Towards precision antibiotic therapy: predictors and outcomes of meropenem target attainment.

To assess the appropriateness of teicoplanin loading dose and therapeutic drug monitoring (TDM) in single-daily regimen (SDR) versus thrice-weekly regimen (TWR), and to compare safety and effectiveness. This single-centre observational retrospective cohort study included adult patients treated with TDM-based teicoplanin for infections between April 2015 and December 2021. Appropriateness of loading dose and TDM, adverse events (AEs) and clinical outcomes were evaluated. A post hoc analysis assessed achievement of target TDM concentrations following appropriate loading dose. Among 183 patients (103 SDR, 80 TWR), appropriate loading doses were less frequent in the SDR group [33/103 (35.9%, missing = 11) versus 56/80 (72.7%, missing = 3); P < 0.001]. First TDM was less commonly performed as recommended in the SDR group on Day 4 [89/103 (86.4%) versus 79/80 (98.8%); P = 0.002] and on Day 7 [31/103 (30.1%) versus 47/80 (58.8%); P < 0.001]. No significant differences were observed in AEs [15/103 (14.6%) versus 8/80 (10%); P = 0.38] or clinical success [60/103 (58.3%) versus 49/80 (61.3%); P = 0.681] between groups. Post hoc analysis showed that 2/16 (13%) patients with deep infections and 9/11 (82%) with non-deep infections on a TWR achieved target concentrations after loading dose. Higher adherence to loading dose and TDM recommendations was observed for TWR compared with SDR. However, the TWR often failed to achieve adequate TDM levels for higher targets, highlighting the need for optimized TWR loading dose strategies.

To determine the incidence of therapeutic target attainment using a three-times per week protocol for vancomycin therapy given during the last hour of intermittent hemodialysis (HD). A single-center retrospective cohort study was conducted of patient medical records in a remote dialysis center from January 2017 to July 2023. Adult patients with chronic kidney disease stage 5 on ≥3 months of intermittent HD who had received a course of vancomycin therapy with ≥1 serum vancomycin concentration recorded were included. Demographic and dosing data were collected. Clinician adherence with the dosing protocol and attainment of the therapeutic target (trough concentration within 15-20 mg/L) following the loading and maintenance doses were assessed. Factors associated with target nonattainment following the loading dose were analyzed, and the 48- and 72-h maintenance dosing intervals were analyzed for target nonattainment. A total of 98 vancomycin courses (67 patients) were available for analysis. Only 38% of the loading doses were prescribed as per protocol. Following the loading dose, 25% of trough concentrations achieved the therapeutic target concentration (15-20 mg/L), 25% returned a supra-therapeutic concentration (>20 mg/L) and 50% were sub-therapeutic (<15 mg/L). When compared with those achieving target, sub-therapeutic concentrations were associated with a lower loading dose (median 16.6 vs 20.0 mg/kg, P < 0.002), and supra-therapeutic concentrations had a shorter dosing interval between the loading dose and first maintenance dose (median 31.5 vs 39.0 h, P = 0.06). Of the 201 maintenance trough concentrations collected, 65% were therapeutic, 21% were sub-therapeutic and 14% were supra-therapeutic, with an overall median trough concentration of 17.3 mg/L. As the treatment duration increased, an increase was seen in the number of dose adjustments required to achieve the target trough concentration. The 48-h dosing interval was associated with more supra-therapeutic concentrations and the 72-h interval was associated with more sub-therapeutic concentrations (df = 2, P = 0.022). We have identified a high rate of target nonattainment for HD patients on a three times a week vancomycin dosing regimen. We recommend a loading dose of 20 to 25 mg/kg irrespective of the indication and a better-defined dosing interval after the loading dose. A higher maintenance dose should be prescribed when the time to next dialysis session is 72 h. Further pharmacokinetic studies are needed to assess factors influencing target concentration attainment following the maintenance doses and to determine an optimal dosing regimen.

To design an updated vancomycin dosing protocol for initiating therapy in patients undergoing chronic intermittent high-flux hemodialysis (iHFHD) that is congruent with the revised 2020 consensus guidelines for therapeutic drug monitoring (TDM). Monte Carlo simulation methods were used to study vancomycin dosing for patients on iHFHD. Vancomycin regimens were constructed as intravenous infusions (for intradialytic administration) of a loading dose and maintenance doses 3 times weekly during subsequent dialysis sessions. Vancomycin plasma concentrations were simulated, and the probability of target attainment (PTA) for a 24-hour area under the time-concentration curve (AUC24) of 400 to 700 mg · h/L was determined. Standardized weight-based (ie, dose-banding) regimens were investigated, and an optimized protocol was selected based on TDM target attainment and practical considerations for use in the dialysis setting. The proposed vancomycin dosing protocol (for intradialytic administration) specifies 3 regimens: (1) a 1,500-mg loading dose and 750-mg maintenance doses for patients weighing 50 kg to 69 kg; (2) a 2,000-mg loading dose and 1,000-mg maintenance doses for patients weighing 70 kg to 89 kg; and (3) a 2,500-mg loading dose and 1,250-mg maintenance doses for patients weighing 90 kg to 110 kg. In a simulated hemodialysis population (n = 5,000), the proposed protocol delivered median (interquartile range [IQR]) loading and maintenance doses of 25.0 (23.4-26.6) mg/kg and 12.5 (11.8-13.3) mg/kg, respectively. The PTA for an AUC24 of 400 to 700 mg · h/L was 74.7% on day 1 and 70.8% on day 8, with less than 10% of values exceeding the target range. Our proposed dosing protocol for patients undergoing iHFHD offers an updated and practical approach for initiating vancomycin therapy that can be optimized with early TDM.

Historically, pharmacokinetic (PK) studies and therapeutic drug monitoring (TDM) have relied on plasma as a sampling matrix. Noninvasive sampling matrices, such as saliva, can reduce the burden on pediatric patients. The variable plasma-saliva relationship can be quantified using population PK models (nonlinear mixed-effect models). However, criteria regarding acceptable levels of variability in such models remain unclear. In this simulation study, the authors aimed to propose a saliva TDM evaluation framework and evaluate model requirements in the context of TDM, with gentamicin and lamotrigine as model compounds. Two population pharmacokinetic models for gentamicin in neonates and lamotrigine in pediatrics were extended with a saliva compartment including a delay constant (kSALIVA), a saliva:plasma ratio, and between-subject variability (BSV) on both parameters. Subjects were simulated using a realistic covariate distribution. Bayesian maximum a posteriori TDM was applied to assess the performance of an increasing number of TDM saliva samples and varying levels of BSV and residual variability. Saliva TDM performance was compared with plasma TDM performance. The framework was applied to a known voriconazole saliva model as a case study. TDM performed using saliva resulted in higher target attainment than no TDM, and a residual proportional error <25% on saliva observations led to saliva TDM performance comparable with plasma TDM. BSV on kSALIVA did not affect performance, whereas increasing BSV on saliva:plasma ratios by >25% for gentamicin and >50% for lamotrigine reduced performance. The simulated target attainment for voriconazole saliva TDM was >90%. Saliva as an alternative matrix for noninvasive TDM is possible using nonlinear mixed-effect models combined with Bayesian optimization. This article provides a workflow to explore TDM performance for compounds measured in saliva and can be used for evaluation during model building.

Zander et al. [1] have recently conducted a prospective observational study to describe the variability of piperacillin (PIP) concentrations and target attainment in a heterogeneous cohort of 60 critically ill patients. An intermittent bolus dosing regimen of piperacillin-tazobactam (PIP-TAZ) was used 4.5 g three times daily (TID) or twice daily (BID), depending on renal function. As PIP-TAZ is largely renally excreted, it was unsurprising that the investigators found that no patient within the highest quartile of creatinine clearance (CrCl) attained specified pharmacokinetic/pharmacodynamic (PK/PD) targets (trough concentrations ≥22.5 mg/L) on days 1 or 4. These results are consistent with previous data showing that ‘augmented renal clearance’ (ARC), defined as a CrCl ≥130 mL/min [2], is frequently being associated with subtherapeutic PIP concentrations, even when dosing PIP-TAZ four times daily (QID) [2, 3]. Of more interest, however, was that the investigators found that 0 % and 55 % of patients with a CrCl >65 mL/min and 30–65 mL/min, respectively, attained the target PIP trough concentrations [1]. This is a very important finding as it highlights that initiating TID PIP-TAZ dosing as a blanket strategy in critically ill patients with ‘normal’ renal function or even mild to moderate renal impairment will not reliably attain PK/PD targets. In line with these findings, and perhaps reflective of the ongoing challenges with dose optimization in this group of patients, previous work has shown QID dosing of PIP-TAZ to be insufficient in achieving free PIP concentrations that are four times the target minimum inhibitory concentration (MIC) at 50 % of the dosing interval (50%fT>4xMIC), even in patients not displaying ARC [4, 5]. Solutions for target non-attainment of PIP-TAZ in intensive care unit (ICU) patients include use of prolonged infusions and therapeutic drug monitoring (TDM). Administering PIP-TAZ as a prolonged infusion—that is, either administering the antibiotic over half the dosing interval (e.g., over 3 h if given QID), or administering the total daily dose as a continuous infusion over 24 h after an initial loading dose—may help overcome subtherapeutic PIP concentrations in the critically ill [6]. There are now observational studies as well as randomized controlled trial (RCT) data that show increased likelihood of PIP concentrations being maintained above the MIC of pathogens using the prolonged infusion strategy [7–9]. Furthermore, there were higher rates of clinical cure associated with PIP-TAZ administered as a continuous infusion in the RCTs [7, 9]. Both of the RCTs included patients with mild to moderate renal impairment, and so, coupled with the results from the study by Zander et al. [1] showing PK/PD target attainment being problematic in these groups of patients via intermittent bolus dosing, the use of prolonged infusions may be a simple strategy that ICUs can employ. Notably, however, prolonged infusions may still not achieve therapeutic targets in certain groups of patients, such as those displaying ARC [10]. In these circumstances, dose up-titration may also be advisable, but can only be comfortably performed with use of TDM. To this end, a major challenge in determining optimal PIP-TAZ dosing for individual critically ill patients is the high inter-patient variability in serum PIP trough concentrations. Zander and investigators noted a 123-fold to >1785-fold range of PIP trough concentrations among their study patients, which was more pronounced in patients with higher creatinine clearances than those with severely impaired renal function [1]. Other investigators have also shown high inter-patient variability with PIP-TAZ dosing [11, 12], albeit in studies with smaller sample sizes of more homogeneous groups of critically ill patients. From these PK data, as well as due to pathogen-related factors such as decreasing antibiotic susceptibilities, as reflected by higher MICs, it is becoming evident that an individualized dosing approach needs to be adopted in order to maximize PIP-TAZ efficacy. Given this, there is significant scope for TDM of PIP-TAZ as well as other beta-lactam antibiotics in the ICU. Monitoring of trough concentrations at a steady state (usually after 3 to 4 doses) is generally recommended to see whether PK/PD targets are being met [13]. Earlier measurement should be preferred where dosing can be optimized using Bayesian dosing software [14]. Additionally, measurement of the ‘free’ or unbound PIP concentrations, rather than ‘total’ concentrations as described by Zander et al. [1], is advised. Although PIP is not highly protein bound (typically 30 %), differences in protein binding among patients, particularly those in hypoalbuminemic states, as well as alterations in protein binding during assay preparation, means there is much guess work determining PK/PD targets when using ‘total’ rather than ‘unbound’ antibiotic concentrations [15]. Interestingly, although Zander and colleagues found intra-patient variability to be less than inter-patient variability in their study cohort, the coefficient of variations (CV) for intra-patient PIP concentration variability was still wide, ranging from 6.4 to 129 % (median of 30 %) [1]. The heterogeneity of the study population most likely contributed to this wide intra-patient variability; however, the median CV for intra-patient variability is comparable to the median CV of 40 % reported by Carlier et al. [11], and reflects the key message that consistent dosing of PIP-TAZ does not necessarily result in consistent PIP concentrations throughout the period of therapy. This suggests that the use of merely ‘once-off’ TDM may be inadequate in determining if PK/PD targets are being attained consistently throughout therapy duration. We believe this study and previous work make the case for more frequent, perhaps even daily, use of TDM to ensure ongoing efficacy of PIP-TAZ in the critically ill patient [11].

Ceftolozane/tazobactam (TOL/TAZ) and ceftazidime-avibactam (CAZ/AVI) are increasingly used to treat pneumonia caused by multidrug-resistant Gram-negative bacilli. However, data on intrapulmonary penetration to confirm dosing adequacy are limited. Therefore, the aim of this study was to compare epithelial lining fluid (ELF) penetration and pharmacokinetic/pharmacodynamic (PK/PD) target attainment of TOL/TAZ versus CAZ/AVI administered by continuous infusion (CI) in critically ill patients with nosocomial pneumonia. Single-center, open-label, randomized pharmacokinetic (PK) study. Thirty patients were randomized 1:1 to receive 6g/3g of TOL/TAZ or 6g/1.5g of CAZ/AVI administered by CI. A population PK model was constructed using plasma and ELF concentrations. Lung penetration was estimated based on the ratio AUC0-8ELF/AUC0-8plasma. Simulations were performed to estimate the probability of attaining predefined joint ELF PK/PD target defined as free concentration 100% fT> minimum inhibitory concentration (MIC) for the β-lactam component and 100% fT> concentration threshold (CT) for the β-lactamase inhibitors, among relevant MIC scenarios. Three different dosing regimens (low, standard and high) were evaluated for each combination. A total of 298 plasma and 58 ELF samples were analyzed. The median [IQR] age, body mass index, and creatinine clearance were 77 [9.8] years, 26.48 [5.5] kg/m², and 76.0 [96.0] mL/min, respectively. Median intrapulmonary penetration was 0.66 [0.32] for ceftolozane, 0.41 [0.30] for ceftazidime 0.44 [0.05] for tazobactam and 0.44 [0.46] for avibactam. Under the prespecified ELF PK/PD target, standard dosing achieved adequate target attainment for both combinations. Simulations showed that all CAZ/AVI regimens achieved high ELF target attainment under conservative inhibitor threshold assumptions (assuming ceftazidime MIC = 8mg/L and avibactam CT =1mg/L), whereas for TOL/TAZ (assuming ceftolozane MIC = 4mg/L and tazobactam CT 2mg/L) at least the standard-dose regimen was required. More aggressive target scenarios reduced the probability of target attainment, particularly for inhibitor thresholds of 4mg/L and for Enterobacterales-oriented joint targets. In critically ill adults with nosocomial pneumonia receiving TOL/TAZ or CAZ/AVI by CI, standard doses achieved ELF exposures consistent with dual PK/PD target attainment against all susceptible isolates. Interindividual variability and the risk of plasma overexposure support individualized dosing and consideration of therapeutic drug monitoring. The trial was registered in the European Union Drug Regulating Authorities Clinical Trials Database (EudraCT No. 2021-006908-32). Registered 10 February 2022; https://www.clinicaltrialsregister.eu/ctr-search/trial/2021-006908-32/ES.

Cefepime is a key carbapenem-sparing agent due to its stability against AmpC β-lactamases. However, high plasma concentrations are associated with cefepime-induced neurotoxicity (CIN). Following 2019 EUCAST reclassification of 'intermediate' as 'susceptible, increased exposure', higher doses (6 g/day) are often recommended. Pharmacokinetic/pharmacodynamic (PK/PD) simulations suggest that a reduced daily dose of cefepime 4 g/day administered by continuous infusion may achieve adequate target attainment while limiting toxicity, but real-world clinical data are scarce. We conducted a prospective, single-centre observational study including adult inpatients treated with cefepime administered as a 2 g loading dose followed by continuous infusion of 4 g/day. Therapeutic drug monitoring was performed to assess steady-state free cefepime concentrations (ƒCss). The primary endpoint was pharmacodynamic target attainment (100% ƒT > MIC) for EUCAST 'susceptible, increased exposure' breakpoints. Among 46 included patients, median ƒCss was 26.2 mg/L (IQR 18.4-33.2). Pharmacodynamic targets were achieved in 96% of patients for Enterobacterales (MIC 4 mg/L) and 93% for Pseudomonas aeruginosa (MIC 8 mg/L). Clinical efficacy was observed in 96% of cases. Signs consistent with CIN occurred in three patients (6.5%), mainly in the context of renal function deterioration or pre-existing neurological vulnerability. A reduced-dose cefepime regimen consisting of 4 g/day administered by continuous infusion achieves high pharmacodynamic target attainment with a favourable efficacy-toxicity balance in real-life clinical practice. This strategy represents a promising alternative to higher-dose regimens and supports individualized dosing guided by renal function and therapeutic drug monitoring.

Pharmacodynamic comparisons of antimicrobials against nosocomial isolates of escherichia coli, klebsiella pneumoniae, acinetobacter baumannii and pseudomonas aeruginosa from the MYSTIC surveillance program: the OPTAMA Program, South America 2002

Cefepime is a fourth-generation cephalosporin and is a workhorse for the empiric treatment of febrile neutropenia (FN). Beta-lactam therapeutic drug monitoring (TDM) has emerged as a dose optimization strategy in patient populations with altered kinetics. Prior literature has demonstrated that patients with FN exhibit augmented renal clearance which may lead to subtherapeutic drug concentrations with standard dosing regimens. The aim of this study was to evaluate pharmacokinetic/pharmacodynamic (PK/PD) target attainment and clinical outcomes in patients with hematologic malignancies and FN who were treated empirically with cefepime. This was a prospective, single-center study of adults with hematologic malignancies and FN admitted to the inpatient unit. The primary outcome was PK/PD target attainment (defined as 100% free time greater than minimum inhibitory concentration (100% fT > MIC)). Secondary clinical outcomes were time to defervescence, time to ANC recovery, in-hospital mortality, and cefepime failure. There were 55 patients in our study. Forty-three (78%) patients achieved the primary outcome of PK/PD target attainment. The mean time to defervescence was similar between those that achieved PK/PD target attainment and those that did not (95% CI -0.75 to 1.25, p = 0.62). This study showed that standard cefepime dosing in patients with hematologic malignancies and FN does not result in achievement of 100% fT > MIC in all patients. Patients in the group that did not achieve PK/PD target attainment were younger with increased creatinine clearance, indicating that cefepime TDM may be especially beneficial in these patients.

A single-center retrospective cohort study. To develop a predictive scoring system for bone union after conservative treatment of lumbar spondylolysis and assess its internal validity. Lumbar spondylolysis, a common stress fracture in young athletes, is typically treated conservatively. Predicting bone union rates remains a challenge. This study included patients aged 18 years or younger with lumbar spondylolysis undergoing conservative treatment. A multivariable logistic regression analysis was used to develop a scoring system containing 6 factors: sex, age, lesion level, main side stage of the lesion, contralateral side stage of the lesion, and spina bifida occulta. The predictive scoring system was internally validated from the receiver operating characteristic (ROC) curve using bootstrap methods. The final analysis included 301 patients with 416 lesions, with an overall bone union rate of 80%. On multivariable analysis, the main and contralateral stages were identified as factors associated with bone union. The predictive scoring system was developed from the main side stage score (prelysis, early=0, progressive stage=1) and the contralateral side stage score (none=0, prelysis, early, progressive stage=1, terminal stage=3). The area under the curve was 0.855 (95% confidence interval, 0.811-0.896) for the ROC curve, showing good internal validity. The predicted bone union rates were generally consistent with the actual rates. A simple predictive scoring system was developed for bone union after conservative treatment of lumbar spondylolysis, based on the stage of the lesion on the main and contralateral sides. The predicted bone union rate was ~90% for a total score of 0-1 and ≤30% for a score of 3-4. This system demonstrated good internal validity, suggesting its potential as a useful tool in clinical decision-making for the management of spondylolysis.

ObjectivePosaconazole is a first-line drug for preventing invasive fungal disease (IFD) in patients undergoing haematopoietic stem cell transplantation (HSCT). Few retrospective studies have examined the impact of therapeutic drug monitoring (TDM) on preventing IFD with posaconazole. This study was designed to evaluate the efficacy, safety, and cost-effectiveness of posaconazole in preventing IFD based on real-world data.MethodsThis single-centre, retrospective cohort study analyzed the use of posaconazole for fungal prophylaxis in HSCT patients at the First Affiliated Hospital of Shandong First Medical University (Shandong Provincial Qianfoshan Hospital). Patients were classified into TDM and non-TDM groups based on their TDM status. Clinical data were analyzed using propensity score matching (PSM) to further elucidate the role of TDM in posaconazole prophylaxis.ResultsAfter PSM, the prophylactic success rate was significantly higher in the TDM group (100%) than in the non-TDM group (52.9%) (P = 0.003). There was no statistically significant difference in gastrointestinal, hepatic and renal adverse effects between the two groups (P > 0.05). Both the total cost of treatment and the cost of medication were lower in the TDM group compared to the non-TDM group.ConclusionReal-world data demonstrate that TDM enhances the effectiveness of posaconazole in preventing IFD in HSCT patients and moderately reduces treatment costs.

Monitoring infliximab (IFX) concentrations is crucial for optimizing IFX therapy in children with inflammatory bowel diseases (IBDs) who show low response rates due to inadequate drug exposure. Substantial variation occurs in IFX trough concentrations in paediatric patients. Objectives: This study aimed to investigate IFX pharmacokinetics (PK) in children with IBD during both the induction phase and maintenance phases and to identify covariates associated with IFX PK. Methods: This single-centre retrospective cohort study was conducted at an academic children's hospital. Data was extracted from paediatric IBD patients receiving IFX between January 2018 and October 2023 and included demographic-, clinical- and laboratory parameters collected from electronic health records. Linear mixed model analysis was performed to investigate associations between these parameters and IFX trough concentrations. Target attainment [≥15 μg/mL in induction or 5-10 μg/mL in maintenance phase] of the IFX dosing regimens was evaluated. Results and Conclusions: A total of 115 children (417 unique IFX concentrations) were included. Multivariate analysis revealed significant positive associations between IFX and albumin concentrations (β = 0.388, p = 0.010) and IFX concentrations with dose (β = 6.534, p < 0.001), and an inversion association between IFX concentrations and treatment phase (β = -4.922, p < 0.001). During the induction and maintenance phases, 57.2% and 30.6% of IFX concentrations were subtherapeutic, respectively. A systematic search of studies investigating factors influencing IFX concentrations was concurrently performed. Our findings were critically compared against existing literature to assess relevant clinical and biochemical determinants of IFX PK in children with IBD. Our findings highlight the need for personalized dosing strategies in pediatric IBD patients, particularly during the induction phase. By implementing therapeutic drug monitoring (TDM) and considering clinical and biochemical factors, clinicians can implement more personalized strategies, potentially improving treatment efficacy and reducing the risk of treatment failure or adverse effects. This approach could lead to better target attainment, potentially enhancing clinical outcomes and minimizing premature switching to other therapies.

Vancomycin and teicoplanin are the glycopeptides currently in use for the treatment of infections caused by beta-lactam-resistant gram-positive organisms [1]. Teicoplanin, a glycopeptide antibiotic, has a lower possibility than vancomycin to cause renal toxicity, and causes fewer anaphylactoid reactions [2]. Teicoplanin has been found to be comparable to vancomycin in efficacy [1]. As teicoplanin can be administered once daily intramuscularly as well as intravenously, it can be used for outpatient therapy of methicillin-resistant staphylococcal infections [1]. Teicoplanin completely excreted unchanged in the urine by glomerular filtration, and doses should be reduced appropriately in patients with renal dysfunction. Its pharmacokinetics include a prolonged terminal half-life of 150 to 180 h, which is important during long-term therapy [1]. Usual dose and dosing interval of teicoplanin for IV injection or infusion consist initially 400 mg every 12 hours for 3 doses and subsequently 200 mg once daily (400 mg once daily for severe infections) [1, 3]. Higher doses are recommended in patients over 85 kg, or in severe burns or methicillin-resistant Staphylococcus aureus (MRSA) infection [1, 3]. For streptococcal endocarditis, initially 6 mg/kg every 12 hours for 3 doses, then 6 mg/kg once daily are typical [1, 3]. For enterococcal endocarditis, initially 10 mg/kg every 12 hours for 3 doses, then 10 mg/kg once daily are standard. For child, initially 10 mg/kg every 12 hours for 3 doses, subsequently 6 mg/kg once daily (10 mg/kg once daily for severe infections or in neutropenia) is a typical regimen [1, 3]. Vancomycin level monitoring is common in the hospitals with increasing minimal inhibitory concentration (MIC) of S. aureus (MIC creep) [1]. For complicated infections (bacteremia, endocarditis, osteomyelitis, meningitis, and hospital-acquired pneumonia) and for infections caused by strains with MICs of >1 µg/mL, trough levels of 15 to 20 µg/mL are recommended [1]. Larger vancomycin doses are associated with increased nephrotoxicity [1], and monitoring of vancomycin trough serum levels is recommended in the view of avoiding nephrotoxicity [4]. Therapeutic drug monitoring (TDM) of teicoplanin is not routine because of the lack of evidence for dose-related adverse effects of teicoplanin [3]. However, measuring of teicoplanin plasma concentrations may help to optimize therapy in some patients. Data of teicoplainin TDM are largely lacking [1]. Harding et al. [5] reported the probability of successful treatment increased with mean pre-dose (trough) serum concentration of teicoplanin and reported that a mean daily dose of 4 mg/kg was associated with treatment failure when compared to a mean daily dose of 6 mg/kg [5]. Also, Harding et al. [5] suggested successful treatment of S. aureus septicemia with teicoplanin requires trough plasma teicoplanin concentration of >10 mg/L as a result of simulation. According to previous reports, higher trough concentrations > 20 mg/L and > 30 mg/L of teicoplanin are considered to be needed for MRSA endocardtis and osteomyelitis, respectively [6, 7]. Nah et al. [8] investigated the TDM of teicoplanin in clinical setting with Korean patients. They reported that there is the suboptimal concentration (< 10 mg/L) of plasma teicoplanin level in nearly half of the study patients in spite of the majority of the patients received loading dose as recommended (400 mg every 12 hours for three times), and emphasized the importance of loading dose and routine TDM of teicoplanin [8]. This article focused the roles of TDM for the optimal efficacy of therapeutic drug, not for avoiding adverse effects of a drug. An area under curve (AUC)/MIC value of ≥400 was associated with a successful outcome with human pharmacodynamic study for vancomycin [9]. The vancomycin target was identified in patients with pulmonary infections [9]. However, established pharmacodynamic targets were not available for teicoplanin [10]. An AUC/MIC value of teicoplanin to Staphylococcus considered important pharmacodynamics parameter [10]. There is no information about MIC values of pathogens and AUC/MIC values and a peak concentrations in the study by Nah et al. [8]. The TDM for vancomycin therapy has been shown to be a cost-effective procedure [11]. However, cost effective study of teicoplanin TDM is still largely lacking. Nah et al. [8] reported the first study about teicoplanin TDM in Korea, which emphasize the importance of loading dose and TDM of teicoplanin. The limitations of this study include that the association between plasma concentrations of teicoplanin and clinical therapeutic effects are not evaluated. We can expect the usefulness of teicoplanin TDM in the same respect of vancomycin TDM. However, we are currently in need of data of pharmacokinetics, clinical pharmacodynamics and TDM of teicoplanin in clinical setting, because of its current significant role for anti-MRSA treatment.

This study investigates the pharmacokinetic/pharmacodynamic (PK/PD) target attainment of linezolid in patients infected with multidrug-resistant (MDR) tuberculosis (TB). A pharmacometric model was developed including 244 timed linezolid concentration samples from 39 patients employing NONMEM 7.4. The probability of target attainment (PTA, PK/PD target: unbound (f) area-under-the-concentration-time-curve (AUC)/minimal inhibitory concentration (MIC) of 119) as well as a region-specific cumulative fraction of response (CFR) were estimated for different dosing regimens. A one-compartment model with linear elimination with a clearance (CL) of 7.69 L/h (interindividual variability 34.1%), a volume of distribution (Vd) of 45.2 L and an absorption constant (KA) of 0.679 h-1 (interoccasion variability 143.7%) allometric scaled by weight best described the PK of linezolid. The PTA at an MIC of 0.5 mg/L was 55% or 97% if patients receiving 300 or 600 mg twice daily, respectively. CFRs varied greatly among populations and geographic regions. A desirable global CFR of ≥90% was achieved if linezolid was administered at a dose of 600 mg twice daily but not at a dose of 300 mg twice daily. This study showed that a dose of 300 mg twice daily of linezolid might not be sufficient to treat MDR-TB patients from a PK/PD perspective. Thus, it might be recommendable to start with a higher dose of 600 mg twice daily to ensure PK/PD target attainment. Hereby, therapeutic drug monitoring and MIC determination should be performed to control PK/PD target attainment as linezolid shows high variability in its PK in the TB population.

This study is intended to shed new light on the role of neutrophils in rectal cancer and in the meanwhile emphasizing the differences between rectal and colon cancer, strengthening and highlight a new clinical prognostic and predictive scoring (Sarandria Score). This paper describes a novel scoring system that can be utilised as an inclusion criterion as well as a predictive and prognostic scoring system for patients with stage III rectal cancer. Background: Colorectal cancer (CRC) is a major public health issue, since it is the third most commonly diagnosed cancer in men and the second most usually diagnosed cancer in women. Various studies have found significant differences in the responsiveness to adjuvant treatment and prognosis based on the main location of CRC (right-sided colon, left-sided colon, rectum). Previous research has linked a higher density of tumor-associated neutrophils (TANs) to a better response to 5-FU-based treatment in stage III CRC patients. Results: The present state of knowledge on the involvement of neutrophils in colorectal cancer is assessed in this chapter, which includes a novel finding on the role of neutrophils in rectal cancer discovered by Dr. Nicola Sarandria. It covers a number of variables that point to neutrophils playing an anti-tumor role in rectal cancer when chemotherapeutic drugs are present (such as 5-fluorouracil). The clinical importance of TANs was investigated, as well as if it differed based on the main CRC's location (right-sided colon, left-sided colon, rectum). Conclusions: This chapter introduces a new clinical prognostic and predictive scoring system (Sarandria Score) for rectal cancer patients with intratumoral neutrophilic infiltration, as well as the possibility of a new inclusion criteria based on this infiltrate for Stage III rectal cancer patients receiving 5-FU therapy. This chapter also includes information from the author's medical degree thesis, which showed that higher TANs densities were linked to better disease-free survival (DFS) in rectal cancer patients treated with 5-FU (while it was inversely related in patients without 5-FU therapy). This also adds to the evidence that what is now recognised as colorectal cancer can be divided into two types: colon and rectal cancer.