Therefore, renal insufficiency necessitates an appropriate decrease in antibiotic dose to ensure therapeutic, but not toxic concentrations. It should be mentioned, however, that decreasing the dose of an antibiotic can also lead to subtherapeutic concentrations of the drug, which in turn may cause therapeutic failure. To further complicate the situation, renal replacement therapies in patients with acute kidney injury (AKI) have an impact on Vd and CL of drugs. A wide range of different modalities are used for renal replacement therapy in the ICU including intermittent hemodialysis (IHD), continuous veno-venous hemofiltration (CVVH), continuous veno-venous hemodialysis (CVVHD), continuous veno-venous hemodiafiltration (CVVHDF), or sustained low-efficiency dialysis (SLED). In principle, all methods possess different capacities of drug CL, which are also determined by different procedural settings [12]. As a result, dose adjustments of antibiotics in patients on different forms of renal replacement therapy are difficult and ultimately unpredictable. Only an individualized dosing schedule guided by TDM can help to ensure therapeutic concentrations, while minimizing the risk of adverse effects.

8.3 Aminoglycosides Since their discovery in the 1940s, aminoglycosides remained important antibiotics especially in the treatment of infections by gram-negative pathogens, although their nephrotoxic and ototoxic potential limits their use [1]. Over the years, the use of aminoglycosides has decreased, due to the emergence of bacterial resistance and the development of better-tolerated and potentially more effective drugs, such as extended-spectrum penicillins, cephalosporins, and the fluoroquinolones [15]. With the global spread of multidrugresistant bacteria, there is a renewed interest in the use of other aminoglycosides [15]. Aminoglycosides display concentration-dependent bactericidal killing. Their effect is increased when the ratio of the peak serum concentration (Cmax) to the bacterial minimal inhibitory concentration (MIC) reaches values of 10e12 [1]. Older literature with commonly used agents like gentamicin offered the basis for the widespread belief that high doses of aminoglycosides with trough levels >2 mg/L and peak level >12 mg/L carry a high risk for toxicity. These observations lead to intermittent dosing strategies that maintain Cmax of 4e10 mg/L and troughs of <1e2 mg/L [1]. Alternatively, a dosing method, by which the whole daily dose is given once daily, was adopted in the 1970s and gained popularity throughout the years [16]. This dosing strategy is commonly referred to as once-daily aminoglycosides (ODA) therapy [1,16]. Pharmacodynamic advantages of ODA are apparent

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including enhanced concentration-dependent killing kinetics, increased aminoglycoside postantibiotic effect, leukocyte enhancement, and decreased adaptive resistance of the bacterial pathogen [16]. High trough concentrations and a high drug exposure correlated a high area under the concentrationetime curve over 24 h (AUC24h), and have been linked with higher toxicity [16]. Still several studies found that trough concentrations were not meaningfully different with once-daily versus multiple-daily dosing, suggesting that ODA is at least as effective as more frequent dosing with less nephrotoxicity [16e18]. Nephrotoxicity and ototoxicity are the main adverse effects of aminoglycosides which are seen during therapy. While previous reports indicated that the toxicity is related to high drug concentrations (especially high trough concentrations), recent studies suggest that drug accumulation and duration of drug exposure are also important [1].The mechanisms leading to (often reversible) nephrotoxicity and irreversible ototoxicity are still unknown. It is assumed that following a reuptake of aminoglycosides in the proximal renal tubules, they accumulate within the lysosomal enzymes and phospholipids, leading to cell death and kidney injury [1,19]. For ototoxicity, which can manifest as vestibular or cochlear injury and may have a unilateral or bilateral involvement, saturable mechanisms and accumulation are discussed [1]. Presumably aminoglycosides bind to phosphoinositides, inhibit decarboxylase, and cause mitochondrial dysfunction leading to cell death [1,20]. Due their high potential for severe toxicity, a TDM is strictly recommended for all aminoglycosides, especially in patients with compromised kidney function and unstable pathophysiology.

8.3.1 Gentamicin Comparable with the other aminoglycosides, gentamicin demonstrates concentrationdependent killing and also has a postantibiotic effect. The regularly recommended dose of gentamicin is 4e7 mg/kg per day administered as a single dose or divided into two or three equal doses [15]. In severe infections or infections involving extensively drug-resistant bacteria, the dosage is 5e10 mg/kg daily [15]. The best predictor for clinical efficacy of gentamicin is the ratio of Cmax to MIC [15,21]. For a Cmax/MIC ratio of 2, clinical efficacy was just above 50%, whereas at a Cmax/MIC ratio >10, clinical efficacy rose to 90% [15,22,23]. For susceptible Enterobacteriaceae, a Cmax of 15e20 mg/L is considered sufficient [21]. Trough concentrations >0.5e2 mg/L have been associated with nephrotoxicity because of drug accumulation [21].

8.3.2 Tobramycin Tobramycin is somewhat similar compared to gentamicin, but its advantages include a greater intrinsic activity against Pseudomonas aeruginosa and activity against some gentamicin-resistant Pseudomonas aeruginosa and Acinetobacter baumannii strains. In addition, a lower nephrotoxicity was described [24]. The recommended dose of tobramycin is 4e7 mg/kg per day, administered as a single dose or divided into two or three equal doses [24]. As for gentamicin, a Cmax/MIC ratio of >10 predicts clinical efficacy of tobramycin [24]. Trough levels should be < 1 mg/L to minimize the risk of toxicity [2].

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8.3.3 Amikacin Amikacin incorporates an additional (S)-4-amino-2-hydroxybutyl (AHB) side chain into the 1-amino position of the deoxystreptamine moiety of kanamycin A, resulting in increased stability against most of the bacterial plasmid-mediated enzymes, which are responsible for resistance to aminoglycosides [25]. Because of this, amikacin is active against many gentamicin- and tobramycin-resistant gram-negative bacteria [25]. A dose of 15e20 mg/kg is recommended both as a once-daily dose or in two divided doses [25]. To avoid toxicity, trough concentrations of <5 mg/L have been proposed [2].

8.4 Vancomycin and teicoplanin More than 50 years after the approval of vancomycin, the necessity of applying TDM when the substance is used is still controversial [26]. As the early use was associated with a number of adverse effects, including nephrotoxicity, infusion-related toxicities, and possible ototoxicity, TDM was mainly advocated to minimize these adverse effects. In addition, the relationship between treatment success or therapeutic failure and serum concentration has not been established over a long period of time. In the consensus review from the American Society of Health-System Pharmacists, the Infectious Diseases Society of America (IDSA), and the Society of Infectious Diseases Pharmacists, it is highlighted that there is evidence, which demonstrated that adequate serum concentrations are inextricably linked with clinical success [27]. Based on these findings, they insist that TDM of vancomycin is mandatory especially in the treatment of serious Staphylococcus aureus infections. Also a recent systematic review and meta-analysis by Ye et al. showed a clear relation between serum concentration and clinical success and supported the use of TDM of vancomycin to increase efficacy and decrease nephrotoxicity [26]. Trough levels obtained at steady-state conditions (regularly right before the fourth dose) are recommended, representing the most practical method of monitoring the effectiveness of vancomycin [27]. They assume an acceptable relationship between trough and AUC [2]. Trough vancomycin levels should always maintain values > 10 mg/L to avoid the development of resistance [27]. To reach an AUC/MIC ratio of >400 for pathogens with MIC <1 mg/L, trough concentrations of 15e20 mg/L are recommended. Conventional dosing methods of vancomycin will not reach an AUC/MIC ratio of >800 for pathogens with MIC >2, especially in patients with normal to high renal function [27]. In these cases, alternative therapies should be considered [27]. In seriously ill patients, a rapid attainment of the target concentration is necessary, and the application of a loading dose of 25e30 mg/kg (based on actual body weight) can be considered [27]. 15e20 mg/kg given every 8e12 h seems to be an adequate maintenance dose in most patients with normal renal function [27]. It should be noted that even in patients with impaired renal function, the loading dose should not be adjusted. The fear of too high and potentially toxic vancomycin levels in the important early phase of infection is regularly unfounded, not least because close measurements of concentrations help preventing drug accumulation. The guidelines by Rybak et al. do not recommend continuous infusion of vancomycin [27]. The superiority of this application route had not been evidenced, and meta-analysis did not find a significant impact on clinical success, although nephrotoxicity seems to be reduced [27].

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The risk for vancomycin-associated nephrotoxicity increases in patients with trough concentration >20 mg/L, high daily doses (>4 g/d), concomitant treatment with nephrotoxic agents, and prolonged duration of therapy (>7 days) [28,29]. While trough concentrations were found to underestimate AUC of vancomycin by about 20% and therefore may lead to excessive dosing and an increasing risk of nephrotoxicity, an AUC-guided dosing strategy could be more suitable to maintain the target AUC24h > 400 [30,31]. Meng et al. performed a prospective observational quality study in hospitalized patients to compare the achievement of therapeutic target attainment after switching from a trough-based to an AUC-based dosing strategy by using a two-point sampling method. After implementation of the AUC-based dosing method, a lower percentage of patients had subtherapeutic concentrations (26.5% vs. 45%; P ¼ .0014), but nephrotoxicity only decreased from 11% to 9.4% (P ¼ .70 [30]). It is a debatable point whether these results can be transferred to critically ill patients, because the authors excluded patients with renal replacement therapy and AKI, thus a large proportion of patients in the ICU. Furthermore, determination of AUC requires at least taking two blood samples, and someone responsible for calculating it, and creating adequate dosage suggestions, which can be discussed with the prescribers [32]. In clinical routine, it seems more important that TDM is performed and the measured trough concentrations lead to dose adjustments, raising the chance of reaching the therapeutic range. Teicoplanin is a glycopeptide antibiotic. It was licensed during the early 1990s throughout Europe and in some other countries, with the exception of the United States. Vancomycin and teicoplanin show a similar spectrum of activity, with the exception of coagulase-negative staphylococci, where a higher MIC of teicoplanin can be found [33,34]. In patients treated with teicoplanin, the incidence of nephrotoxicity is smaller than in those treated with vancomycin [35,36]. The best predictor for clinical efficacy the AUC24h/MIC ratio with a target value of >400 is proposed [37,38]. Performing TDM is recommended to raise the probability of target attainment, and the intended trough levels are >10 mg/L for most severe infections and >20 mg/L in life-threatening infections, endocarditis, and bone and joint infections [39e41]. As with vancomycin, a loading dose is necessary to reach those targets as soon as possible. Today three to five loading doses of 12 mg/kg (based on actual body weight) every 12 h, followed by a daily maintenance dose of 6e12 mg/kg, are recommended.

8.5 Beta-lactam antibiotics Beta-lactam antibiotics still represent the cornerstone of antibacterial therapy in many clinical settings. They are the most commonly prescribed class of antibiotics, have a wide therapeutic range, are rarely toxic, and have demonstrated strong clinical effectiveness using empiric regimes with fixed doses [3,42]. Nevertheless, an increase in MICs of common pathogens and the clinically important alterations in physiology of critically ill patients are factors that narrow the therapeutic window of beta-lactams and set the record straight on TDM, particularly in the ICU [3]. For beta-lactams, the PK/pharmacodynamic (PD) parameter associated with the most successful outcome is the percentage of time (T) of the dosing interval during which the unbound (free, f) serum antibiotic concentration remains at least above the MIC for the targeted organism [3]. These time-dependent antibiotics achieve more bacterial killing the longer they remain

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at serum levels above the MIC [3,42]. Ariano et al. reported that febrile neutropenic adults with bacteremia reach an 80% clinical response rate when the %T > MIC for meropenem exceeded 75% of the dosing interval [43]. McKinnon et al. showed that patients treated with cefepime or ceftazidime in serious bacterial infections with %T > MIC of 100% had a significantly greater cure (82% vs. 33%; P ¼ .002) and bacteriological eradication (97% vs. 44%; P < .001) than patients with %T > MIC of <100% [44]. Optimal bacterial killing is reached when the antibiotic’s concentration in a target tissue is four to six times higher than that of the MIC of the treated pathogen [42,45e47]. A further increase in drug concentrations does not improve the killing rate significantly [45]. Roberts et al. determined in an international point prevalence study whether contemporary beta-lactam antibiotic dosing in critically ill patients achieves concentrations associated with maximal activity [42]. They evaluated blood samples of 361 patients from 68 ICUs across 10 countries. They found a wide variation in the unbound antibiotic concentrations and demonstrated that achievement of PK/PD targets was highly inconsistent [42]. In patients treated with piperacillin/tazobactam (n ¼ 109) and meropenem (n ¼ 89), only 30.3% and 41.6%, respectively, reached the suggested PK/PD target of 100% T > four times above the MIC. Also other reports confirmed that the recommended doses of beta-lactam antibiotics do not reach PK targets in a considerable fraction of critically ill patients with severe infections, especially in the early phase of sepsis and among those patients on continuous renal replacement therapy (CRRT) or with augmented renal CL [48e51]. This emphasizes the need for a more individual dosing regimen. One option is the optimization of administration strategies of betalactams. Due to their time-dependent bacterial killing properties, it seems reasonable that extended or continuous infusions may have a higher probability of reaching PK targets leading to a better outcome, particularly in the critically ill. A recent meta-analysis by Vardakas et al. compared the effect of prolonged (continuous application or > 3 h) versus short-term infusions of antipseudomonal beta-lactams (<60 min) on mortality of critically ill patients with sepsis [52]. When comparing 17 studies with 1597 patients, they were able to show that the prolonged infusion was associated with lower all-cause mortality (risk ratio 0.70, 95% CI 0.56e0.87) while clinical cure was not significantly higher with prolonged infusions [52]. The attainment of pharmacokinetic targets was not investigated in this analysis and the authors concluded that the contribution of TDM on the outcome of patients treated with prolonged infusion of betalactams merits further studies [52]. While prolonged infusion (over 3e4 h) reduces the risk of underdosing, continuous infusion without the support of TDM bears the risk of applying concentrations lower than MIC for the whole dosage interval. However, data showing superior clinical outcomes using TDM-guided dosing are still lacking [3].

8.6 Fluoroquinolones Fluoroquinolones exhibit concentration-dependent bacterial killing and also offer a postantibiotic effect. Their bactericidal activity becomes more pronounced as serum drug concentrations increase to approximately 10 times the MIC [53]. The best PK/PD parameter which predicts the efficacy is the 24-hr AUC/MIC ratio and the Cmax/MIC ratio [53]. The underdosage of fluoroquinolones can result in the selection of resistant strains and may promote resistance also against other classes of antibiotics [53e55].

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For ciprofloxacin, a Cmax/MIC ratio >10 and an AUC24h/MIC >100 have been proposed as predictors of therapeutic efficacy [53]. The Cmax/MIC is closely correlated with the AUC/MIC ratio and also predictive of clinical cure and predicting resistance selection with various fluoroquinolones, especially when Cmax/MIC is < 10 [54,56]. As early as 1993 Forrest et al. described that an AUC24h/MIC ratio of >125 was associated with a higher probability of clinical cure in 64 patients [57]. In a retrospective study of ciprofloxacin PD in the treatment of Pseudomonas aeruginosa bacteriemia, a Cmax/MIC ratio >7 was independently associated with better treatment outcome and the probability increased to >90% when Cmax/MIC ratio was at least 8 [58]. Zelenitsky and Ariano suggested in 2010 that a higher AUC24h/MIC ratio of >250 might be more appropriate [59]. The results of their review on clinical outcomes of 178 patients with gram-negative bloodstream infections showed that clinical cure was found in 91% of the cases with the higher AUC24h/MIC value, compared with 26% of the cases with an AUC24h/MIC value of <250 [59]. According to their data and a Monte Carlo simulation, they suggest an intravenous dosage of 400 mg twice daily may be sufficient for achieving the therapeutic targets in 88% of their targets [59]. For levofloxacin, the best predictor of clinical and microbiological outcomes is a Cmax/MIC ratio >12 [60]. Preston et al. showed that 99% of patients achieving this ratio have a successful outcome [60]. But standard doses of levofloxacin do not seem to reach this target. In a simulation comparing the probability of target attainment of levofloxacin and ciprofloxacin against Pseudomonas aeruginosa using PK data from healthy patients, levofloxacin achieved sufficient concentrations in only 48% of the simulated [61]. In a 5000-subject Monte Carlo simulation using the MIC of 230 isolates of Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis, standard doses of 400 mg moxifloxacin once daily achieved the target AUC24h/MIC (>33.7) in 100% of the simulated patients [62]. The disposition of fluoroquinolones might be different in obese patients and can be affected in the presence of organ failure especially in renal, but also in hepatic failure, as well as under organ replacement therapy and also in critical illness [53,63]. An increase in dosage may compensate the risk of underdosing but may be associated with an increase in toxicity. Sufficient PK data in special patient populations and especially in the critically ill are still lacking. As a result, recommended doses of fluoroquinolones, and in particular those for ciprofloxacin for special patient populations, offer an extensive range, raising the risk for both under- and overdosage. TDM may be an opportunity to optimize drug dosing of fluoroquinolones especially in critically ill patients.

8.7 Linezolid Linezolid is an oxazolidinone antibiotic. It possesses bacteriostatic activity against enterococci and staphylococci but is bactericidal for most streptococcal strains [2]. Its use has become increasingly important for the treatment of multidrug-resistant infections caused by grampositive microorganisms, e.g., methicillin-resistant Staphylococcus aureus (MRSA) or vancomycin-resistant enterococci (VRE) [64]. The recommended dosage of linezolid is 600 mg twice daily in a fixed-dose formulation, and current guidelines do not recommend TDM [64]. However, there is concern, that “one fits all” dosage does not reach a sufficient therapeutic range in a considerable number of patients. Recent studies report a wide inter- and

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intraindividual variability in PK, especially in critically ill patients or those with renal impairment [2,65,66]. In a prospective study of inpatients receiving standard doses of linezolid for empirical or targeted treatment, Galar et al. report that 65.5% of the patients had outrange, 41.1% had subtherapeutic, and 24.4% had supratherapeutic trough levels of linezolid [64]. Still, no correlation between abnormal levels and adverse events, in-hospital mortality, or overall poor outcome was found [64]. Another study suggests that the application of TDM for linezolid might be especially worthwhile in about 30% of cases to avoid either the risks of dose-dependent toxicity or treatment failure [67]. Among 92 patients, Pea et al. found a high variability in plasma concentrations. An optimal target attainment was obtained in about 60%e70% of the studied subjects, while a potential overexposure was documented in about 12% [67]. A high risk for overexposure was found in elderly patients, those with low body weight, and in patients with renal dysfunction [65,68,69]. High plasma concentrations of linezolid may exacerbate the risk of linezolid to cause hematological toxicity, especially thrombocytopenia [70e72]. Particularly critically ill patients are at risk of potential subtherapeutic levels of linezolid, raising the risk of treatment failure. In a prospective observational study, Zoller et al. found a high variability of linezolid levels (of more than 100-fold between the different patients) and subtherapeutic concentrations among the majority (63%) of the critically ill patients included in the observation [73]. Based on these findings, TDM of linezolid seems indicated to prevent serious adverse events (especially thrombocytopenia) and also to enable an effective treatment. Until today, the exact threshold for toxicity of linezolid is not defined and different values including 6.5 mg/L, 7e10 mg/L, and 22.1 mg/L have been proposed [2]. Also the optimal plasma concentration to achieve the highest clinical efficacy is still unknown [2]. Dong H et al. propose that a trough concentration of >2 mg/L may be a predictor of bacterial eradication especially in pathogens with a low or normal MIC [2,74]. Considering the individual MIC of bacteria to achieve an optimal PK/PD ratio, an AUC/MIC ratio between 80 and 120 is cited [2,72,74]. In some patients, the PK of linezolid is profoundly altered, due to changes in protein binding and an increased Vd and metabolism, leading to a high interindividual variability of plasma concentrations. This indicates a strong need for TDM and more population-based PK studies in the future to identify and quantify the influence of various factors affecting CL and plasma concentrations [66]. Maybe there is the possibility to optimize the achievement of therapeutic targets by applying linezolid via continuous infusion but data for this approach are lacking [2,66].

8.8 Daptomycin Daptomycin has been developed in the 1980s and is a cyclic lipopeptide antibiotic with a concentration-dependent bactericidal antimicrobial activity which is best described by AUC/MIC or Cmax/MIC [75]. In vitro it is more active than glycopeptides against a wide range of gram-positive aerobic as well as anaerobic organisms, including multidrugresistant strains [75]. It displays a significant postantibiotic effect, which is dose and concentration dependent and lasts for up to 6 h [75]. While Falcone et al. reported an increased risk of mortality in daptomycin-treated septic patients suffering from gram-positive infections associated with an AUC/MIC ratio <666 [76], a mean AUC/MIC ratio of approximately 1000

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should be sufficient for the bactericidal effect against S. aureus [75]. The recommended dose is 4e6 mg/kg once daily but in critically ill patients [77] and in situations with a high bacterial inoculum, as in cases of endocarditis or strains with a reduced susceptibility, a higher dosage of 10 mg/kg is endorsed [78,79]. In infections due to bacteria with MIC values > 4 mg/L, even higher doses could be insufficient to reach this target [80]. Overall, a high variability in the PK of daptomycin has been found in different studies, including high-dosage regimes (>10 mg/ kg) [77,80,81]. In a prospective study of Galar et al. at a tertiary care hospital, 63 patients were included and a trough concentration of <3.18 mg/L was independently related to treatment failure and poor outcome [81]. Bhavbani et al. showed that a trough level >24.3 mg/L is associated with a higher risk of creatinine kinase elevation, raising the risk for musculoskeletal toxicity. Also, in other studies, these correlations were not found [81], and until today, no validated serum target levels have been established. Not only due to the limited data on TDM of daptomycin, its application in clinical practice remains unclear. In most cases, subtherapeutic concentrations could be prevented by using a high-dose regimen (>10 mg/mL) [77,80,82], and the associated risk of musculoskeletal toxicity appears limited and can be prevented by close monitoring of creatinine kinase.

8.9 Colistin Colistin, or polymyxin E, is a cationic polypeptide antibiotic and became available in the 1940e1950s. Its use has recently resurged, assuming an important role as salvage therapy for otherwise untreatable infections caused by gram-negative bacteria, such as Pseudomonas aeruginosa, Acinetobacter baumannii, and Enterobacteriaceae [2,83]. Colistin is administered parenterally in the form of the sodium salt of colistin methanesulfonate (CMS), which represents a prodrug and is converted in vivo to the active compound, colistin [2]. After being marketed, its clinical use became more and more abandoned in most countries because of reports of serious adverse events, such as nephrotoxicity and neurotoxicity. However, a renaissance of colistin in clinical routine began in the 1980s as a result of the continuously rising resistance of important gram-negative bacteria and the lack of approval of new drugs. While mandatory for modern pharmaceuticals, preclinical and clinical drug development and regulatory approval procedures did not exist in the 1950s [84]. As a consequence, data on the PK and PD of colistin, which are necessary to allow the design of rational dosage regimes to achieve therapeutic targets and maximize efficacy, have been lacking [84]. Furthermore, prior to approximately 2000, almost all of the pharmacokinetic studies following administration of CMS employed microbiological assays for quantification, which are usually less accurate and precise and often lack of specificity in regard to coadministered antibiotics, in comparison with modern analytical methods [84]. Especially the microbiological assays are problematic for PK studies with CMS, because the obtained colistin concentrations are not reliable due to the ongoing conversion of CMS to colistin [84]. Thereby the results of the assays have regularly overestimated the actual colistin concentrations [84]. Now separate highpressure liquid chromatography (HPLC) methods have been developed for CMS and colistin, allowing new insights in the PK and providing updated data to optimize dosing, improve the clinical efficacy, and limit toxicities and emergence of resistance [2,84].

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A steady-state plasma trough concentration (Css) of 2e2.5 mg/L, corresponding to a target AUC 0e24 of 60 mg h/L, is suggested to be appropriate for treatment of relatively accessible infections with organisms having colistin MICs of 1(-2) mg/L or lower [2,83]. Although, based on preclinical data, a plasma colistin Css of 2 mg/L achieved via intravenous administration may not be adequate for the treatment of lung infections in critically ill patients, especially those caused by organisms that have elevated MIC organisms [83]. Based on more recent data for colistin, there are established relationships between plasma exposure and both antibacterial effect and the risk of AKI. Colistin possesses an extremely narrow therapeutic window because plasma exposures required for antibacterial effect overlap those associated with increased AKI risk [2,83]. In addition especially in critically ill patients, there is an unpredictable and substantial inter- and intrapatient variability in PK. But until today the benefit of TDM was not demonstrated in appropriately designed studies. In a randomized clinical trial, including patients with different types of multidrug-resistant bacterial infections, assessing TDM failed to demonstrate a benefit in terms of clinical cure or 30-day mortality [2]. Nevertheless, international consensus guidelines for the optimal use of the polymyxins recommend TDM and adaptive feedback control for colistin, because drug dosage cannot be safely optimized using clinical observations and dosing algorithms alone, especially in the important early treatment period [83]. When performing TDM, it is essential to ensure that sample collection, handling, and analysis are conducted appropriately to minimize ex vivo conversion of CMS to colistin [83]. This can be attained by the measurement of through concentrations, when CMS concentrations are the lowest and the potential for artificially elevated plasma colistin concentrations is minimized (but not eliminated) [83]. According to the findings from recent PK studies and the international guidelines, a high loading dose of colistin and also higher maintenance dosages, than declared in the recommendations of the manufacturers, are mandatory to rapidly attain therapeutic concentrations [83]. For adults, a loading dose of 9 million IU CMS infused over 0.5e1 h should be applied and the first maintenance dose should be administered 12e24 h later [83]. The maintenance dose has to be adapted to renal function [83]. By using higher dosages of colistin without routinely performed TDM, the incidence for nephrotoxicity may rise in clinical use. In a prospective observational cohort study, the trough level of colistin was an independent risk factor for nephrotoxicity, and the breakpoints that better predicted AKI were 3.33 mg/L on day 7 of therapy and 2.42 mg/L at the end of the treatment [85].

8.10 Conclusions In times of rising antibiotic resistance, it is clinically important to attend to factors that offer the opportunities to minimize the risk of treatment failure. Although antibiotics are frequently prescribed and most clinicians accept that blood levels must exceed the MIC of the pathogen, too few clinicians seem to be aware of the tangible risk of underdosing in patients [86]. There is growing evidence that fixed-dosage regimes based on PK data from healthy individuals in preclinical studies are not suitable for “real-world” clinical practice, where the patient’s pathophysiology is exceptionally heterogeneous. Besides a wide range of PK variability between patients, the MIC of pathogens can vary by more than 1000-fold even between susceptible organisms of the same species [86]. Although the knowledge about the relationships between

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antibiotic dosing, exposure and clinical effect has increased during the last years, insufficient antibiotic therapy characterized by both under- and overdosage is still too common. TDM of antibiotics, especially of the widely used beta-lactams, has become more widespread and represents one of the most practical and important means of assessing adequate antibiotic exposure.

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