Educational and organizational interventions to improve the usefulness of clinical pharmacological advice for personalized drug dosing based on therapeutic drug monitoring.

This study was aimed at increasing the clinical usefulness of clinical pharmacological advice (CPA) for personalized drug dosing based on therapeutic drug monitoring (TDM). Educational and organizational interventions focused on improving the knowledge of clinical pharmacology among hospital healthcare workers and reducing the incidence of errors throughout the process were planned. After a pre-interventional period of risk assessment, different list forms of the types of error occurring in the various phases of the process (Phase 1, request for CPA and blood sampling for TDM; Phase 2, sample delivery to and check in at the CPU; Phase 3, TDM execution and CPA production) were created.

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.

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).

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.

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

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.

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 real-time 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.

Fluoxetine disposition in patients with chronic hepatitis C treated with interferon-α.

Background And Objectives: Combination therapy with interferon-α and ribavirin is considered the treatment of choice for chronic hepatitis C. However, interferon-α may induce severe depression. It has been suggested that interferon-α is able to modify cytochrome P450 (CYP) 1A2 and 2D6 activity.

Therapeutic drug monitoring of linezolid: a retrospective monocentric analysis.

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 simple method to monitor serum concentrations of fluoxetine and its major metabolite for pharmacokinetic studies.

A rapid, selective and sensitive isocratic reversed-phase HPLC assay coupled with MS/MS detection for simultaneous quantification of fluoxetine and its major active metabolite in serum samples has been developed. Analytes were extracted with a simple three step liquid-liquid procedure and chromatographic separation was achieved on a C18 column. Because of its sensitivity, this HPLC/MS/MS method is suitable both for routine therapeutic drug monitoring and for pharmacokinetic studies, due to its low limits of quantification.

Treatment of pyogenic (non-tuberculous) spondylodiscitis with tailored high-dose levofloxacin plus rifampicin.

The purpose of this study was to assess the clinical efficacy of high-dose levofloxacin plus rifampicin in the empirical treatment of non-tuberculous spondylodiscitis in an epidemiological context of low incidence of staphylococcal fluoroquinolone resistance. All consecutive adult patients with spondylodiscitis (January 2003 to December 2006) were empirically treated with high-dose levofloxacin (500 mg every 12 h normalised to renal function and optimised by means of therapeutic drug monitoring whenever feasible) plus rifampicin 600 mg every 24 h. Trough and peak plasma concentrations were targeted at 1-3 mg/L and 6-9 mg/L, respectively, to maximise the concentration-dependent activity of levofloxacin in bone.

Biliary penetration and pharmacodynamic exposure of linezolid in liver transplant patients.

Objectives: The aim of the study was to assess the biliary penetration of linezolid and the probabilities of attaining optimal pharmacodynamic exposure against vancomycin-resistant enterococci (VRE) in the bile of liver transplant (LTx) patients who received linezolid for the treatment of multidrug-resistant Gram-positive hospital infections.

Methods: After at least 2 days of standard 600 mg twice-daily therapy, simultaneous bile and blood samples for linezolid assay were collected from six LTx patients just prior to drug administration to determine trough concentrations (Cmin) at steady-state in both sites. Linezolid concentrations in plasma and in bile were analysed by means of HPLC.

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.

Drop in trough blood concentrations of tacrolimus after switching from nelfinavir to fosamprenavir in four HIV-infected liver transplant patients.

Solid organ transplantation in HIV-infected individuals requires concomitant use of immunosuppressants and antiretrovirals that may cause significant drug interactions. Here we report on a peculiar pharmacokinetic interaction between tacrolimus and protease inhibitors (PIs) which occurred in four HIV-infected liver transplant patients who had to shift PI therapy from nelfinavir to fosamprenavir as a consequence of regulatory restrictions. After the switch, tacrolimus trough blood concentrations significantly dropped in all patients (mean +/- SD 6.

Clinical relevance of pharmacokinetics and pharmacodynamics in cardiac critical care patients.

Pharmacokinetics is a discipline aimed at predicting the best dosage and dosing regimen for each single drug in order to ensure and maintain therapeutically effective concentrations at the action sites. In cardiac critical care patients, various pathophysiological conditions may significantly alter the pharmacokinetic behaviour of drugs. Gastrointestinal drug absorption may be erratic and unpredictable in the early postoperative period, and so patients may be unresponsive to oral therapy; thus the intravenous route should be preferred for life-saving drugs whenever feasible.

Pharmacokinetic considerations for antimicrobial therapy in patients receiving renal replacement therapy.

Continuous renal replacement therapy (CRRT), particularly continuous venovenous haemofiltration (CVVH) and continuous venovenous haemodiafiltration (CVVHDF), are gaining increasing relevance in routine clinical management of intensive care unit patients. The application of CRRT, by leading to extracorporeal clearance (CL(CRRT)), may significantly alter the pharmacokinetic behaviour of some drugs. This may be of particular interest in critically ill patients presenting with life-threatening infections, since the risk of underdosing with antimicrobial agents during this procedure may lead to both therapeutic failure and the spread of breakthrough resistance.

Tamoxifen and its main metabolites serum and tissue concentrations in breast cancer women.

Because of a possible relationship between tamoxifen (T) concentrations and clinical effects, we initiated a preliminary investigation on serum and tissue concentrations of T and its main active metabolites, and 4-hydroxytamoxifen, in women with positive breast cancer estrogen receptor. One hundred forty-eight patients were studied: 80 were admitted for monitoring of therapeutic serum drug concentrations, 22 had tissue concentrations taken at surgery, and 46 patients had uterine mucosa levels measured at diagnostic hysteroscopy. Steady-state serum concentrations were reached after 1 month of continuous treatment, with desmethyltamoxifen being the highest represented derivative from the third week onward.

Major role of levofloxacin in the treatment of a case of Listeria monocytogenes meningitis.

We report a case of acute bacterial meningitis due to Listeria monocytogenes whose successful treatment was mainly attributable to high-dose levofloxacin therapy (500 mg iv bid). This supports the hypothesis that levofloxacin may be an effective option for the treatment of listerial meningitis.

Penetration of levofloxacin into paranasal sinuses mucosa of patients with chronic rhinosinusitis after a single 500 mg oral dose.

Respiratory fluoroquinolones are currently considered by several guidelines among the most effective antimicrobial agents for the treatment of acute bacterial rhinosinusitis. The aim of this study was to assess levofloxacin penetration into paranasal sinuses mucosa of 15 patients with chronic rhinosinusitis 1h (n = 4), 2 h (n = 5) and 3 h (n = 6) after a single 500 mg oral dose. Levofloxacin concentrations in plasma and tissue samples were assessed by means of HPLC.

Chronopharmacokinetics of ciclosporin and tacrolimus.

The correct use of immunosuppressive drugs has a considerable influence on the prognosis of patients with organ transplants. The appropriate utilisation of the drugs involves the administration of an adequate dosage to reach the blood concentrations that will suppress the alloimmune response, while avoiding secondary toxicities. However, transplanted patients exhibit heterogeneous immunological responses and high inter- and intraindividual pharmacokinetic variabilities.

Which reliable pharmacodynamic breakpoint should be advised for ciprofloxacin monotherapy in the hospital setting? A TDM-based retrospective perspective.

Objectives: To define in critically ill patients receiving intravenous (iv) ciprofloxacin (200 mg or 400 mg twice daily) and undergoing routine therapeutic drug monitoring (TDM) the interindividual pharmacokinetic variability and the reliable pharmacodynamic breakpoint enabled by these fixed dosing regimens according to the PK/PD principles and to the pattern of susceptibility to this antibiotic.

Methods: Ciprofloxacin plasma concentrations [trough (Cmin) and 30 min post-dose peak (Cmax) levels] were analysed by means of an HPLC method. Optimal pharmacodynamic exposure was assessed by estimating the theoretical pharmacodynamic breakpoints (PD BP) for either Cmax or AUC.

Acute oxcarbazepine, benazepril, and hydrochlorothiazide overdose with alcohol.

An epiletic patient, suffering from partial complex seizures and hypertension, ingested approximately 42 g of oxcarbazepine (OXC) and an undefined number of tablets containing an association of benazepril and hydrochlorothiazide along with some glasses of wine. Four hours later he was brought to the emergency room. He was stuporous and gradually became unconscious.

The effect of multifactorial, multidisciplinary educational interventions on appropriate use of teicoplanin.

The aim of this study was to determine the effect of multifactorial, multidisciplinary educational interventions over a 3-year period on the appropriate use of teicoplanin. Teicoplanin was considered a valid surrogate marker of good antibiotic use in clinical practice owing to its peculiar pharmacokinetics (i.e.