Giorgio Graziano

Bloodstream infections in intensive care unit patients: distribution and antibiotic resistance of bacteria

Bloodstream infections (BSIs) are among the leading infections in critically ill patients. The case-fatality rate associated with BSIs in patients admitted to intensive care units (ICUs) reaches 35%–50%. The emergence and diffusion of bacteria with resistance to antibiotics is a global health problem. Multidrug-resistant bacteria were detected in 50.7% of patients with BSIs in a recently published international observational study, with methicillin resistance detected in 48% of Staphylococcus aureus strains, carbapenem resistance detected in 69% of Acinetobacter spp., in 38% of Klebsiella pneumoniae, and in 37% of Pseudomonas spp. Prior hospitalization and antibiotic exposure have been identified as risk factors for infections caused by resistant bacteria in different studies. Patients with BSIs caused by resistant strains showed an increased risk of mortality, which may be explained by a higher incidence of inappropriate empirical therapy in different studies. The molecular genetic characterization of resistant bacteria allows the understanding of the most common mechanisms underlying their resistance and the adoption of surveillance measures. Knowledge of epidemiology, risk factors, mechanisms of resistance, and outcomes of BSIs caused by resistant bacteria may have a major influence on global management of ICU patients. The aim of this review is to provide the clinician an update on BSIs caused by resistant bacteria in ICU patients.

Use of Cepheid Xpert Carba-R® for Rapid Detection of Carbapenemase-Producing Bacteria in Abdominal Septic Patients Admitted to Intensive Care Unit

Early institution of effective antibiotic therapy and source control are pivotal to improve survival of abdominal septic patients. Xpert® Carba-R is a real time polymerase chain reaction assay for rapid detection and differentiation of five genes (blaKPC, blaVIM, blaOXA-48, blaIMP-1, blaNDM) responsible for carbapenem resistance. We performed an observational study investigating the clinical usefulness and applicability of Xpert® Carba-R to detect carbapenem resistance in abdominal septic patients admitted to intensive care unit. We compared the results of Xpert® Carba-R with standard microbiological culture. We collected a set of two rectal/stomia swabs and two swabs from abdominal drainage fluid for each patient. We included 20 patients for a total of 45 comparisons between the two methods. In our clinical setting, the overall performance of Xpert® Carba-R for detection of carbapenem resistance in the presence of genes detectable and non-detectable by the method was: sensitivity 50% (95% CI 24.6–75.3); specificity 93.1% (95% CI 77.2–99.1); positive predictive value (PPV) 80% (95% CI 44.4–97.5); negative predictive value (NPV) 77.1% (95% CI 56.9–89.6). The inter-rater agreement was 0.47 (SE 0.14; 95% CI 0.20–0.74). When considering the only 5 mechanisms of resistance detected by both methods, the overall diagnostic performance was: sensitivity 100% (95% CI 69.1–100), specificity 94.2 (95% CI 80.8–99.3), PPV 83.3 (95% CI 59.6–97.9) and NPV 100% (95% CI 89.4–100). The inter-rater agreement was 0.88 (SE 0.08; 95% CI 0.71–1). Xpert® Carba-R may be considered an additional diagnostic tool for early diagnosis of carbapenem resistance in abdominal septic patients. Clinicians should be aware of their epidemiology before its introduction in the diagnostic protocol of their intensive care units.

Is the monoclonal spread of the ST258, KPC-3-producing clone being replaced in southern Italy by the dissemination of multiple clones of carbapenem-nonsusceptible, KPC-3-producing Klebsiella pneumoniae?

D. M. Geraci, C. Bonura, M. Giuffre, L. Saporito, G. Graziano, A. Aleo, T. Fasciana, F. Di Bernardo, T. Stampone, D. M. Palma and C. Mammina 1) Department of Sciences for Health Promotion and Mother-Child Care ‘G. D’Alessandro’, University of Palermo, 2) Postgraduate Specialty School in Hygiene and Preventive Medicine, University of Palermo, 3) Laboratory of Microbiology, General Hospital ARNAS ‘Civico, Di Cristina & Benfratelli’, 4) Laboratory of Microbiology, General Hospital Azienda Ospedaliera ‘Villa Sofia-V, Cervello’ and 5) II Intensive Care Unit, General Hospital ARNAS ‘Civico, Di Cristina & Benfratelli’, Palermo, Italy

The Increasing Challenge of Multidrug-Resistant Gram-Negative Bacilli: Results of a 5-Year Active Surveillance Program in a Neonatal Intensive Care Unit

AbstractColonization and infection by multidrug-resistant gram-negative bacilli (MDR GNB) in neonatal intensive care units (NICUs) are increasingly reported.We conducted a 5-year prospective cohort surveillance study in a tertiary NICU of the hospital “Paolo Giaccone,” Palermo, Italy. Our objectives were to describe incidence and trends of MDR GNB colonization and the characteristics of the most prevalent organisms and to identify the risk factors for colonization. Demographic, clinical, and microbiological data were prospectively collected. Active surveillance cultures (ASCs) were obtained weekly. Clusters of colonization by extended spectrum &bgr;-lactamase (ESBL) producing Escherichia coli and Klebsiella pneumoniae were analyzed by conventional and molecular epidemiological tools.During the study period, 1152 infants were enrolled in the study. Prevalences of colonization by MDR GNB, ESBL-producing GNB and multiple species/genera averaged, respectively, 28.8%, 11.7%, and 3.7%. Prevalence and incidence density of colonization by MDR GNB and ESBL-producing GNB showed an upward trend through the surveillance period. Rates of ESBL-producing E coli and K pneumoniae colonization showed wide fluctuations peaking over the last 2 years. The only independent variables associated with colonization by MDR GNB and ESBL-producing organisms and multiple colonization were, respectively, the days of NICU stay (odds ratio [OR] 1.041), the days of exposure to ampicillin–sulbactam (OR 1.040), and the days of formula feeding (OR 1.031). Most clusters of E coli and K pneumoniae colonization were associated with different lineages. Ten out of 12 clusters had an outborn infant as their index case.Our study confirms that MDR GNB are an increasing challenge to NICUs. The universal once-a-week approach allowed us to understand the epidemiology of MDR GNB, to timely detect new clones and institute contact precautions, and to assess risk factors. Collection of these data can be an important tool to optimize antimicrobials use and control the emergence and dissemination of resistances in NICU.

Cost-effectiveness of bedaquiline in MDR and XDR tuberculosis in Italy

ABSTRACT Objective: To evaluate the cost-effectiveness of bedaquiline plus background drug regimens (BR) for multidrug-resistant tuberculosis (MDR-TB) and extensively drug-resistant tuberculosis (XDR-TB) in Italy. Methods: A Markov model was adapted to the Italian setting to estimate the incremental cost-effectiveness ratio (ICER) of bedaquiline plus BR (BBR) versus BR in the treatment of MDR-TB and XDR-TB over 10 years, from both the National Health Service (NHS) and societal perspective. Cost-effectiveness was evaluated in terms of life-years gained (LYG). Clinical data were sourced from trials; resource consumption for compared treatments was modelled according to advice from an expert clinicians panel. NHS tariffs for inpatient and outpatient resource consumption were retrieved from published Italian sources. Drug costs were provided by reference centres for disease treatment in Italy. A 3% annual discount was applied to both cost and effectiveness. Deterministic and probabilistic sensitivity analyses were conducted. Results: Over 10 years, BBR vs. BR alone is cost-effective, with ICERs of €16,639/LYG and €4081/LYG for the NHS and society, respectively. The sensitivity analyses confirmed the robustness of the results from both considered perspectives. Conclusion: In Italy, BBR vs. BR alone has proven to be cost-effective in the treatment of MDR-TB and XDR-TB under a range of scenarios.

A Snapshot on MRSA epidemiology in a neonatal intensive care unit network, Palermo, Italy

Objectives: We performed a 1-year prospective surveillance study on MRSA colonization within the five NICUs of the metropolitan area of Palermo, Italy. The purpose of the study was to assess epidemiology of MRSA in NICU from a network perspective. Methods: Transfer of patients between NICUs during 2014 was traced based on the annual hospital discharge records. In the period February 2014–January 2015, in the NICU B, at the University teaching hospital, nasal swabs from all infants were collected weekly, whereas in the other four NICUs (A, C, D, E) at 4 week-intervals of time. MRSA isolates were submitted to antibiotic susceptibility testing, SCCmec typing, PCR to detect lukS-PV and lukF-PV (lukS/F-PV) genes and the gene encoding the toxic shock syndrome toxin (TSST-1), multilocus variable number tandem repeat fingerprinting (MLVF), and multilocus sequence typing (MLST). Results: In the period under study, 587 nasal swabs were obtained from NICU B, whereas 218, 180, 157, and 95 from NICUs A, C, D, and E, respectively. Two groups of NICUs at high prevalence and low prevalence of MRSA colonization were recognized. Overall, 113 isolates of MRSA were identified from 102 infants. Six MLVF types (A–F) were detected, with type C being subdivided into five subtypes. Five sequence types (STs) were found with ST22-IVa being the most frequent type in all NICUs. All the MRSA molecular subtypes, except for ST1-IVa, were identified in NICU B. Conclusions: Our findings support the need to approach surveillance and infection control in NICU in a network perspective, prioritizing referral healthcare facilities.

Childhood and Adolescence Cancers in the Palermo Province (Southern Italy): Ten Years (2003–2012) of Epidemiological Surveillance

Italy has one of the highest paediatric cancer incidence rates in Europe. We compared cancer incidence and survival rates in children (0–14 years) and adolescents (15–19 years) residing in Palermo Province (PP) with statistics derived from Italian and European surveillance systems. We included all incident cancer cases, malignant tumours and non-malignant neoplasm of central nervous system (benign and uncertain whether malignant or benign), detected in children and adolescents by the Palermo Province Cancer Registry (PPCR) between 2003 and 2012. A jointpoint regression model was applied. Annual Average Percentage Changes were calculated. The Besag–York-Mollie model was used to detect any cluster. The 5-year survival analysis was computed using Kaplan-Meier and actuarial methods. We identified 555 paediatric cancer incident cases (90% “malignant tumours”). No difference in incidence rates was highlighted between PPCR and Italy 26 registries and between PPCR and Southern Europe. No jointpoint or significant trend was identified and no cluster was detected. The 5-year overall survival didn’t differ between PP and the Italian AIRTUM pool. A borderline higher statistically significant survival was observed in age-group 1–4 when comparing PPCR to EUROCARE-5. The epidemiological surveillance documented in the PP was a paediatric cancer burden in line with Italy and southern Europe. The study supports the supplementary role of general population-based cancer registries to provide paediatric cancer surveillance of local communities.

The burden of Candida species colonization in NICU patients: a colonization surveillance study

Fungal infections are an important cause of morbidity and mortality in neonatal intensive care units (NICUs). The identification of specific risk factors supports prevention of candidemia in neonates. Effective prophylactic strategies have recently become available, but the identification and adequate management of high-risk infants is still a priority. Prior colonization is a key risk factor for candidemia. For this reason, surveillance studies to monitor incidence, species distribution, and antifungal susceptibility profiles, are mandatory. Among 520 infants admitted to our NICU between January 2013 and December 2014, 472 (90.77%) were included in the study. Forty-eight out of 472 (10.17%) patients tested positive for Candida spp. (C.), at least on one occasion. All the colonized patients tested positive for the rectal swab, whereas 7 patients also tested positive for the nasal swab. Fifteen out of 472 patients (3.18%) had more than one positive rectal or nasal swab during their NICU stay. Moreover, 9 out of 15 patients tested negative at the first sampling, suggesting they acquired Candida spp. during their stay. Twenty-five of forty-eight (52.1%) colonized patients carried C.albicans and 15/48 (31.25%) C.parapsilosis. We identified as risk factors for Candida spp. colonization: antibiotic therapy, parenteral nutrition, the use of a central venous catheter, and nasogastric tube. Our experience suggests that effective microbiological surveillance can allow for implementing proper, effective and timely control measures in a highrisk setting.

Healthcare associated pathogens in a changing world

In developed countries about 10% of the hospitalizations are complicated by a healthcare-associated infection [1]. Up to 75% of these infections are due to multidrug-resistant organisms (MDROs) [1]. Antimicrobial resistant bacterial infections are associated to higher morbidity, mortality and healthcare costs than those caused by susceptible organisms [1]. The findings of the point prevalence survey in European acute care hospitals published in 2013 by the European Centre for Disease Control and Prevention (ECDC) show large variations between countries and between different regions of the same country, with Italy being allocated within the high-endemic areas for both MRSA and MDROs [2]. Despite antimicrobial resistance affects most bacterial species, MDR Gram negatives represent the most serious threat. In a few years Enterobacteriaceae, mainly Escherichia coli and Klebsiella pneumoniae, have evolved from extended spectrum β-lactamase (ESBL) producing to carbapanem-resistant organisms [3]. Simultaneously, Acinetobacter baumannii has quickly become extremely or pan-drug resistant [4]. Carbapenem resistant Gram negatives heavily impact on clinical outcomes with mortality rates significantly higher than the susceptible strains of the same species [1]. Of further concern, very few antimicrobial agents are available for an effective treatment of these infections and new agents active against these organisms are not currently in development. Many intertwining factors are driving these epidemiological changes, involving patients, healthcare delivery systems, infection control practices and, most important, misuse and inappropriate use of antibiotics in all healthcare facilities, in community and in animal husbandry. In particular, the transition of the healthcare delivery systems from a hospital-centered model to a healthcare facility network has gradually blurred the borders between hospital and community and the patients’ travel within this network has critically contributed to disseminate MDROs [5]. As a consequence, antimicrobial resistance is now as common, if not more so, in post-acute clinical facilities, such as long term care settings and nursing homes [5]. The “revolving door” is the very efficacious image used as the paradygm of the spreading routes of organisms with hospital and community reservoirs, as E. coli or MRSA. The revolving door, indeed, enlightens how the colonized patients entering back and forth several healthcare settings drive the amplification of the antibiotic resistance [6]. Stringent infection control and prevention practices and wise use of antibiotics are unanimously agreed as the key actions to fight MDROs. Of course, we need new antibiotics, but first we have to learn how to protect them from a precipitous erosion of their effectiveness.