Prolonged treatment with linezolid may cause toxicity. The purpose of this study was to define pharmacodynamic thresholds for improving safety outcomes of linezolid. We performed a retrospective study of patients who had trough (C_min) and peak (C_max) plasma levels measured during prolonged linezolid treatment. Dosage adjustments were performed when C_min ≥10 mg/L and/or AUC₂₄ ≥400 mg/L · h. Patients were divided into two subgroups according to the absence or presence of co-treatment with rifampicin (the linezolid group and the linezolid + rifampicin group, respectively). Data on demographic characteristics, disease, microbiology and haematochemical parameters were collected and outcomes in relation to drug exposure were compared between groups. A total of 45 patients were included. Dosage adjustments were needed in 40% versus 0% of patients in the linezolid group (n = 35) versus the linezolid + rifampicin group (n = 10), respectively. Patients in the linezolid group had either significantly higher C_min [3.71 mg/L (1.43–6.38) versus 1.37 mg/L (0.67–2.55), P < 0.001] or AUC₂₄ [212.77 mg/L · h (166.67–278.42) versus 123.33 mg/L · h (97.36–187.94), P < 0.001]. Thrombocytopenia appeared in 51.4% versus 0% of cases in the linezolid group versus the linezolid + rifampicin group, respectively. In 33.3% of those patients who were experiencing thrombocytopenia, therapeutic drug monitoring (TDM)-guided dosage reductions allowed recovery from toxicity and prosecution of therapy with good outcome. A logistic regression model for thrombocytopenia estimated a probability of 50% in the presence of C_min of 6.53 mg/L and/or of AUC₂₄ of 280.74 mg/L · h. Maintenance over time of C_min between 2 and 7 mg/L and/or of AUC₂₄ between 160 and 300 mg/L · h may be helpful in improving safety outcomes while retaining appropriate efficacy in adult patients receiving prolonged linezolid treatment.

The objective of the present retrospective observational study carried out in patients receiving a standard dosage of linezolid and undergoing routine therapeutic drug monitoring (TDM) was to assess the interindividual variability in plasma exposure, to identify the prevalence of attainment of optimal pharmacodynamics, and to define if an intensive program of TDM may be warranted in some categories of patients. Linezolid plasma concentrations (trough [ C _min ] and peak [ C _max ] levels) were analyzed by means of a high-performance liquid chromatography (HPLC) method, and daily drug exposure was estimated (daily area under the plasma concentration-time curve [AUC ₂₄ ]). The final database included 280 C _min and 223 C _max measurements performed in 92 patients who were treated with the fixed 600-mg dose every 12 h (q12h) intravenously ( n = 58) or orally ( n = 34). A wide variability was observed (median values [interquartile range]: 3.80 mg/liter [1.75 to 7.53 mg/liter] for C _min , 14.70 mg/liter [10.57 to 19.64] for C _max , and 196.08 mg·h/liter [144.02 to 312.10 mg·h/liter] for estimated AUC ₂₄ ). Linezolid C _min was linearly correlated with estimated AUC ₂₄ ( r ² = 0.85). Optimal pharmacodynamic target attainment (defined as C _min of ≥2 mg/liter and/or AUC ₂₄ /MIC ₉₀ ratio of >80) was obtained in about 60 to 70% of cases, but potential overexposure (defined as C _min of ≥10 mg/liter and/or AUC ₂₄ of ≥400 mg·h/liter) was documented in about 12% of cases. A significantly higher proportion of cases with potential overexposure received cotreatment with omeprazole, amiodarone, or amlodipine. Our study suggests that the application of TDM might be especially worthwhile in about 30% of cases with the intent of avoiding either the risk of dose-dependent toxicity or that of treatment failure.

The worrisome increase in Gram-negative bacteria with borderline susceptibility to carbapenems and of carbapenemase-producing Enterobacteriaceae has significantly undermined their efficacy. Continuous infusion may be the best way to maximize the time-dependent activity of meropenem. The aim of this study was to create dosing nomograms in relation to different creatinine clearance (CL _Cr ) estimates for use in daily clinical practice to target the steady-state concentrations ( C _ss s) of meropenem during continuous infusion at 8 to 16 mg/liter (after the administration of an initial loading dose of 1 to 2 g over 30 min). The correlation between meropenem clearance (CL _m ) and CL _Cr was retrospectively assessed in a cohort of critically ill patients (group 1, n = 67) to create a formula for dosage calculation to target C _ss . The performance of this formula was validated in a similar cohort (group 2, n = 56) by comparison of the observed and the predicted C _ss s. A significant relationship between CL _m and CL _Cr was observed in group 1 ( r = 0.72, P < 0.001). The application of the formula to meropenem dosing in group 2, infusion rate (g/24 h) = [0.078 × CL _Cr (ml/min) + 2.85] × target C _ss × (24/1,000), led to a significant correlation between the observed and the predicted C _ss s ( r = 0.92, P < 0.001). Dosing nomograms based on CL _Cr were created to target the meropenem C _ss at 8, 12, and 16 mg/liter in critically ill patients. These nomograms could be helpful in improving the treatment of severe Gram-negative infections with meropenem, especially in the presence of borderline susceptible pathogens or even of carbapenemase producers and/or of pathophysiological conditions which may enhance meropenem clearance.

Background: Emerging data suggest that more aggressive beta-lactam PK/PD targets could minimize the occurrence of microbiological failure and/or resistance development. This study aims to assess whether a PK/PD target threshold of continuous infusion (CI) beta-lactams may be useful in preventing microbiological failure and/or resistance development in critically ill patients affected by documented Gram-negative infections. Methods: Patients admitted to intensive care units from December 2020 to July 2021 receiving continuous infusion beta-lactams for documented Gram-negative infections and having at least one therapeutic drug monitoring in the first 72 h of treatment were included. A receiver operating characteristic (ROC) curve analysis was performed using the ratio between steady-state concentration and minimum inhibitory concentration (C_ss/MIC) ratio as the test variable and occurrence of microbiological failure as the state variable. Area under the curve (AUC) and 95% confidence interval (CI) were calculated. Independent risk factors for the occurrence of microbiological failure were investigated using logistic regression. Results: Overall, 116 patients were included. Microbiological failure occurred in 26 cases (22.4%). A C_ss/MIC ratio ≤ 5 was identified as PK/PD target cut-off with sensitivity of 80.8% (CI 60.6–93.4%) and specificity of 90.5% (CI 74.2–94.4%), and with an AUC of 0.868 (95%CI 0.793–0.924; p < 0.001). At multivariate regression, independent predictors of microbiological failure were C_ss/MIC ratio ≤ 5 (odds ratio [OR] 34.54; 95%CI 7.45–160.11; p < 0.001) and Pseudomonas aeruginosa infection (OR 4.79; 95%CI 1.11–20.79; p = 0.036). Conclusions: Early targeting of CI beta-lactams at C_ss/MIC ratio > 5 during the treatment of documented Gram-negative infections may be helpful in preventing microbiological failure and/or resistance development in critically ill patients.

A population pharmacokinetic analysis of dalbavancin was conducted in patients with different infection sites. Non-linear mixed effect modeling was used for pharmacokinetic analysis and covariate evaluation. Monte Carlo simulations assessed the probability of target attainment (PTA) of total dalbavancin concentration ≥ 8.04 mg/L over time (associated with ≥90% probability of optimal pharmacodynamic target attainment of fAUC_24h/MIC > 111.1 against S. aureus) associated with a single or double dosage, one week apart, of 1000 or 1500 mg in patients with different classes of renal function. Sixty-nine patients with 289 concentrations were included. Most of them (53/69, 76.8%) had bone and joint infections. A two-compartment model adequately fitted dalbavancin concentration–time data. Creatinine clearance (CL_CR) was the only covariate associated with dalbavancin clearance. Monte Carlo simulations showed that, in patients with severe renal dysfunction, the 1000 mg single or double one week apart dosage may ensure optimal PTAs of 2 and 5 weeks, respectively. In patients with preserved renal function, the 1500 mg single or double one-week apart dosage may ensure optimal PTAs of 2 and 4 to 6 weeks, respectively. Therapeutic drug monitoring should be considered mandatory for managing inter-individual variability and for supporting clinicians in long-term treatments of subacute and chronic infections.

Objective: To describe a case of severe cellulitis, successfully treated with high-dose daptomycin plus continuous infusion meropenem, in a patient with morbid obesity and renal failure, in whom drug exposure over time was optimized by means of realtime therapeutic drug monitoring (TDM). Case Summary: A 63-year-old man with morbid obesity (body mass index 81.6 kg/m ² ) and renal failure was admitted to the emergency department because of severe cellulitis. The patient had an admission Laboratory Risk Indicator for Necrotizing Fasciitis score of 9, and broad-spectrum antimicrobial therapy with daptomycin and meropenem was started. Because of rapidly changing renal function, dosage adjustments were guided by an intensive program of TDM (daptomycin ranging from 1200 mg every 48 hours over 30 minutes to 1200 mg every 36 hours over 30 minutes; meropenem ranging from 0.25 g every 8 hours over 6 hours to 500 mg every 4 hours by continuous infusion). Clinical response was observed within 72 hours. However, a sudden increase of serum creatine kinase (SCK) raised questions about the need for discontinuation of daptomycin. The drug concentrations were not toxic; therefore, we decided to continue therapy. Significant clinical improvement, with SCK normalization, was observed within a few days. Antimicrobial therapy was switched on day 29 to amoxicillin/clavulanate plus levofloxacin, and then discontinued at discharge on day 53. Discussion: High-dose daptomycin plus continuous infusion meropenem may ensure adequate empiric antimicrobial coverage in patients with possible early necrotizing fasciitis. However, in patients with morbid obesity and changing renal function, significant challenges may arise because of the hydrophilic nature of these drugs and the inaccuracy of standard methods of estimating renal function. Conclusions: Real-time TDM may represent an invaluable approach in optimizing drug exposure with high-dose daptomycin plus continuous infusion meropenem in patients with severe cellulitis, morbid obesity, and changing renal function.