Publications by authors named "Valerio del Bono"

57 Publications

Risk Factors for Mortality in COVID-19 Hospitalized Patients in Piedmont, Italy: Results from the Multicenter, Regional, CORACLE Registry.

J Clin Med 2021 May 1;10(9). Epub 2021 May 1.

Department of Medical Sciences, University of Turin, 10126 Turin, Italy.

Background: CORACLE is a retrospective and prospective, regional multicenter registry, developed to evaluate risk factors for mortality in a cohort of patients admitted with SARS-CoV-2 infection within non-intensive wards.

Methods: The primary objective was to estimate the role of several prognostic factors on hospital mortality in terms of adjusted Odds Ratios (aOR) with multivariable logistic regression models.

Results: A total of 1538 patients were enrolled; 42% were female, and 58% were >70 years old. Deceased patients were 422 (27%), with a median age of 83 years (IQR (Inter Quartile Range) 76-87). Older age at admission (aOR 1.07 per year, 95%CI 1.06-1.09), diabetes (1.41, 1.02-1.94), cardiovascular disease (1.79, 1.31-2.44), immunosuppression (1.65, 1.04-2.62), estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m (3.53, 2.26-5.51), higher C-reactive protein values and a decreased PaO/FiO ratio at admission were associated with a higher risk of hospital mortality. Amongst patients still alive on day 7, only hydroxychloroquine (HCQ) treatment was associated with reduced mortality (0.57, 0.36-0.90).

Conclusions: Several risk factors were associated with mortality in SARS-CoV-2 positive patients. Although HCQ seems to be the only factor significantly associated with reduced mortality, this result is in contrast with evidence from randomized studies. These results should be interpreted in light of the study limitations.
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http://dx.doi.org/10.3390/jcm10091951DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8124506PMC
May 2021

Persistence of Elevated Procalcitonin in a Patient with Covid-19 Uncovering a Diagnosis of Medullary Thyroid Carcinoma.

AACE Clin Case Rep 2021 May 12. Epub 2021 May 12.

Objectives: During this ongoing pandemic of coronavirus disease 2019 (COVID-19), procalcitonin (PCT) assay has proven to be a useful tool in assisting clinicians to diagnose bacterial superinfection. However, in the absence of signs of infection or at resolution thereof, inappropriately and persistently high PCT may suggest and reveal the presence of other pathologies We report a patient with acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pneumonia in whom persistence of initially elevated PCT during recovery prompted the diagnosis of medullary thyroid cancer (MTC).

Case Report: A 43- year-old man presented with a two-day history of fever, sneezing, sore throat and dry cough. Physical exam revealed decreased sounds and coarse crackles in both lung bases at auscultation. Medical history was positive for cognitive impairment since birth, arterial hypertension, systemic lupus erythematosus with nephritis. Initial studies included mild lymphocytopenia 650/μl (760 - 5000), D-Dimer 0.73 μg/ml (< 0.5), C reactive protein (CRP) of 62 mg/l (< 5) and PCT of 94 ng/ml (0.00 - 0.10). Positivity for SARS-Cov-2 RNA was detected and chest computerized tomography showed bilateral ground-glass opacities in the basilar lung zones and hyperdense and irregular foci in the thoracic vertebral bodies. Empirical antibiotic therapy was started and was maintained for seven days but, despite clinical improvement and the normalization of CRP, serum PCT was persistently high (84 ng/ml). Serum calcitonin (CTN) was 2120 pg/ml (normal up to 12 pg/ml). Neck ultrasound revealed inhomogeneously echogenic lymph nodes with small punctate calcifications and a non-homogeneous thyroid with multiple nodules. Cytological examination by fine needle aspiration and CTN measurement on washing liquid confirmed the suspicion of MTC. The patient underwent total thyroidectomy with bilateral cervical lymph node dissection. Histological analysis confirmed MTC of right thyroid lobe and metastasis at lymph nodes of the central right midneck area. Blood tests performed 48 hours after surgery showed a lowering of CTN (986 pg/mL) and PCT (16 ng/mL). A 6-months follow up showed persistent increased CTN and PCT levels (921 pg/ml and 16 ng/ml, respectively) while a (18)F-fluorodihydro-xyphenylalanine ((18)F-DOPA) PET did not reveal any suspicious fixations at thyroid lodge and cervical lymph node stations while multiple osteoblastic foci in the skeletal area were described. A close follow-up was planned with establishment of the results of RET gene analysis.

Discussion: Although CTN is the gold standard biochemical parameter for the diagnosis and follow-up of MTC, PCT can be useful as a biochemical marker of MTC suspicion in patients with inflammatory conditions and persistently elevated PCT even after resolution. In the present CASE, high levels of PCT in a patient with Covid-19 pneumonia without signs of bacterial infection, allowed to diagnose MCT.

Conclusion: In the absence of any other signs of infection, a complete clinical assessment, including neck palpation, CTN measurement and thyroid ultrasound should be performed in the presence of persistently elevated PCT.
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http://dx.doi.org/10.1016/j.aace.2021.05.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8113110PMC
May 2021

Effect of Tocilizumab vs Standard Care on Clinical Worsening in Patients Hospitalized With COVID-19 Pneumonia: A Randomized Clinical Trial.

JAMA Intern Med 2021 01;181(1):24-31

Malattie Infettive e Tropicali, AO S. Croce e Carle, Cuneo, Italy.

Importance: The coronavirus disease 2019 (COVID-19) pandemic is threatening billions of people worldwide. Tocilizumab has shown promising results in retrospective studies in patients with COVID-19 pneumonia with a good safety profile.

Objective: To evaluate the effect of early tocilizumab administration vs standard therapy in preventing clinical worsening in patients hospitalized with COVID-19 pneumonia.

Design, Setting, And Participants: Prospective, open-label, randomized clinical trial that randomized patients hospitalized between March 31 and June 11, 2020, with COVID-19 pneumonia to receive tocilizumab or standard of care in 24 hospitals in Italy. Cases of COVID-19 were confirmed by polymerase chain reaction method with nasopharyngeal swab. Eligibility criteria included COVID-19 pneumonia documented by radiologic imaging, partial pressure of arterial oxygen to fraction of inspired oxygen (Pao2/Fio2) ratio between 200 and 300 mm Hg, and an inflammatory phenotype defined by fever and elevated C-reactive protein.

Interventions: Patients in the experimental arm received intravenous tocilizumab within 8 hours from randomization (8 mg/kg up to a maximum of 800 mg), followed by a second dose after 12 hours. Patients in the control arm received supportive care following the protocols of each clinical center until clinical worsening and then could receive tocilizumab as a rescue therapy.

Main Outcome And Measures: The primary composite outcome was defined as entry into the intensive care unit with invasive mechanical ventilation, death from all causes, or clinical aggravation documented by the finding of a Pao2/Fio2 ratio less than 150 mm Hg, whichever came first.

Results: A total of 126 patients were randomized (60 to the tocilizumab group; 66 to the control group). The median (interquartile range) age was 60.0 (53.0-72.0) years, and the majority of patients were male (77 of 126, 61.1%). Three patients withdrew from the study, leaving 123 patients available for the intention-to-treat analyses. Seventeen patients of 60 (28.3%) in the tocilizumab arm and 17 of 63 (27.0%) in the standard care group showed clinical worsening within 14 days since randomization (rate ratio, 1.05; 95% CI, 0.59-1.86). Two patients in the experimental group and 1 in the control group died before 30 days from randomization, and 6 and 5 patients were intubated in the 2 groups, respectively. The trial was prematurely interrupted after an interim analysis for futility.

Conclusions And Relevance: In this randomized clinical trial of hospitalized adult patients with COVID-19 pneumonia and Pao2/Fio2 ratio between 200 and 300 mm Hg who received tocilizumab, no benefit on disease progression was observed compared with standard care. Further blinded, placebo-controlled randomized clinical trials are needed to confirm the results and to evaluate possible applications of tocilizumab in different stages of the disease.

Trial Registration: ClinicalTrials.gov Identifier: NCT04346355; EudraCT Identifier: 2020-001386-37.
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http://dx.doi.org/10.1001/jamainternmed.2020.6615DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7577199PMC
January 2021

Risk Factors for Candidemia After Open Heart Surgery: Results From a Multicenter Case-Control Study.

Open Forum Infect Dis 2020 Aug 19;7(8):ofaa233. Epub 2020 Jun 19.

Department of Health Sciences (DISSAL), University of Genoa, Genoa, Italy.

Background: species are among the most frequent causative agents of health care-associated bloodstream infections, with mortality >40% in critically ill patients. Specific populations of critically ill patients may present peculiar risk factors related to their reason for intensive care unit admission. The primary objective of the present study was to assess the predictors of candidemia after open heart surgery.

Methods: This retrospective, matched case-control study was conducted in 8 Italian hospitals from 2009 to 2016. The primary study objective was to assess factors associated with the development of candidemia after open heart surgery.

Results: Overall, 222 patients (74 cases and 148 controls) were included in the study. Candidemia developed at a median time (interquartile range) of 23 (14-36) days after surgery. In multivariable analysis, independent predictors of candidemia were New York Heart Association class III or IV (odds ratio [OR], 23.81; 95% CI, 5.73-98.95;  < .001), previous therapy with carbapenems (OR, 8.87; 95% CI, 2.57-30.67;  = .001), and previous therapy with fluoroquinolones (OR, 5.73; 95% CI, 1.61-20.41;  = .007). Crude 30-day mortality of candidemia was 53% (39/74). Septic shock was independently associated with mortality in the multivariable model (OR, 5.64; 95% CI, 1.91-16.63;  = .002). No association between prolonged cardiopulmonary bypass time and candidemia was observed in this study.

Conclusions: Previous broad-spectrum antibiotic therapy and high NYHA class were independent predictors of candidemia in cardiac surgery patients with prolonged postoperative intensive care unit stay.
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http://dx.doi.org/10.1093/ofid/ofaa233DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7397829PMC
August 2020

Changing epidemiology of candidaemia: Increase in fluconazole-resistant Candida parapsilosis.

Mycoses 2020 Apr 20;63(4):361-368. Epub 2020 Feb 20.

Department of Health Sciences (DiSSal), University of Genova, Genova, Italy.

Aim: During the last decade a continuous increase in non-albicans species isolation has been observed with Candida parapsilosis being one of the leading species. Aim of this study was to describe the epidemiology of candidemia, particularly of C parapsilosis, its predictors and clinical outcome.

Materials And Methods: Incidences of candidemia was evaluated analyzing data from both a prospective collection (2012-2016) and a retrospective one (2008-2011). Predictors and outcome were based only on the prospective phase. C parapsilosis potential clusters were analysed by randomly amplified polymorphic DNA (RAPD) technique.

Results: 1240 episodes were identified. Incidences of candidemia increased from 1.97 episodes/10 000 patient-days in 2008 to 4.59/10 000 patient-days in 2016 (P < .001), mainly due to an increase of C parapsilosis (incidence rate ratio, IRR: 1.04, P < .001). 33.0% of C parapsilosis strains were resistant to fluconazole; no resistance to echinocandins was found. Independent predictors of C parapsilosis candidemia were time of infection (P = .007), previous use of echinocandins (P < .0001) and year in which the episode was registered (P < .0001). 30 days mortality was 32.4% for C parapsilosis, with a significant difference compared to C non-parapsilosis. Potential clonal C parapsilosis strains were detected by genetic analyses, showing RAPD profile A as the most represented (72.6% of isolates).

Discussion: C parapsilosis candidemia is an emerging issue in our center, possibly attributed to some extent to horizontal transmission of the pathogen, as confirmed by the analysis of isolates similarities. Further microbiological and epidemiological investigations are needed in order to identify the most effective measures to reduce the rate of this infection.
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http://dx.doi.org/10.1111/myc.13050DOI Listing
April 2020

Ceftobiprole: drug evaluation and place in therapy.

Expert Rev Anti Infect Ther 2019 09 25;17(9):689-698. Epub 2019 Sep 25.

Department of Health Sciences, University of Genoa , Genoa , Italy.

: Ceftobiprole is a fifth-generation cephalosporin with a broad spectrum of antimicrobial activity, including also methicillin-resistant (MRSA). Ceftobiprole is approved for the treatment of community-acquired pneumonia (CAP) and hospital-acquired pneumonia (HAP), excluding ventilator-associated pneumonia, in several European and non-European countries. : In this narrative review, we discuss the current place in therapy of ceftobiprole, both within and outside approved indications. An inductive MEDLINE/PubMed search of the available literature was conducted. : There are three main reasons which render ceftobiprole an attractive option for the empirical and targeted treatment of CAP and HAP: () its broad spectrum of activity; () its activity against MRSA; () its good safety profile. For these indications, ceftobiprole should be employed thoughtfully, in those scenarios in which its intrinsic advantages could be maximized. The use of ceftobiprole outside approved indications could be justified in specific scenarios, such as when other approved alternatives are ineffective, when the risk of toxicity due to other agents is unacceptable, and for salvage therapy. In the near future, ongoing phase 3 studies and further observational experiences could both enlarge the current panel of approved indications and enrich our knowledge on the use of ceftobiprole for off-label indications.
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http://dx.doi.org/10.1080/14787210.2019.1667229DOI Listing
September 2019

Use of colistin in adult patients: A cross-sectional study.

J Glob Antimicrob Resist 2020 03 15;20:43-49. Epub 2019 Jun 15.

Department of Medical and Surgical Sciences, Infectious and Tropical Diseases Unit, 'Magna Graecia' University of Catanzaro, Catanzaro, Italy.

Objectives: The aim of this study was to assess colistin use in a country endemic for multidrug-resistant Gram-negative bacteria (MDR-GNB).

Methods: Colistin prescription patterns were evaluated in 22 Italian centres. Factors associated with use of colistin in combination with other anti-MDR-GNB agents were also assessed.

Results: A total of 221 adults receiving colistin were included in the study. Their median age was 64 years (interquartile range 52-73 years) and 134 (61%) were male. Colistin was mostly administered intravenously (203/221; 92%) and mainly for targeted therapy (168/221; 76%). The most frequent indications for colistin therapy were bloodstream infection and lower respiratory tract infection. Intravenous colistin was administered in combination with at least another anti-MDR-GNB agent in 80% of cases (163/203). A loading dose of 9 MU of colistimethate was administered in 79% of patients receiving i.v. colistin and adequate maintenance doses in 85%. In multivariable analysis, empirical therapy [odds ratio (OR) = 3.25, 95% confidence interval (CI) 1.24-8.53;P = 0.017] and targeted therapy for carbapenem-resistant Enterobacterales infection (OR = 4.76, 95% CI 1.69-13.43; P = 0.003) were associated with use of colistin in combination with other agents, whilst chronic renal failure (OR = 0.39, 95% CI 0.17-0.88; P =  0.024) was associated with use of colistin monotherapy.

Conclusion: Colistin remains an important option for severe MDR-GNB infections when other treatments are not available. Despite inherent difficulties in optimising its use owing to peculiar pharmacokinetic/pharmacodynamic characteristics, colistin was mostly used appropriately in a country endemic for MDR-GNB.
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http://dx.doi.org/10.1016/j.jgar.2019.06.009DOI Listing
March 2020

Bloodstream infections caused by carbapenem-resistant Acinetobacter baumannii: Clinical features, therapy and outcome from a multicenter study.

J Infect 2019 08 28;79(2):130-138. Epub 2019 May 28.

Department of Public Health and Infectious Diseases, Sapienza University of Rome, Policlinico Umberto I, Viale dell'Università 37, 00161 Rome, Italy. Electronic address:

Objectives: bloodstream infections (BSI) due to multidrug-resistant (MDR) Acinetobacter baumannii (AB) have been increasingly observed among hospitalized patients.

Methods: prospective, observational study conducted among 12 large tertiary-care hospitals, across 7 Italian regions. From June 2017 to June 2018 all consecutive hospitalized patients with bacteremia due to MDR-AB were included and analyzed in the study.

Results: During the study period 281 episodes of BSI due to MDR-AB were observed: 98 (34.8%) episodes were classified as primary bacteremias, and 183 (65.2%) as secondary bacteremias; 177 (62.9%) of them were associated with septic shock. Overall, 14-day mortality was observed in 172 (61.2%) patients, while 30-day mortality in 207 (73.6%) patients. On multivariate analysis, previous surgery, continuous renal replacement therapy, inadequate source control of infection, and pneumonia were independently associated with higher risk of septic shock. Instead, septic shock and Charlson Comorbidity Index >3 were associated with 14-day mortality, while adequate source control of infection and combination therapy with survival. Finally, septic shock, previous surgery, and aminoglycoside-containing regimen were associated with 30-day mortality, while colistin-containing regimen with survival.

Conclusions: BSI caused by MDR-AB represents a difficult challenge for physicians, considering the high rates of septic shock and mortality associated with this infection.
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http://dx.doi.org/10.1016/j.jinf.2019.05.017DOI Listing
August 2019

Use of Aspergillus fumigatus real-time PCR in bronchoalveolar lavage samples (BAL) for diagnosis of invasive aspergillosis, including azole-resistant cases, in high risk haematology patients: the need for a combined use with galactomannan.

Med Mycol 2019 Nov;57(8):987-996

Division of Infectious Diseases, Department of Health Sciences (DISSAL), University of Genoa, Genoa, Italy.

Diagnosis of invasive aspergillosis (IA) is challenging, particularly in high-risk patients with lung lesions other than typical according to 2008-EORTC/MSG criteria. Even if microbiology is positive, they still remain unclassified according to 2008-EORTC/MSG. Quantitative polymerase chain reaction (qPCR) provides new mycological documentation of IA. This retrospective study assessed Aspergillus fumigatus real time qPCR (MycoGENIE®) in BAL to diagnose IA and identify azole-resistant strains. Clinical, radiological, and microbiological data from 114 hematology patients (69% HSCT recipients; 29% on mould active agents) from years 2012-2017 were collected; and 123 BAL samples were tested with qPCR (cutoff: Ct < 40) and galactomannan (GM, Platelia®, cutoff: 0.5 ODI). Patients were classified as proven/probable, possible, and no-IA. "Atypical-IA" referred to patients with lesions other than typical according to 2008-EORTC/MSG and positive mycology. Proven IA was diagnosed in two cases (1.6%), probable in 28 (22.8%), possible in 27 (22%), atypical in 14 (11.4%). qPCR was positive in 39 samples (31.7%). Sensitivity and specificity of qPCR for proven/probable IA (vs no-IA; atypical-IA excluded) were 40% (95% confidence interval [CI]: 23-59) and 69% (95%CI: 55-81), respectively. Sensitivity of qPCR was higher when combined with GM (83%, 95%CI: 65-94) and in those receiving mould-active agents at BAL (61%, 95%CI: 32-86). One sample had TR34/L98H mutation. In conclusion, in high-risk hematology patients with various lung lesions, A. fumigatus qPCR in BAL contributes to diagnosing IA, particularly if combined with GM and in patients receiving mould-active agents might allow detecting azole-resistant mutations in culture negative samples.
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http://dx.doi.org/10.1093/mmy/myz002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7107636PMC
November 2019

Desirability of outcome ranking (DOOR) for comparing diagnostic tools and early therapeutic choices in patients with suspected candidemia.

Eur J Clin Microbiol Infect Dis 2019 Feb 30;38(2):413-417. Epub 2018 Nov 30.

Infectious Diseases Unit, Ospedale Policlinico San Martino - IRCCS per l'Oncologia, University of Genoa, Largo R. Benzi, 10, 16132, Genoa, Italy.

Desirability of outcome ranking (DOOR) has been developed for assessing desirability of outcome in interventional studies. However, its possible use in observational studies of the diagnosis and early treatment of infectious diseases has not been explored so far, and it might introduce interesting features in specific scenarios. This was a post hoc analysis of a prospective observational study in intensive care unit patients with sepsis and at risk of candidemia. The probabilities that a randomly selected patient would have a more, less, and equally cost-effective early therapeutic choice following a BDG-based diagnostic strategy rather than the empirical administration of antifungals to all patients were calculated using DOOR methods. The probability of a more cost-effective therapeutic choice following the BDG-based rather than the empirical strategy was 67.81% (95% CI 67.32-68.30), whereas the probabilities of a less and equally cost-effective early therapeutic choice were 19.68% (95% CI 19.27-20.10) and 12.50% (95% CI 12.16-12.85), respectively. The application of DOOR methods to observational studies focused on diagnosis and early treatment is a novel field that could merit further investigation.
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http://dx.doi.org/10.1007/s10096-018-3441-1DOI Listing
February 2019

Hypoalbuminemia as a predictor of acute kidney injury during colistin treatment.

Sci Rep 2018 08 10;8(1):11968. Epub 2018 Aug 10.

Infectious Diseases Department, Azienda Sanitaria Universitaria Integrata di Trieste, Trieste, Italy.

This study aimed to assess the predictors of acute kidney injury (AKI) during colistin therapy in a cohort of patients with bloodstream infections (BSI) due to colistin-susceptible Gram-negative bacteria, focusing on the role of serum albumin levels. The study consisted of two parts: (1) a multicentre retrospective clinical study to assess the predictors of AKI during colistin therapy, defined according to the Kidney Disease: Improving Global Outcomes (KDIGO) criteria; and (2) bioinformatic and biochemical characterization of the possible interaction between human serum albumin and colistin. Among the 170 patients included in the study, 71 (42%), 35 (21%), and 11 (6%) developed KDIGO stage 1 (K1-AKI), KDIGO stage 2 (K2-AKI), and KDIGO stage 3 (K3-AKI), respectively. In multivariable analyses, serum albumin <2.5 g/dL was independently associated with K1-AKI (subdistribution hazard ratio [sHR] 1.85, 95% confidence interval [CI] 1.17-2.93, p = 0.009) and K2-AKI (sHR 2.37, 95% CI 1.15-4.87, p = 0.019). Bioinformatic and biochemical analyses provided additional information nurturing the discussion on how hypoalbuminemia favors development of AKI during colistin therapy. In conclusion, severe hypoalbuminemia independently predicted AKI during colistin therapy in a large cohort of patients with BSI due to colistin-susceptible Gram-negative bacteria. Further study is needed to clarify the underlying causal pathways.
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http://dx.doi.org/10.1038/s41598-018-30361-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6086859PMC
August 2018

Performance of serum (1,3)-ß-d-glucan screening for the diagnosis of invasive aspergillosis in neutropenic patients with haematological malignancies.

Mycoses 2018 Sep 13;61(9):650-655. Epub 2018 Jun 13.

Infectious Diseases Unit, Department Health Sciences (DISSAL), Ospedale Policlinico San Martino - IRCCS per l'Oncologia, University of Genoa, Genoa, Italy.

We report our experience with the use of (1,3)-ß-d-glucan (BDG) screening for the diagnosis of invasive aspergillosis (IA) in neutropenic patients with haematological malignancies. The performance of BDG screening was assessed retrospectively in per patient and per sample analyses. Overall, 20 among 167 patients developed IA (12%). In the per patient analysis, BDG showed 60% sensitivity and 78% specificity when the criterion for positivity was the presence of at least one BDG value ≥80 pg/mL. For 2 consecutive positive results, sensitivity decreased to 40%, while specificity increased to 93% and was similar to that of a positive galactomannan (GM; 90%). The highest specificity (97%) was observed for combined positivity of at least one BDG and at least one GM. In the per sample analysis, the specificity of BDG was 100% in the best scenario, 96% in the median scenario and 89% in the worst scenario. BDG became positive before GM in 33% of IA patients with both markers positive (n = 12). Despite good specificity for 2 consecutive positive results, the BDG test offered unsatisfactory performance for the diagnosis of IA due to low sensitivity. The combination of BDG and GM showed the potential for increasing specificity.
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http://dx.doi.org/10.1111/myc.12787DOI Listing
September 2018

Aortic cross-clamp time and cardiopulmonary bypass time: prognostic implications in patients operated on for infective endocarditis.

Interact Cardiovasc Thorac Surg 2018 09;27(3):328-335

Division of Cardiac Surgery, University of Genoa (DISC), Ospedale Policlinico San Martino, Genoa, Italy.

Objectives: Prolonged aortic cross-clamp (XCT) and cardiopulmonary bypass time (CPBT) are associated with increased morbidity and mortality following cardiac surgery. The aim of this study was to assess the predictors of mortality and other severe postoperative complications in patients undergoing surgery for infective endocarditis (IE), focusing in particular on the role of prolonged XCT and CPBT.

Methods: A retrospective single-centre study was conducted from January 2000 to January 2017, including all patients undergoing valvular surgery for IE. The primary end point was early postoperative mortality. The main secondary end point was a composite end point for severe postoperative complications.

Results: During the study period, 264 patients were included. Early postoperative mortality was 14%. Prolonged CPBT [odds ratio (OR) 1.008, 95% confidence intervals (CIs) 1.003-1.01; P = 0.009] and increasing age (OR 1.04, 95% CI 1.01-1.07; P = 0.02) independently predicted mortality, while an inverse association was observed for left ventricular ejection fraction (OR 0.93, 95% CI 0.89-0.97; P = 0.0007). The best mortality cut-offs were >72 min for XCT and >166 min for CPBT. Prolonged CPBT also predicted severe complications, along with age, stroke, preoperative mechanical ventilation and reduced left ventricular ejection fraction. When XCT was included in the multivariable models instead of CPBT, it was associated with both mortality and severe complications.

Conclusions: Prolonged XCT and CPBT are associated with mortality and development of severe complications after valvular surgery for IE. Further validation of safe limits for XCT and CPBT might provide novel insights on how to improve intraoperative and postoperative outcomes of patients with IE.
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http://dx.doi.org/10.1093/icvts/ivy085DOI Listing
September 2018

De-Escalation and Discontinuation of Empirical Antibiotic Treatment in a Cohort of Allogeneic Hematopoietic Stem Cell Transplantation Recipients during the Pre-Engraftment Period.

Biol Blood Marrow Transplant 2018 08 22;24(8):1721-1726. Epub 2018 Mar 22.

Division of Infectious Diseases, Department of Health Science (DISSAL), Ospedale Policlinico San Martino-IRCCS per l'Oncologia, University of Genoa, Genoa, Italy. Electronic address:

To investigate rates and outcomes of antibiotic de-escalation during pre-engraftment neutropenia in allogeneic hematopoietic stem cell transplantation (HSCT) recipients. 110 consecutive HSCTs performed between January 2013 and March 2014 were analyzed. De-escalation was defined as narrowing the spectrum of antibiotic treatment either within (early) or after 96 hours (late) from starting antibiotics. Discontinuation, considered a form of de-escalation, was defined as stopping antibiotics before engraftment. De-escalation failure was defined as restarting/escalating antibiotics within 96 hours after de-escalation. Predictors of de-escalation were analyzed. Among 102 patients who started antibiotics and were included, 68 (67%) received monotherapy (mainly piperacillin-tazobactam, n = 58), whereas 34 (33%) received combination therapy (mainly meropenem plus glycopeptide, n = 24). Median duration of neutropenia was 17 days. Bloodstream infections (BSIs) were diagnosed in 28 patients (20%). Early de-escalation rate was 25.5% (n = 26) and mostly consisted of reducing the spectrum of β-lactams (n = 11, 42%). In comparison with theoretical scenario of continuing therapy until engraftment, the median savings in terms of antibiotic days were 10 for meropenem, 8 for piperacillin-tazobactam, and 7 for vancomycin. Failure rate of early de-escalation was 15% (4/26). Late de-escalation rate was 30.4% (n = 31) and failure rate 19% (6/31). The rate of de-escalation any time before engraftment was 55.9% (n = 57), including discontinuation in 33 patients (32%). Death at day 60 after HSCT occurred in 3 patients who never underwent de-escalation. Acute myeloid disease and BSIs were independent predictors of early de-escalation. De-escalation, including discontinuation, is feasible and safe in pre-engraftment neutropenia after allogeneic HSCT.
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http://dx.doi.org/10.1016/j.bbmt.2018.03.018DOI Listing
August 2018

Ceftolozane/tazobactam: place in therapy.

Expert Rev Anti Infect Ther 2018 04 9;16(4):307-320. Epub 2018 Mar 9.

a Infectious Diseases Unit, Ospedale Policlinico San Martino - IRCCS per l'Oncologia and Department of Health Sciences , University of Genoa , Genoa , Italy.

Introduction: Ceftolozane/tazobactam (C/T) is a new antibiotic resulting from the combination of a novel cephalosporin, structurally similar to ceftazidime, with tazobactam, a well-known beta-lactamase inhibitor. C/T remains active against extended-spectrum β-lactamase (ESBL)-producing Enterobacteriaceae and multi-drug resistant (MDR) P. aeruginosa, and has been recently approved for the treatment of complicated intra-abdominal infections (cIAI) and complicated urinary tract infections (cUTI). A trial on hospital-acquired pneumonia is ongoing. Areas covered: The place in therapy of C/T is delineated by addressing the following main topics: (i) antimicrobial properties; (ii) pharmacological properties; (iii) results of clinical studies. Expert commentary: C/T is approved for cIAI and cUTI. However, the drug has a special value for clinicians in any kind of infectious localization for two main reasons. The first is that C/T is especially valuable in suspected or documented severe infections due to MDR P. aeruginosa, which is not a rare occurrence in many countries. The second is that C/T may provide an alternative to carbapenems for the treatment of infections caused by ESBL-producers, thus allowing a carbapenem-sparing strategy. Reporting of off-label use is mandatory to increase the body of evidence and the clinicians' confidence in using it for indications other than cIAI and cUTI.
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http://dx.doi.org/10.1080/14787210.2018.1447381DOI Listing
April 2018

The current role of glycopeptides in the treatment of methicillin-resistant Staphylococcus aureus (MRSA) infections in not neutropenic adults: the viewpoint of a group of Italian experts.

J Chemother 2018 May 30;30(3):157-171. Epub 2018 Jan 30.

c Università degli Studi di Bologna/Ospedale Sant'Orsola-Malpighi, Bologna, Italy - Dipartimento di Scienze Mediche e Chirurgiche, Settore Malattie Infettive.

Staphylococcus aureus is still an important problem in clinical and therapeutic area, worldwide. In Italy, in recent years, methicillin resistance remained stable, yet considerably high, the percentage of strains of MRSA being around 40%. It was deemed interesting and timely to carry out a consensus conference using the RAND/UCLA method to collect the opinion of a group of experts in infectious diseases on the role of glycopeptides in the management of MRSA infections within several clinical scenarios and namely in pneumonia, bacteremia and endocarditis, joint replacement infections, skin and soft tissue infections, diabetic foot, abdominal infections and central nervous system infections. The scenarios proposed by the Scientific Committee have been validated by a group of experts in infectious diseases and then voted in three meetings of infectious disease specialists. The results obtained on each individual condition were analyzed and therapeutic recommendations on each of these were released.
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http://dx.doi.org/10.1080/1120009X.2017.1420610DOI Listing
May 2018

Sepsis by in an Elderly Immunocompetent Patient after a Cat Bite.

Case Rep Infect Dis 2017 26;2017:2527980. Epub 2017 Nov 26.

First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa, 6 Viale Benedetto XV, 16132 Genoa, Italy.

colonizes animal scratches and bites. This bacterium was described to cause sepsis or endocarditis mainly in immunocompromised patients. We report the case of a 92-year-old woman presenting at the Emergency Department with coma and fever a week after the bite of her cat. The cat bite was misdiagnosed at admission partly due to an underestimation of this event by the patient's relatives. An inflamed area localized at perimalleolar skin of the right leg was detected. Laboratory biomarkers of inflammation were elevated. The cerebral computed tomography (CT) scan with angiographic sequences showed a complete occlusion of right intracranial vertebral artery. Total body CT scan and abdominal echocardiography were negative for foci of infection. Three consecutive blood cultures were positive for . A diagnosis of sepsis by was made, and the patient recovered after a specific antimicrobial treatment. In order to confirm the animal transmission, the cat saliva was cultured and found positive for with a similar antibiotic sensitivity to that isolated from the patient. In conclusion, the case of a patient with coma and fever after a cat bite was presented. The transmission of pathogens from pets has to be carefully considered as an important route of infection in immunocompetent patients.
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http://dx.doi.org/10.1155/2017/2527980DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5727562PMC
November 2017

Pharmacokinetics of high-dose extended-infusion meropenem during pulmonary exacerbation in adult cystic fibrosis patients: a case series.

New Microbiol 2018 Jan 9;41(1):47-51. Epub 2018 Jan 9.

Clinical Pharmacology and Toxicology Unit, University of Genoa (DIMI), Genoa, Italy.

This case series explored the pharmacokinetic/pharmacodynamic (PK/PD) characteristics of meropenem (MEM) in adult cystic fibrosis (CF) patients hospitalized for a pulmonary exacerbation. From January 2015 to June 2016, all adult patients with cystic fibrosis (CF) and chronic pulmonary infection due to meropenem (MEM)-susceptible/intermediate Pseudomonas aeruginosa who received at least 48 h of MEM as an extended 3-hour infusion for treating a pulmonary exacerbation were enrolled. MEM plasma concentrations were determined by high-performance liquid chromatography. Six adult CF patients with a median age of 47 years were included in the study. MEM showed a high Vd (mean 45.98 L, standard deviation [SD] ±34.45). A minimal PK/PD target of 40% T > minimum inhibitory concentration (MIC) with respect to the MEM MIC of P. aeruginosa strains isolated from sputum during exacerbation was achieved in 5/6 patients (83%). MEM failed to achieve this target only in one patient, whose strain showed the highest MEM MIC in our cohort (8 mg/L). In all patients, MEM was well tolerated, and no adverse events were reported. In conclusion, high-dose, extended-infusion MEM during pulmonary exacerbation showed a high Vd in six adult CF patients with high median age, and was well tolerated.
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January 2018

Recommendations for the management of pulmonary fungal infections in patients with rheumatoid arthritis.

Clin Exp Rheumatol 2017 Nov-Dec;35(6):1018-1028. Epub 2017 Nov 28.

Department of Medical and Biological Sciences, Rheumatology Clinic, Santa Maria della Misericordia University Hospital, Udine, Italy.

Often life-threatening pulmonary fungal infections (PFIs) can occur in patients with rheumatoid arthritis (RA) receiving disease-modifying anti-rheumatic drugs (DMARDs). Most of the data concerning PFIs in RA patients come from case reports and retrospective case series. Of the ve most widely described PFIs, Pneumocystis jirovecii pneumonia (PJP) has rarely been seen outside Japan, pulmonary cryptococcosis has been diagnosed in only a small number of patients worldwide, pulmonary coccidioidomycosis has almost only been observed in endemic areas, the limited number of cases of pulmonary histoplasmosis have mainly occurred in the USA, and the rare cases of invasive pulmonary aspergillosis have only been encountered in leukopenic patients. Many aspects of the prophylaxis, diagnosis and treatment of PFIs in RA patients remain to be defined, as does the role of each DMARD in increasing the risk of infection, and the possibility of resuming biological and non-biological DMARD treatment after the infection has been cured. The recommendations for the management of PFIs described in this paper are the product of a consensus procedure promoted by the Italian group for the Study and Management of Infections in Patients with Rheumatic Diseases (the ISMIR group).
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March 2018

Use of 1,3-β-D-glucan in invasive fungal diseases in hematology patients.

Expert Rev Anti Infect Ther 2017 12 20;15(12):1101-1112. Epub 2017 Nov 20.

a Infectious Diseases Unit, Ospedale Policlinico San Martino, IRCCS per l'Oncologia, University of Genoa, DISSAL , Genoa , Italy.

Introduction: Invasive fungal diseases (IFD) remain a leading cause of morbidity and mortality in hematology patients. Within a diagnostic-driven approach, the use of the serum (1,3)-ß-D-glucan (BDG) test represents a valid tool for the early diagnosis and treatment of IFD. Areas covered: The available literature on the use of BDG in hematology patients was systematically retrieved. Then, it was reviewed and discussed, to identify key issues pertaining to a clinically-oriented narrative presentation of the topic. Expert commentary: The use of BDG in hematology patients at risk for invasive aspergillosis (IA) is secondary to the use of galactomannan. However, since BDG is not specific for IA, it offers an advantage of diagnosing also other IFD, such as candidiasis and pneumocystosis. The limitations of BDG include high costs and lower sensitivity in hematology patients compared to other cohorts. The risk of false positive results is possibly lower in real life than in theory, since glucan-free equipment is available and modern dialysis membranes and blood products usually do not release BDG. Thus, in experienced hands and selected clinical situations, BDG is a useful diagnostic tool, particularly due to short turnover time to results and versatility in diagnosing different IFD.
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http://dx.doi.org/10.1080/14787210.2017.1401467DOI Listing
December 2017

Correction to: Impact of a mixed educational and semi-restrictive antimicrobial stewardship project in a large teaching hospital in Northern Italy.

Infection 2017 12;45(6):929

U.O. Clinica Malattie Infettive, University of Genoa (DISSAL) and Ospedale Policlinico San Martino-IRCCS per L'Oncologia, L.go R. Benzi, 10, 16132, Genoa, Italy.

A technical error led to incorrect rendering of the author group in this article. The correct authorship is as follows: Daniele Roberto Giacobbe, Valerio Del Bono, Malgorzata Mikulska, Giulia Gustinetti, Anna Marchese, Federica Mina, Alessio Signori, Andrea Orsi, Fulvio Rudello, Cristiano Alicino, Beatrice Bonalumi, Alessandra Morando, Giancarlo Icardi, Sabrina Beltramini, Claudio Viscoli; On behalf of the San Martino Antimicrobial Stewardship Group.
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http://dx.doi.org/10.1007/s15010-017-1068-2DOI Listing
December 2017

Pre-Engraftment Bloodstream Infections after Allogeneic Hematopoietic Cell Transplantation: Impact of T Cell-Replete Transplantation from a Haploidentical Donor.

Biol Blood Marrow Transplant 2018 01 30;24(1):109-118. Epub 2017 Aug 30.

Division of Hematology and Bone Marrow Transplantation, San Martino Hospital, Genoa, Italy.

Bloodstream infections (BSIs) are frequent and important infectious complications after hematopoietic cell transplantation (HCT). The aim of this study was to analyze the incidence, risk factors, and outcome of pre-engraftment BSIs after allogeneic HCT. We retrospectively analyzed data from 553 consecutive patients who underwent HCT between 2010 and 2016. Sixty percent of the patients received T cell-replete unmanipulated haploidentical bone marrow with high-dose post-transplantation cyclophosphamide. The BSI rate was 30%; among isolated 213 pathogens, 54% were Gram-positive, 43% were Gram-negative, and 3% were fungi. Independent risk factors for pre-engraftment BSI were transplantation from a haploidentical donor or from cord blood (P < .001), active disease (P = .002), age (P = .04), and myeloproliferative disorders or aplastic anemia (P < .001). Transplantation from a haploidentical donor was an independent risk factor for both Gram-positive and Gram-negative BSI. The 7-day mortality after any BSI was 5% (9 of 178), and in multivariate analysis, BSI etiology was the sole risk factor, with increased mortality in carbapenem-resistant Gram-negative BSI (P < .001). Nonrelapse mortality at day +60 after HCT was 3.8% (21 of 553); independent predictors were active disease (P = .045), year of HCT (P = .027), nonengraftment (P = .001), and pre-engraftment BSI (P < .001), with significantly higher risk in BSI due to Gram-negative pathogens compared with Gram-positive pathogens, and BSI due to carbapenem-resistant Gram-negative pathogens compared with susceptible pathogens. Pre-engraftment BSI is a frequent complication after HCT from a haploidentical donor or cord blood. Because the negative impact of pre-engraftment BSI on 60-day nonrelapse mortality was caused mainly by carbapenem-resistant Gram-negative pathogens, particular attention should be given to appropriate empiric therapy and management of patients at high risk for Gram-negative BSI.
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http://dx.doi.org/10.1016/j.bbmt.2017.08.024DOI Listing
January 2018

Impact of a mixed educational and semi-restrictive antimicrobial stewardship project in a large teaching hospital in Northern Italy.

Infection 2017 Dec 30;45(6):849-856. Epub 2017 Aug 30.

U.O. Clinica Malattie Infettive, University of Genoa (DISSAL) and Ospedale Policlinico San Martino-IRCCS per L'Oncologia, L.go R. Benzi, 10, 16132, Genoa, Italy.

Background: The overuse of antimicrobials favors the dissemination of antimicrobial resistance, as well as invasive fungal diseases and Clostridium difficile infections (CDI). In this study, we assessed the impact of a mixed educational and semi-restrictive antimicrobial stewardship (AMS) project in a large teaching hospital in Italy.

Methods: The AMS project was conducted from May 2014 to April 2016. It consisted of two initiatives in two consecutive periods: (1) educational activities; (2) semi-restrictive control of antimicrobial prescribing through a computerized software. The primary endpoint was consumption of antibacterials and antifungals. Secondary endpoints were incidence of CDI, methicillin-resistant Staphylococcus aureus (MRSA) bloodstream infections (BSI), carbapenem-resistant Klebsiella pneumoniae (CRKP) BSI, and Candida BSI.

Results: During the study period, a statistically significant reduction in consumption was observed for antibacterials (-1.45 defined daily doses (DDD)/1000 patient-days monthly, 95% confidence intervals [CI] -2.38 to -0.52, p 0.004), mainly driven by reductions in the use of fluoroquinolones, third/fourth generation cephalosporins, and carbapenems. No decrease in consumption of antifungals was observed (-0.04 DDD/1000 patient-days monthly, 95% CI -0.34 to +0.25, p 0.750). A statistically significant trend towards reduction was observed for incidence of CRKP BSI (incidence rate ratio 0.96, 95% CI 0.92-0.99, p 0.013). No statistically significant variations in trends were observed for CDI, MRSA BSI, and Candida BSI.

Conclusions: The mixed AMS project was effective in reducing the use of major antibacterials and the incidence of CRKP BSI. Further research is needed to assess the extent of long-term benefits of semi-restrictive approaches.
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http://dx.doi.org/10.1007/s15010-017-1063-7DOI Listing
December 2017

Effect of combination therapy containing a high-dose carbapenem on mortality in patients with carbapenem-resistant Klebsiella pneumoniae bloodstream infection.

Int J Antimicrob Agents 2018 Feb 24;51(2):244-248. Epub 2017 Aug 24.

Institute of Infectious Diseases, Università Cattolica del Sacro Cuore, Fondazione Policlinico Universitario Agostino Gemelli, Rome, Italy.

Objectives: To evaluate the impact of high-dose (HD) carbapenem-based combination therapy on clinical outcome in patients with monomicrobial carbapenem-resistant Klebsiella pneumoniae (CR-KP) bloodstream-infection (BSI).

Methods: Post hoc analysis of all adult patients with CR-KP BSI who were treated with a combination antibiotic regimen, collected over a six-year period in six large Italian teaching hospitals. To control for confounding effects of HD carbapenem combination on 14-day mortality, a multivariate Cox regression analysis was performed. Due to imbalances between patients, a propensity score for receiving HD carbapenem was added to the model.

Results: 595 patients with CR-KP BSI were analysed, 77% of isolates showed a carbapenem MIC ≥16 mg/L, 428 (71.9%) received HD carbapenem-based combination therapy. Overall, 127 patients (21.3%) died within 14 days after BSI onset. Multivariate analysis showed the Charlson comorbidity index (HR 1.31, 95%CI 1.20-1.43, P <0.001), septic shock at BSI onset (HR 3.14, 95%CI 2.19-4.50, P <0.001), and colistin-resistant strain (HR 1.52, 95%CI 1.02-2.24, P = 0.03) were independently associated with 14-day mortality, whereas admission to surgical ward (HR 0.44, 95%CI 0.25-0.78, P = 0.005) and HD carbapenem use (HR 0.69, 95%CI 0.47-1.00, P = 0.05) were protective factors. When adjusted for the propensity score, HD carbapenem use showed a greater protective effect (HR 0.64, 95%CI 0.43-0.95, P = 0.03). Stratifying the model for carbapenem MIC, the benefit of HD carbapenem was also observed for strains with carbapenem MIC ≥16 mg/L.

Conclusions: In patients receiving combination therapy for CR-KP BSI, the use of HD carbapenem seems to be associated with better outcome, even in the presence of high-level carbapenem resistance.
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http://dx.doi.org/10.1016/j.ijantimicag.2017.08.019DOI Listing
February 2018

Combined use of serum (1,3)-β-D-glucan and procalcitonin for the early differential diagnosis between candidaemia and bacteraemia in intensive care units.

Crit Care 2017 Jul 10;21(1):176. Epub 2017 Jul 10.

Infectious Diseases Division, University of Genoa (DISSAL) and Ospedale Policlinico San Martino - IRCCS per l'Oncologia, L.go R. Benzi, 10 - 16132, Genoa, Italy.

Background: This study aimed to assess the combined performance of serum (1,3)-β-D-glucan (BDG) and procalcitonin (PCT) for the differential diagnosis between candidaemia and bacteraemia in three intensive care units (ICUs) in two large teaching hospitals in Italy.

Methods: From June 2014 to December 2015, all adult patients admitted to the ICU who had a culture-proven candidaemia or bacteraemia, as well as BDG and PCT measured closely to the time of the index culture, were included in the study. The diagnostic performance of BDG and PCT, used either separately or in combination, was assessed by calculating the sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and positive and negative likelihood ratios (LR+ and LR-). Changes from pre-test probabilities to post-test probabilities of candidaemia and bacteraemia were inferred from Fagan's nomograms.

Results: One hundred and sixty-six patients were included, 73 with candidaemia (44%) and 93 with bacteraemia (56%). When both markers indicated candidaemia (BDG ≥80 pg/ml and PCT <2 ng/ml) they showed higher PPV (96%) compared to 79% and 66% for BDG or PCT alone, respectively. When both markers indicated bacteraemia (BDG <80 pg/ml and PCT ≥2 ng/ml), their NPV for candidaemia was similar to that of BDG used alone (95% vs. 93%). Discordant BDG and PCT results (i.e. one indicating candidaemia and the other bacteraemia) only slightly altered the pre-test probabilities of the two diseases.

Conclusions: The combined use of PCT and BDG could be helpful in the diagnostic workflow for critically ill patients with suspected candidaemia.
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http://dx.doi.org/10.1186/s13054-017-1763-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5504626PMC
July 2017

Good tolerability of high dose colistin-based therapy in patients with haematological malignancies.

Infection 2017 Aug 28;45(4):505-511. Epub 2017 Mar 28.

Division of Infectious Diseases, Department of Health Sciences (DISSAL), IRCCS AOU San Martino-IST, University of Genoa, Genoa, Italy.

Purpose: Colistin is usually the only drug fully active against multi-drug resistant Gram-negative bacteria, but its nephrotoxicity might limit its use. Recent pharmacokinetic/pharmacodynamic data suggest that high dose of colistin, preceded by a loading dose, are needed to maximize its antibacterial effect. The aim of this study was to determine the safety of high doses colistin, in haematology population.

Methods: A retrospective review of haematology patients who received high dose colistin-based therapy in years 2011-2016 was performed. Nephrotoxicity was assessed using RIFLE criteria.

Results: Thirty patients who received 38 courses of colistin were included in the study. Colistin was always administered together with other antibiotics. Colistin was well tolerated, with one case of neurological toxicity and one of cutaneous reaction. There were 22 (58%) treatment cycles without any nephrotoxicity, even though during 16 of these cycles other nephrotoxic drugs were administered. Severe (injury or failure) renal toxicity occurred during 6 (16%) treatment courses, requiring colistin discontinuation in 2 patients and colistin dose reduction in 1. Poorer renal function at baseline and younger age were the only variables associated with increased renal toxicity (p = 0.011 and p = 0.031, respectively). Overall mortality was 18% (7/38) and 29% (11/38) at 7 and 30 days after the treatment onset.

Conclusions: In adult haematology population, high dose colistin therapy is safe and efficacious, despite high frequency of concomitant nephrotoxic treatment.
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http://dx.doi.org/10.1007/s15010-017-1010-7DOI Listing
August 2017

MEDical wards Invasive Candidiasis ALgorithms (MEDICAL):Consensus proposal for management.

Eur J Intern Med 2016 Oct 3;34:45-53. Epub 2016 Aug 3.

Internal Medicine Department, Hospital of Legnano, Legnano, Italy.

Introduction: A majority of invasive Candida infections occur in medical wards; however, evidence for management in this setting is scarce and based primarily on the intensive care or surgical setting. On behalf of the Italian Society for Anti-Infective Therapy (SITA) and the Italian Federation of Associations of Hospital Doctors on Internal Medicine (FADOI), the MEDICAL group produced practical management algorithms for patients in internal medicine wards.

Methods: The MEDICAL group panel, composed of 30 members from internal medicine, infectious disease, clinical pharmacology, clinical microbiology and clinical epidemiology, provided expert opinion through the RAND/UCLA method.

Results: Seven clinical scenarios were constructed based on clinical severity and probability of invasive candidiasis. For each scenario, the appropriateness of 63 different diagnostic, imaging, management, or therapeutic procedures was determined in two Delphi rounds. The necessity for performing each appropriate procedure, was then determined in a third Delphi round. Results were summarized in algorithms.

Discussion: The proposed algorithms provide internal medicine physicians and managers with an easy to interpret tool that is exhaustive, clear and suitable for adaption to individual local settings. Attention was paid to individual patient management and resource allocation.
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http://dx.doi.org/10.1016/j.ejim.2016.07.007DOI Listing
October 2016

Meropenem for treating KPC-producing Klebsiella pneumoniae bloodstream infections: Should we get to the PK/PD root of the paradox?

Virulence 2017 01 18;8(1):66-73. Epub 2016 Jul 18.

d Unità di Farmacologia Clinica e Tossicologia, DIMI, Università di Genova , Genova , Italy.

The objective of this study was to assess the achievement of pharmacokinetic/pharmacodynamic (PK/PD) targets of meropenem (MEM) in critically-ill patients with bloodstream infections (BSI) due to Klebsiella pneumoniae-carbapenemase-producing Klebsiella pneumoniae (KPC-Kp) with MEM minimum inhibitory concentrations (MICs) ≥16 mg/L. Nineteen critically-ill patients with KPC-Kp BSI were given combination therapy including MEM, tigecycline, plus colistin or gentamicin (according to susceptibility testing). MEM was administered as an extended 3-hour infusion of 2 g every 8 hours, or adjusted according to renal function. MEM plasma concentrations were determined by high-performance liquid chromatography. PK/PD targets for MEM were defined as T > 40% 1×MIC and T > 40% 4×MIC. Possible synergisms between MEM and coadministered agents were assessed by time-kill assays based on plasma levels for MEM and on fixed plasma concentrations for the other agents. In none of 19 patients MEM reached any PK/PD target. The actual MEM MICs were 256, 512, and 1024 mg/L in 1, 3, and 15 isolates, respectively. However, theoretically, the PK/PD target of T > 40% 1×MIC could have been achieved in 95%, 68%, 32% and 0% of the isolates for MIC equal to 8, 16, 32, and 64 mg/L, respectively. No synergisms were observed between MEM and coadministered agents. In conclusion, high-dose MEM failed to reach PK/PD targets in 19 patients with BSI due to KPC-Kp with very high MEM MICs. On a theoretical basis, our results suggest a possible usefulness of MEM against resistant blood isolates with MICs up to 32 mg/L.
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http://dx.doi.org/10.1080/21505594.2016.1213476DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5963200PMC
January 2017

Risk factors for infections due to carbapenem-resistant Klebsiella pneumoniae after open heart surgery.

Interact Cardiovasc Thorac Surg 2016 11 1;23(5):762-768. Epub 2016 Jul 1.

Division of Cardiac Surgery, IRCCS San Martino-IST, Genoa, Italy.

Objectives: Patients undergoing major surgery are at increased risk of developing infections due to resistant organisms, including carbapenem-resistant Klebsiella pneumoniae (CR-Kp). In this study, we assessed risk factors for CR-Kp infections after open heart surgery in a teaching hospital in northern Italy.

Methods: A retrospective study was conducted from January to December 2014. The primary outcome measure was postoperative CR-Kp infection, defined as a time-to-event end-point. The effect of potentially related variables was assessed by univariable and multivariable analyses. Secondary end-points were in-hospital mortality and 180-day postoperative mortality.

Results: Among 553 patients undergoing open heart surgery, 32 developed CR-Kp infections (6%). In the final multivariable model, CR-Kp colonization [hazard ratio (HR) 227.45, 95% confidence intervals (CI) 67.13-1225.20, P < 0.001], cardiopulmonary bypass time in minutes (HR 1.01, 95% CI 1.01-1.02, P < 0.001), chronic obstructive pulmonary disease (HR 3.99, 95% CI 1.61-9.45, P = 0.004), SOFA score (HR 1.29, 95% CI 1.08-1.53, P = 0.007), preoperative mechanical ventilation (HR 8.10, 95% CI 1.31-48.57, P = 0.026), prolonged mechanical ventilation (HR 2.48, 95% CI 1.08-6.15, P = 0.032) and female sex (HR 2.08, 95% CI 1.00-4.36, P = 0.049) were associated with the development of CR-Kp infection. Increased in-hospital mortality and 180-day mortality were observed in patients who developed CR-Kp infections in comparison with those who did not.

Conclusions: In our cohort, CR-Kp colonization was an important predictor of CR-Kp infection after open heart surgery. CR-Kp infection after surgery significantly affected survival. Preventing colonization is conceivably the most effective current strategy to reduce the impact of CR-Kp.
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http://dx.doi.org/10.1093/icvts/ivw228DOI Listing
November 2016

Population pharmacokinetics and probability of target attainment of meropenem in critically ill patients.

Eur J Clin Pharmacol 2016 Jul 6;72(7):839-48. Epub 2016 Apr 6.

Department of Clinical and Experimental Medicine, University of Pisa, Via Savi, n.10, 56126, Pisa, Italy.

Purpose: Patients admitted to intensive care unit (ICU) with Klebsiella pneumoniae infections are characterized by high mortality. The aims of the present study were to investigate the population pharmacokinetics parameters and to assess the probability of target attainment of meropenem in critically ill patients to provide information for more effective regimens.

Methods: Twenty-seven consecutive patients were included in the study. Meropenem was administered as 3-h intravenous (i.v.) infusions at doses of 1-2 g every 8 or 12 h. Meropenem plasma concentrations were measured by a high-performance liquid chromatography (HPLC) method, and a population pharmacokinetics analysis was performed using NONMEM software. Meropenem plasma disposition was simulated for extended (3 h; 5 h) or continuous i.v. infusions, and the following parameters were calculated: time during which free drug concentrations were above minimum inhibitory concentration (MIC) (fT > MIC), free minimum plasma concentrations above 4× MIC (fCmin > 4× MIC), probability of target attainment (PTA), and cumulative fraction of response (CFR).

Results: Gender and severity of sepsis affected meropenem clearance, whose typical population values ranged from 6.22 up to 12.04 L/h (mean ± standard deviation (SD) value, 9.38 ± 4.47 L/h). Mean C min value was 7.90 ± 7.91 mg/L, suggesting a high interindividual variability. The simulation confirmed that 88 and 97.5 % of patients achieved effective C min > 4× MIC values after 3- and 5-h i.v. infusions of meropenem 2 g × 3/day, respectively. On the contrary, the same total daily doses reached the target C min > 4× MIC values in 100 % of patients when administered as continuous i.v. infusions.

Conclusions: Several factors may influence meropenem pharmacokinetics in ICU patients. Continuous i.v. infusions of meropenem seem to be more effective than standard regimens to achieve optimal therapeutic targets.
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http://dx.doi.org/10.1007/s00228-016-2053-xDOI Listing
July 2016