Pierluigi Viale

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

OBJECTIVESnProlonged treatment with linezolid may cause toxicity. The purpose of this study was to define pharmacodynamic thresholds for improving safety outcomes of linezolid.nnnMETHODSnWe 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/Lu200a·u200ah. Patients were divided into two subgroups according to the absence or presence of co-treatment with rifampicin (the linezolid group and the linezolidu200a+u200arifampicin group, respectively). Data on demographic characteristics, disease, microbiology and haematochemical parameters were collected and outcomes in relation to drug exposure were compared between groups.nnnRESULTSnA total of 45 patients were included. Dosage adjustments were needed in 40% versus 0% of patients in the linezolid group (nu200a=u200a35) versus the linezolidu200a+u200arifampicin group (nu200a=u200a10), 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), Pu200a<u200a0.001] or AUC₂₄ [212.77 mg/Lu200a·u200ah (166.67-278.42) versus 123.33 mg/Lu200a·u200ah (97.36-187.94), Pu200a<u200a0.001]. Thrombocytopenia appeared in 51.4% versus 0% of cases in the linezolid group versus the linezolidu200a+u200arifampicin 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/Lu200a·u200ah.nnnCONCLUSIONSnMaintenance over time of C(min) between 2 and 7 mg/L and/or of AUC₂₄ between 160 and 300 mg/Lu200a·u200ah may be helpful in improving safety outcomes while retaining appropriate efficacy in adult patients receiving prolonged linezolid treatment.

Epidemiology, characteristics, and outcome of infective endocarditis in Italy: the Italian Study on Endocarditis

BackgroundThe characteristics of patients with infective endocarditis (IE) vary significantly by region of the world. The aim of this study was to evaluate the contemporary epidemiology, characteristics, and outcome of IE in a large, nationwide cohort of Italian patients.MethodsWe conducted a prospective, observational study at 24 medical centers in Italy, including all the consecutive patients with a definite or possible diagnosis of IE (modified Duke criteria) admitted from January 2004 through December 2009. A number of clinical variables were collected through an electronic case report form and analyzed to comprehensively delineate the features of IE. We report the data on patients with definite IE.ResultsA total of 1,082 patients with definite IE were included. Of these, 753 (69.6xa0%) patients had infection on a native valve, 277 (25.6xa0%) on a prosthetic valve, and 52 (4.8xa0%) on an implantable electronic device. Overall, community-acquired (69.2xa0%) was more common than nosocomial (6.2xa0%) or non-nosocomial (24.6xa0%) health care-associated IE. Staphylococcus aureus was the most common pathogen (22.0xa0%). In-hospital mortality was 15.1xa0%. From the multivariate analysis, congestive heart failure (CHF), stroke, prosthetic valve infection, S. aureus, and health care-associated acquisition were independently associated with increased in-hospital mortality, while surgery was associated with decreased mortality.ConclusionsThe current mortality of IE remains high, and is mainly due to its complications, such as CHF and stroke.

The potential impact of antifungal drug resistance mechanisms on the host immune response to Candida

A large number of studies have been published over the last two decades examining molecular mechanisms of antifungal resistance in Candida species. However, few of these studies have explored how such mechanisms influence the host immune response to this opportunistic pathogen. With recent advances in our understanding of host immunity to Candida, a body of emerging literature has begun to explore how intrinsic and adaptive resistance mechanisms in Candida alter host immune system evasion and detection, which could have important implications for understanding (1) why certain resistance mechanisms and Candida species predominate in certain patient populations, (2) the biological context for understanding why high in vitro levels of resistance in may not necessarily correlate with risk of drug failure in vivo and (3) insight into effective immunotherapeutic strategies for combatting Candida resistance. Although this area of research is still in its infancy, two themes are emerging: First, the immunoevasion and intracellular persistence of C. glabrata may be a key factor in the capability of this species to persist in the course of multiple antifungal treatments and develop multidrug resistance. Second, changes in the cell wall associated with antifungal resistance often favor evasion for the host immune response.

A prospective survey of febrile events in hematological malignancies

The Hema e-Chart prospectively collected data on febrile events (FEs) in hematological malignancy patients (HMs). The aim of the study was to assess the number, causes and outcome of HM-related FEs. Data were collected in a computerized registry that systematically approached the study and the evolution of FEs developing in a cohort of adult HMs who were admitted to 19 hematology departments in Italy from March 2007 to December 2008. A total of 869 FEs in 3,197 patients with newly diagnosed HMs were recorded. Fever of unidentified origin (FUO) was observed in 386 cases (44.4%). The other causes of FE were identified as noninfectious in 48 cases (5.5%) and infectious in 435 cases (50.1%). Bacteria were the most common cause of infectious FEs (301 cases), followed by fungi (95 cases), and viruses (7 cases). Mixed agents were isolated in 32 episodes. The attributable mortality rate was 6.7% (58 FEs). No deaths were observed in viral infection or in the noninfectious groups, while 25 deaths were due to FUO, 16 to bacterial infections, 14 to fungal infections, and three to mixed infections. The Hema e-Chart provided a complete system for the epidemiological study of infectious complications in HMs.

Cost-effectiveness analysis of initial HIV treatment under Italian guidelines

Introduction Since the mid-1990s, highly active antiretroviral therapy (HAART) has modified the clinical course of human immunodeficiency virus (HIV) infection, reducing the rate of disease progression, the incidence of opportunistic infections, and mortality. The authors of this paper performed an economic analysis to estimate the cost-effectiveness of the HAART regimens in Italy for managing HIV-infected patients according to national guidelines. Patients and methods The incremental cost-effectiveness analysis was carried out by means of a Markov model, which through a decision-analytic approach, made it possible to compare the studied antiretroviral regimens. The population considered in the model consisted of adult subjects with HIV who received antiretroviral HAART treatment for the first time. The population considered in the analysis reflects the patients’ characteristics according to one of the regional surveillance systems HIV/AIDS infection report currently operating in Italy. The analysis was carried out from the point of view of the Italian health care system. The considered outcome measures were quality-adjusted life years (QALYs) and direct health costs calculated for the year 2010. Both the outcomes (QALYs) and the costs were discounted by 3.5%. The time horizon adopted in the model was 10 years. Results The model shows, in terms of cost per gained QALY, single tablet regimen (STR) appeared to be the most cost-effective therapeutic choice (€22,017), followed by tenofovir (TDF) + lamivudine + efavirenz (EFV) (€24,526), and TDF/emtricitabine (FTC) + nevirapine (€26,416), and TDF + FTC + EFV (€26,558); the remaining strategies have an incremental cost-effectiveness ratio (ICER) value varying from €28,000 to €41,000 per QALY. The sensitivity analysis on the main variables confirmed the validity of the base case scenario. Conclusion STR is the most cost-effective treatment strategy, compared with the other therapeutic regimens recommended by the Italian guidelines. All the ICER values of the various regimens considered by the Italian guidelines were lower than the threshold value of €50,000 commonly accepted at the international level. The model developed represents a tool for policy makers and health care professionals to make short- and long-term cost projections and thus evaluate their impact on the available budgets for HIV patients.

Toscana virus infections in northern Italy: laboratory and clinical evaluation.

Toscana virus (TOSv) is a neurotropic arthropod-borne virus that causes meningitis in the Mediterranean basin during the summer months. A total of 120 patients suffering from acute aseptic meningitis between July 1 and October 31, 2010 in northern Italy were evaluated. Eighteen of them (15%) were in the acute stage of TOSv disease.

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.

Prevalence of renal disease within an urban HIV-infected cohort in northern Italy

BackgroundRenal disease is an increasingly recognized noninfectious comorbidity associated with human immunodeficiency virus (HIV) infection.MethodsOur retrospective, cross-sectional study evaluated prevalence of nephropathy among HIV-infected patients followed up in our outpatient clinic during the year 2011. Renal dysfunction and chronic kidney disease (CKD) were defined as estimated glomerular filtration rate (eGFR) <90xa0ml/min per 1.73xa0m2 and as renal damage or eGFR <60xa0ml/min per 1.73xa0m2 over a 3-month or greater period, respectively.ResultsWe enrolled 894 HIV-infected patients with a mean age of 44.2xa0years and a mean current CD4 lymphocyte count of 508xa0cells/mm3. The prevalence of renal dysfunction and CKD was 27.4 and 21.3xa0%, respectively. Older age, male gender, hypertension, diabetes, proteinuria, hypertriglyceridemia, lower nadir CD4 cell count, current use of tenofovir or tenofovir plus a ritonavir-boosted protease inhibitor were independently associated with renal dysfunction.ConclusionRenal dysfunction is a frequent comorbidity among HIV-infected persons and requires a careful clinical and laboratory monitoring of renal function.

Lopinavir/ritonavir trough concentrations with the tablet formulation in HIV-1-infected women during the third trimester of pregnancy

Abstract Objectives: An observational, open-label study was performed to assess changes of lopinavir/ritonavir plasma concentrations during pregnancy. Methods: Adult HIV-1-infected women during the third trimester of pregnancy and on stable antiretroviral treatment including zidovudine/lamivudine plus lopinavir/ritonavir tablets (400/100 mg twice daily) were asked to participate. This group was compared with a group of non-pregnant HIV-1-infected women receiving the same antiretroviral regimen. The trough plasma concentration (Ctrough) of lopinavir and ritonavir was assessed at steady-state by a validated high-performance liquid chromatography (HPLC)-tandem mass spectrometry method. Results: A total of 41 HIV-positive female patients were enrolled in the study, with a median age of 28 y (range 20–37 y). These patients were stratified into 2 groups: 21 women in the third trimester of pregnancy (group A) and 20 non-pregnant women (group B). The geometric mean (95% confidence interval (CI)) plasma Ctrough of lopinavir was 4205 (2418–6896) ng/ml in group A and 5098 (3187–8084) ng/ml in group B. The reduction in lopinavir plasma levels observed in group A was not significant (geometric mean ratio 0.87, 95% CI 0.62–1.32; p = 0.411). No correlation was found between lopinavir plasma levels and adverse events (such as diarrhoea and hyperlipidaemia) or immunological parameters of HIV disease, and no changes in plasma HIV viral load were reported. Conclusion: In this study, a slight but not significant decrease in the plasma lopinavir Ctrough was found during the third trimester of pregnancy, suggesting that standard dosing of the tablet formulation is also appropriate during the later stages of pregnancy.

Complicated Intra-Abdominal Infections Observational European study (CIAO Study).

Complicated intra-abdominal infections are frequently associated with poor prognoses and high morbidity and mortality rates.Despite advances in diagnosis, surgery, and antimicrobial therapy, mortality rates associated with complicated intra-abdominal infections remain exceedingly high.In order to describe the clinical, microbiological, and management-related profiles of both community-acquired and healthcare-acquired complicated intra-abdominal infections (IAIs), the World Society of Emergency Surgery (WSES), in collaboration with the Surgical Infections Society of Europe (SIS-E) and other prominent European surgical societies, has designed the CIAO study.The CIAO study is a multicenter, observational study and will be carried out in various surgical departments throughout Europe. The study will include patients undergoing surgery or interventional drainage for complicated IAI.