Piergiorgio Cojutti

Therapeutic drug monitoring may improve safety outcomes of long-term treatment with linezolid in adult patients

OBJECTIVES Prolonged treatment with linezolid may cause toxicity. The purpose of this study was to define pharmacodynamic thresholds for improving safety outcomes of linezolid. METHODS 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. RESULTS 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. CONCLUSIONS 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.

Therapeutic Drug Monitoring of Linezolid: a Retrospective Monocentric Analysis

ABSTRACT 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 [Cmin] and peak [Cmax] 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 [AUC24]). The final database included 280 Cmin and 223 Cmax 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 Cmin, 14.70 mg/liter [10.57 to 19.64] for Cmax, and 196.08 mg·h/liter [144.02 to 312.10 mg·h/liter] for estimated AUC24). Linezolid Cmin was linearly correlated with estimated AUC24 (r2 = 0.85). Optimal pharmacodynamic target attainment (defined as Cmin of ≥2 mg/liter and/or AUC24/MIC90 ratio of >80) was obtained in about 60 to 70% of cases, but potential overexposure (defined as Cmin of ≥10 mg/liter and/or AUC24 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.

TDM-Guided Therapy with Daptomycin and Meropenem in a Morbidly Obese, Critically Ill Patient

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/m2) 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.

Dosing Nomograms for Attaining Optimum Concentrations of Meropenem by Continuous Infusion in Critically Ill Patients with Severe Gram-Negative Infections: a Pharmacokinetics/Pharmacodynamics-Based Approach

ABSTRACT 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 (CLCr) estimates for use in daily clinical practice to target the steady-state concentrations (Csss) 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 (CLm) and CLCr was retrospectively assessed in a cohort of critically ill patients (group 1, n = 67) to create a formula for dosage calculation to target Css. The performance of this formula was validated in a similar cohort (group 2, n = 56) by comparison of the observed and the predicted Csss. A significant relationship between CLm and CLCr 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 × CLCr (ml/min) + 2.85] × target Css × (24/1,000), led to a significant correlation between the observed and the predicted Csss (r = 0.92, P < 0.001). Dosing nomograms based on CLCr were created to target the meropenem Css 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.

Antifungal Prophylaxis with Posaconazole in Patients with Acute Myeloid Leukemia: Dose Intensification Coupled with Avoidance of Proton Pump Inhibitors Is Beneficial in Shortening Time to Effective Concentrations

ABSTRACT This study aimed to assess the influence of dose frequency and the presence or absence of cotreatment with proton pump inhibitors (PPIs) on the time to a target trough concentration (Cmin) of >700 ng/ml with posaconazole in the first 8 days of antifungal prophylaxis in hematological patients. This was a retrospective, observational study performed with 42 adult patients with acute myeloid leukemia who underwent posaconazole prophylaxis with 200 mg every 8 h (q8h) or 200 mg q6h after receiving induction chemotherapy and who had at least three subsequent therapeutic drug monitoring assessments during the first 8 days of treatment. The cohort was split into four groups (group 1, 200 mg q8h without PPI; group 2, 200 mg q8h with PPI; group 3, 200 mg q6h without PPI; group 4, 200 mg q6h with PPI). Rapid attainment of the target Cmin was obtained only in group 3 (P < 0.01) (median Cmin on day 4 of 935.5 ng/ml [interquartile range, 760.0 to 1,270.0 ng/ml] in group 3, versus 567.0 ng/ml [346 to 906 ng/ml] in group 1, 420.0 ng/ml [326.2 to 527.2 ng/ml] in group 2, and 514.0 ng/ml [403.7 to 564.7 ng/ml] in group 4). A linear accumulation of posaconazole over time was observed among patients in groups 1 and 3, regardless of the total daily dosage, differently from what occurred among those receiving PPI cotreatment (groups 2 and 4). Dose intensification (200 mg q6h) coupled with avoidance of PPI coadministration may represent a very powerful strategy to rapidly achieve effective concentrations with posaconazole in neutropenic hematological patients.

Pharmacokinetic Interaction Between Everolimus and Antifungal Triazoles in a Liver Transplant Patient

Objective: TO describe the management of a pharmacokinetic interaction between azole antifungals (fluconazole and voriconazole) and everolimus in a patient who underwent an orthotopic liver transplant. Case Summary: A 65-year-old male who received an orthotopic liver transplant experienced an iatrogenic retroperitoneal duodenal perforation on postoperative day 55. His condition was subsequently complicated by severe sepsis and acute renal failure. Intravenous fluconazole 400 mg, followed by 100 mg every 24 hours according to impaired renal function, was immediately started; to avoid further nephrotoxicity, immunosuppressant therapy was switched from cyclosporine plus mycophenolate mofetil to oral everolimus 0.75 mg every 12 hours. Satisfactory steady-state minimum concentration (Cmin) of everolimus was achieved (∼5 ng/mL). On day 72 posttransplant, because of invasive aspergillosis, antifungal therapy was switched to intravenous voriconazole 400 mg every 12 hours on the first day, followed by 200 mg every 12 hours; to prevent drug toxicity, the everolimus dosage was promptly lowered to 0.25 mg every 24 hours. At that time, the everolimus Cmin averaged approximately 3 ng/mL. The concentration/dose ratio of everolimus (ie, Cmin reached at steady-state for each milligram per kilogram of drug administered) was markedly lower during fluconazole versus voriconazole cotreatment (mean ± SD, 3.49 ± 0.29 vs 11.05 ± 0.81 ng/mL per mg/kg/daily; p < 0.001). Despite intensive care, the patients condition continued to deteriorate and he died on day 84 posttransplant Discussion: Both azole antifungals were considered probable causative agents of an interaction with everolimus according to the Drug Interaction Probability Scale. The Interaction is due to the inhibition of CYP3A4–mediated everolimus clearance. Of note, prompt reduction of the everolimus dosage since the first azole coadministration, coupled with intensive therapeutic drug monitoring, represented a useful strategy to prevent drug overexposure. Conclusions: Our data suggest that during everolimus-azole cotreatment, a dose reduction of everolimus is needed to avoid overexposure. According to the different inhibitory potency of CYP3A4 activity, the reduction should be lower during fluconazole than during voriconazole cotreatment.

Variability of Voriconazole Trough Levels in Haematological Patients: Influence of Comedications with cytochrome P450(CYP) Inhibitors and/or with CYP Inhibitors plus CYP Inducers.

Voriconazole plasma exposure greatly varies among haematological patients. The purpose of this study was to identify the magnitude of influence of comedications with CYP inhibitors and/or with CYP inhibitors plus CYP inducers on voriconazole trough level (Cmin). Voriconazole Cmin was retrospectively assessed among haematological patients who underwent therapeutic drug monitoring (TDM). Univariate and multivariate linear mixed‐effect regression analyses were performed to identify the independent predictors of normalized Cmin. Of the 83 included patients, 35 had comedications with CYP inhibitors (omeprazole or pantoprazole) and 21 with CYP inhibitors (omeprazole or pantoprazole) plus CYP inducers (methylprednisolone, dexamethasone, phenobarbital, rifampin or carbamazepine). Median Cmin value (n = 199) was 2.4 mg/L with a wide range of distribution (<0.2–13.5 mg/L). Median (IQR) normalized voriconazole Cmin value was significantly higher in the presence of CYP inhibitors (4.20 mg/L, 3.23–5.51 mg/L) than either in the absence of interacting cotreatments (2.55 mg/L, 1.54–3.47 mg/L) or in the presence of CYP inhibitors plus CYP inducers (2.16 mg/L, 1.19–3.09 mg/L). The presence of CYP inhibitors was highly significantly associated with Cmin >5.5 mg/L (OR: 23.22, 95% CI: 3.01–179.09, p = 0.003). No significant association emerged when CYP inhibitors were coadministered with CYP inducers (OR: 3.53, 95% CI: 0.36–34.95, p = 0.280). The amount of expected Cmin increase was significantly influenced by both the type and the dose of the administered proton pump inhibitor. The study highlights that the benefit from TDM of voriconazole may be maximal in those patients who are cotreated with CYP inhibitors and/or with CYP inhibitors plus CYP inducers, especially when receiving proton pump inhibitors (PPIs) at very high dosages intravenously.

Pharmacokinetic/pharmacodynamic evaluation of linezolid in hospitalized paediatric patients: a step toward dose optimization by means of therapeutic drug monitoring and Monte Carlo simulation

OBJECTIVES To report on linezolid exposure in a paediatric population who routinely underwent therapeutic drug monitoring (TDM) for dosage optimization and to assess the factors affecting interpatient variability. METHODS We performed a retrospective study of patients whose plasma C(min) and Cmax levels were measured during linezolid treatment. Adequate exposure was defined as a C(min) of 2-7 mg/L and/or an estimated AUC24 of 160-300 mg · h/L. Patients were divided into two subgroups (Group 1, 2-11 years; Group 2, 12-18 years). Monte Carlo simulation was performed to investigate whether or not the currently recommended dosages might enable a high probability of target attainment (PTA) of two thresholds for linezolid efficacy (AUC24/MIC ≥ 80 or ≥ 100). Data on demographic characteristics, disease, microbiology and haematochemical parameters and outcomes were collected. RESULTS A total of 23 patients were included. Standard dosages were suboptimal in 50.0% and 44.4% of patients in Group 1 and Group 2, respectively. Among those who underwent multiple instances of TDM, the dosages were increased in 33.3% of cases in both groups, and decreased in 6.6% and 9.5% of cases in Group 1 and Group 2, respectively. Co-treatment with phenobarbital, proton pump inhibitors and amiodarone accounted for most of the variability in C(min) (adjusted R(2) of 0.692). Simulations showed a PTA of ≥ 90% with the current dosing regimens in both groups only for pathogens with an MIC ≤ 1 mg/L. CONCLUSIONS Higher dosages of linezolid may be needed, especially in Group 1 when in the presence of pathogens with an MIC >1 mg/L. The role of TDM should be encouraged for optimization of linezolid exposure in the paediatric setting in the presence of infections caused by pathogens with borderline susceptibility and/or for patients co-treated with drugs that may alter linezolid exposure.

Successful long-term treatment of cerebral nocardiosis with unexpectedly low doses of linezolid in an immunocompromised patient receiving complex polytherapy

ABSTRACT Cerebral nocardiosis is a severe infection that carries the highest mortality rate among all bacterial cerebral abscesses. We report on a case in an immunocompromised patient which was successfully treated with unexpectedly low doses of linezolid. Therapeutic drug monitoring was very helpful in highlighting issues of poor compliance and of drug-drug interactions.

Stability of generic meropenem solutions for administration by continuous infusion at normal and elevated temperatures.

Abstract: Administration by continuous infusion may represent an effective tool for the treatment of multidrug-resistant gram-negative related infections with meropenem. Currently, no data on chemical stability of generic bioequivalent versions of meropenem over time are available. Triplicate samples of 5 mg/mL solutions of a generic meropenem formulation, Hospira, were evaluated for chemical stability at increasing temperatures (25°C, 30°C, 35°C, and 40°C) by means of a high-performance liquid chromatography technique over 4 separate days. Degradation of generic meropenem was both time and temperature dependent, and the aqueous solutions were stable for up to 8 hours in the temperature range between 25°C and 35°C, and for up to 5 hours at 40°C. Continuous infusion of generic meropenem Hospira may be applied in clinical settings with ambient temperature below 35°C, provided that the 5 mg/mL aqueous solution is reconstituted at most after 6–8 hours.