Matteo Bassetti

Epidemiological trends in nosocomial candidemia in intensive care

BackgroundInfection represents a frequent complication among patients in Intensive Care Units (ICUs) and mortality is high. In particular, the incidence of fungal infections, especially due to Candida spp., has been increasing during the last years.MethodsIn a retrospective study we studied the etiology of candidemia in critically ill patients over a five-year period (1999–2003) in the ICU of the San Martino University Hospital in Genoa, Italy.ResultsIn total, 182 episodes of candidaemia were identified, with an average incidence of 2.22 episodes/10 000 patient-days/year (range 1.25–3.06 episodes). Incidence of candidemia increased during the study period from 1.25 in 1999 to 3.06/10 000 patient-days/year in 2003. Overall, 40% of the fungemia episodes (74/182) were due to C.albicans, followed by C. parapsilosis(23%), C.glabrata (15%), C.tropicalis (9%) and other species (13%). Candidemia due to non-albicans species increased and this was apparently correlated with an increasing use of azoles for prophylaxis or empirical treatment.ConclusionThe study demonstrates a shift in the species of Candida causing fungemia in a medical and surgical ICU population during a 5 year period. The knowledge of the local epidemiological trends in Candida species isolated in blood cultures is important to guide therapeutic choices.

Colistin and Rifampicin Compared With Colistin Alone for the Treatment of Serious Infections Due to Extensively Drug-Resistant Acinetobacter baumannii: A Multicenter, Randomized Clinical Trial

BACKGROUND Extensively drug-resistant (XDR) Acinetobacter baumannii may cause serious infections in critically ill patients. Colistin often remains the only therapeutic option. Addition of rifampicin to colistin may be synergistic in vitro. In this study, we assessed whether the combination of colistin and rifampicin reduced the mortality of XDR A. baumannii infections compared to colistin alone. METHODS This multicenter, parallel, randomized, open-label clinical trial enrolled 210 patients with life-threatening infections due to XDR A. baumannii from intensive care units of 5 tertiary care hospitals. Patients were randomly allocated (1:1) to either colistin alone, 2 MU every 8 hours intravenously, or colistin (as above), plus rifampicin 600 mg every 12 hours intravenously. The primary end point was overall 30-day mortality. Secondary end points were infection-related death, microbiologic eradication, and hospitalization length. RESULTS Death within 30 days from randomization occurred in 90 (43%) subjects, without difference between treatment arms (P = .95). This was confirmed by multivariable analysis (odds ratio, 0.88 [95% confidence interval, .46-1.69], P = .71). A significant increase of microbiologic eradication rate was observed in the colistin plus rifampicin arm (P = .034). No difference was observed for infection-related death and length of hospitalization. CONCLUSIONS In serious XDR A. baumannii infections, 30-day mortality is not reduced by addition of rifampicin to colistin. These results indicate that, at present, rifampicin should not be routinely combined with colistin in clinical practice. The increased rate of A. baumannii eradication with combination treatment could still imply a clinical benefit. CLINICAL TRIALS REGISTRATION NCT01577862.

Colistin and rifampicin in the treatment of multidrug-resistant Acinetobacter baumannii infections

OBJECTIVES The increased incidence of nosocomial infections by multidrug-resistant organisms has motivated the re-introduction of colistin in combination with other antimicrobials in the treatment of infections. We describe the clinical and microbiological outcomes of patients infected with multidrug-resistant Acinetobacter baumannii who were treated with a combination of colistin and rifampicin. PATIENTS AND METHODS Critically ill patients with pneumonia and bacteraemia caused by A. baumannii resistant to all antibiotics except colistin in medical and surgical intensive care units were enrolled. Clinical and microbiological responses and safety were evaluated. RESULTS Twenty-nine patients (47 +/- 14 years and APACHE II score 17.03 +/- 3.68), of whom 19 were cases of nosocomial pneumonia and 10 were cases of bacteraemia, were treated with intravenous colistin sulphomethate sodium (2 million IU three times a day) in addition to intravenous rifampicin (10 mg/kg every 12 h). All A. baumannii isolates were susceptible to colistin. The mean duration of treatment with intravenous colistin and rifampicin was 17.7 (+/-10.4) days (range 7-36). Clinical and microbiological responses were observed in 22 of 29 cases (76%) and the overall infection-related mortality was 21% (6/29). Three of the 29 evaluated patients (10%) developed nephrotoxicity when treated with colistin, all of whom had previous renal failure. No cases of renal failure were observed among patients with normal baseline renal function. No neurotoxicity was noted. CONCLUSIONS Colistin and rifampicin appears to be an effective and safe combination therapy for severe infections due to multidrug-resistant A. baumannii.

Detection and investigation of invasive mould disease

A comprehensive review of diagnostic techniques for opportunistic systemic mycoses focused on invasive mould disease in immunocompromised patients is presented. We first analysed conventional diagnostic methods, such as microscopy examination, culture and radiology, underlining their limitations, which have led to the development of alternative methods, such as the detection of fungal components. Among these we highlight fungal antigen and DNA quantification, which make it possible to detect infections early and start appropriate treatment. We also briefly review the methods for carrying out susceptibility tests for antifungal drugs, including reference procedures, commercial techniques and their indications. Furthermore, we analyse the recommendations for therapeutic drug monitoring of antifungal agents in body fluids.

Identifying patients harboring extended-spectrum-beta-lactamase-producing Enterobacteriaceae on hospital admission: derivation and validation of a scoring system.

ABSTRACT Increases in community-acquired infections caused by extended-spectrum-β-lactamase (ESBL)-producing Enterobacteriaceae have important implications for hospital infection control and empirical antibiotic therapy protocols. We developed and validated a tool for identifying patients harboring these organisms at hospital admission. We retrospectively analyzed chart data for 849 adult inpatients. The derivation cohort included 339 patients admitted to a large hospital in Rome during 2008, with (n = 113) or without (n = 226) culture positivity for ESBL-producing Escherichia coli, Klebsiella spp., or Proteus mirabilis within 48 h after admission. Logistic-regression-based prediction scores were calculated based on variables independently associated with the outcome. The model was validated in a second cohort (n = 510) selected with identical criteria in hospitals in Genoa and Turin during 2009. Prediction scores were based on the following six variables (reported with odds ratio for study outcome and the 95% confidence intervals in brackets): recent (≤12 months before admission) hospitalization (5.69 [2.94 to 10.99]), transfer from another health care facility (5.61 [1.65 to 19.08]), Charlson comorbidity score ≥ 4 (3.80 [1.90 to 7.59]), recent (≤3 months before admission) β-lactam and/or fluoroquinolone treatment (3.68 [1.96 to 6.91]), recent urinary catheterization (3.52 [1.96 to 6.91]), and age ≥ 70 years (3.20 [1.79 to 5.70]). The model displayed good calibration and good-to-excellent discrimination in the derivation and validation sets (Hosmer-Lemshow χ2 = 15.28 and 14.07; P = 0.17 and 0.23; areas under the receiver-operating characteristic curve, 0.83 and 0.92). It reliably identified patients likely to be harboring ESBL-producing Enterobacteriaceae at hospital admission who may need special infection control measures. Further study is needed to confirm this models potential as a guide for prescribing empirical antibiotic therapy.

Incidence of candidaemia and relationship with fluconazole use in an intensive care unit

OBJECTIVES Candida spp. are the most important non-bacterial pathogens in critically ill patients. The aim of this study was to evaluate trends in the incidence of candidaemia and the distribution of Candida albicans and non-albicans over a 9 year period (1999-2007), and to assess their relationship with fluconazole use. METHODS This was an interventional cross-over study. Patients admitted to the intensive care unit (ICU) who developed a clinically and microbiologically documented candidaemia were analysed. Fluconazole was used as prophylaxis in critically ill patients until 2002; from January 2003 infectious disease consultants strongly discouraged its use. Fluconazole use, measured as defined daily dose per 1000 patient-days, was calculated. The main outcome of the study is the evaluation of the restriction policy in terms of change in fluconazole use and in incidence of candidaemia. RESULTS During the 108 month period (January 1999-December 2007), a total of 213 episodes of candidaemia (average incidence 1.42 episodes/10 000 patient-days/year, range 0.36-3.02 episodes) were recorded in a mixed medical and surgical ICU in Italy. C. albicans was the most prevalent isolated species (n = 98, 46%); non-albicans (n = 115, 54%) were mainly represented by Candida parapsilosis (n = 46, 22%) and by Candida glabrata (n = 28, 13%). Segmented regression analysis of the interrupted time series showed that a change in the fluconazole prophylactic strategy resulted in a significant reduction in fluconazole use from the second semester of 2002. A dramatic decrease in the incidence of fungaemia due to C. non-albicans was observed from the second semester of 2003 (intervention effect in the second semester of 2007: -2.31/10 000 patient-days); minor changes in the incidence of C. albicans fungaemia emerged (intervention effect in the second semester of 2007: -0.23/10 000 patient-days). CONCLUSIONS The study showed a clear correlation between fluconazole use control and decreasing incidence of non-albicans candidaemia. Even if fluconazole remains a first-line treatment option in several cases of invasive candidiasis, its prophylactic use should be carefully evaluated.

Multidrug-resistant Pseudomonas aeruginosa bloodstream infections: risk factors and mortality.

We retrospectively studied patients diagnosed with P. aeruginosa bloodstream infections (BSIs) in two Italian university hospitals. Risk factors for the isolation of multidrug-resistant (MDR) or non-MDR P. aeruginosa in blood cultures were identified by a case-case-control study, and a cohort study evaluated the clinical outcomes of such infections. We identified 106 patients with P. aeruginosa BSI over the 2-year study period; 40 cases with MDR P. aeruginosa and 66 cases with non-MDR P. aeruginosa were compared to 212 controls. Independent risk factors for the isolation of MDR P. aeruginosa were: presence of central venous catheter (CVC), previous antibiotic therapy, and corticosteroid therapy. Independent risk factors for non-MDR P. aeruginosa were: previous BSI, neutrophil count <500/mm3, urinary catheterization, and presence of CVC. The 21-day mortality rate of all patients was 33·9%. The variables independently associated with 21-day mortality were presentation with septic shock, infection due to MDR P. aeruginosa, and inadequate initial antimicrobial therapy.

Risk factors and mortality of healthcare-associated and community-acquired Staphylococcus aureus bacteraemia

Staphylococcus aureus bacteraemia (SAB) is a leading cause of mortality and morbidity in both nosocomial and community settings. The objective of the study is to explore epidemiological characteristics and predisposing risk factors associated with healthcare-associated (HCA) and community-acquired (CA) SAB, and to evaluate any differences in mortality and efficacy of initial antimicrobial therapy on treatment outcome. We conducted a two-part analysis. First, a triple case-control study in which groups of HCA SAB with onset ≥ 48 h after hospital admission (HCA ≥ 48 h), HCA SAB with onset <48 h of hospital admission (HCA <48 h), and CA SAB were compared with controls. Second, a cohort study including all patients with SAB was performed to identify factors associated with in-hospital mortality. SAB was diagnosed in 165 patients over the study period (January 2007 to December 2007). Five variables were independently associated with HCA ≥ 48 h SAB: presence of central venous catheter, solid tumour, chronic renal failure, previous hospitalization and previous antibiotic therapy. Significant risk factors for HCA <48 h SAB were: Charlson Comorbidity Index ≥ 3, previous hospitalization, living in long-term care facilities and corticosteroid therapy. Factors independently associated with CA SAB were: diabetes mellitus, HIV infection and chronic live disease. Patients with HCA <48 h SAB were significantly more likely to receive initial inadequate antimicrobial treatment than patients with CA or HCA ≥ 48 h SAB (44.8% versus 33.3% and 31.5%, respectively). Logistic-regression analysis identified three variables as independent predictors of mortality: presentation with septic shock, infection with methicillin-resistant S. aureus, and initial inadequate antimicrobial treatment. More than half of patients with SAB have MRSA strains and presentation with septic shock, and inappropriate empirical therapy was associated with increased mortality.

Why is community-associated MRSA spreading across the world and how will it change clinical practice?

Meticillin-resistant Staphylococcus aureus (MRSA) emerged in 1960 and over the following 40 years was a problem confined largely to the healthcare setting. In the late 1990s the first US reports of so-called community-associated MRSA (CA-MRSA) infections appeared. CA-MRSA infections were defined as MRSA infections occurring in patients who had no identifiable predisposing risk factors, such as healthy children and young adults. CA-MRSA is associated with a novel genetic profile and phenotype; it is remarkably fit and capable of spreading within communities, it is virulent and is often susceptible to multiple narrow-spectrum antimicrobials other than beta-lactams. CA-MRSA infections involve predominantly skin and soft tissue; however, necrotizing pneumonia and necrotizing fasciitis have been described. At present, several reports suggest that CA-MRSA may be replacing the hospital-acquired MRSA strains (HA-MRSA), with potentially catastrophic consequences. Given the rapid spread and the high virulence of CA-MRSA, global strategies are needed. Prompt, appropriate treatment, guided by the site and type of infection and risk factors for HA-MRSA or CA-MRSA, increases the chances of a successful outcome and is urgently needed.

High-dose daptomycin in documented Staphylococcus aureus infections

Daptomycin is approved at a dose of 4-6 mg/kg/day for the treatment of complicated skin and soft-tissue infection and Staphylococcus aureus bloodstream infection. Clinical experience with doses >6 mg/kg/day is limited, but data reported to date suggest that daptomycin can be safe and effective at higher doses. We describe our experience with daptomycin at doses >6 mg/kg/day and ≤6 mg/kg/day for S. aureus infections. A retrospective chart review of all patients treated with daptomycin from January 2008 to 28 February 2010 was performed. During the study period, 53 patients received daptomycin, including 22 patients receiving daptomycin at a standard dose (SD) (mean 5 mg/kg/day, range 4-6 mg/kg/day) and 31 patients receiving a higher dose (HD) (mean 8 mg/kg/day, range 7-9 mg/kg). The median treatment duration was 13.5 days and 19 days for the SD and HD groups, respectively. Clinical success was observed in 16/22 patients (73%) in the SD group and 29/31 patients (94%) in the HD group (P=0.05). Microbiological success was observed in 13/19 patients (68%) and 27/29 patients (93%) in the SD and HD groups, respectively (P<0.05). Of the 53 patients, 2/22 treated with SD daptomycin and 3/31 treated with HD daptomycin experienced a grade 1 adverse event while receiving therapy (i.e. anaemia, diarrhoea, nausea, hypokalaemia and arthralgia) but did not require discontinuation of daptomycin treatment. These results suggest that daptomycin may be used at doses higher than 6 mg/kg/day without toxicity and possibly with better outcome than conventional doses. We recommend further randomised controlled prospective studies with higher doses of daptomycin.