Valerio Del Bono

Infections caused by KPC-producing Klebsiella pneumoniae: differences in therapy and mortality in a multicentre study

OBJECTIVES Infections caused by Klebsiella pneumoniae (Kp) carbapenemase (KPC)-producing strains of Kp have become a significant threat in recent years. To assess their outcomes and identify risk factors for 14 day mortality, we conducted a 4 year (2010-13) retrospective cohort study in five large Italian teaching hospitals. METHODS The cohort included 661 adults with bloodstream infections (BSIs; n = 447) or non-bacteraemic infections (lower respiratory tract, intra-abdominal structure, urinary tract or other sites) caused by a KPC-Kp isolate. All had received ≥48 h of therapy (empirical and/or non-empirical) with at least one drug to which the isolate was susceptible. RESULTS Most deaths occurred within 2 weeks of infection onset (14 day mortality: 225/661, 34.1%). Logistic regression analysis identified BSI (OR, 2.09; 95% CI, 1.34-3.29), presentation with septic shock (OR, 2.45; 95% CI, 1.47-4.08), inadequate empirical antimicrobial therapy (OR, 1.48; 95% CI, 1.01-2.18), chronic renal failure (OR, 2.27; 95% CI, 1.44-3.58), high APACHE III score (OR, 1.05; 95% CI, 1.04-1.07) and colistin-resistant isolates (OR, 2.18; 95% CI, 1.37-3.46) as independent predictors of 14 day mortality. Combination therapy with at least two drugs displaying in vitro activity against the isolate was associated with lower mortality (OR, 0.52; 95% CI, 0.35-0.77), in particular in patients with BSIs, lung infections or high APACHE III scores and/or septic shock at infection onset. Combinations that included meropenem were associated with significantly higher survival rates when the KPC-Kp isolate had a meropenem MIC of ≤8 mg/L. CONCLUSIONS KPC-Kp infections are associated with high mortality. Treatment with two or more drugs displaying activity against the isolate improves survival, mainly in patients who are critically ill.

Blood Stream Infections in Allogeneic Hematopoietic Stem Cell Transplant Recipients: Reemergence of Gram-Negative Rods and Increasing Antibiotic Resistance

Blood stream infections (BSI) are a well-known cause of morbidity and mortality in hematopoietic stem cell transplant (HSCT) patients. The aim of this study was to analyze etiology and microbial resistance of BSI in patients undergoing allogeneic HSCT in a single center over a 4-year period (2004-2007). There were 168 episodes of BSI in 132 patients (median 10 days after HSCT) and 182 pathogens were isolated. Gram-positive bacteria (GPB) accounted for 57% of 182 isolates. Gram-negative rods (GNR) for 37% and fungi for 6%. All patients received routine fluoroquinolone prophylaxis. There was a significant decrease in GPB/GNR ratio over time, from 2.4 in 2004 to 1 in 2007 (P = .043). Among GPB, staphylococci decreased from 37 of 68 (64%) in 2004-2005 to 8 of 35 (23%) in 2006-2007 (P < .002). The Enterococcus faecalis/E. faecium ratio decreased from 4.5 in 2004 to 0.33 in 2007 (P = .006), whereas the total number of enterococcal strains per year did not change. The incidence of Escherichia coli among GNR increased from 3 of 15 (20%) in 2004 to 13 of 21 (62%) in 2007 (P = .003). Fluoroquinolone-resistance was common, both among GPB and GNR (81% and 74%, respectively). Mortality rate at 7 days after BSI was 11% (19 of 168), reaching 39% for Pseudomonas aeruginosa BSI (7 of 18). BSI remains a frequent and potentially life-threatening complication of allogeneic HSCT, the causative organism influencing 7- and 30-day mortality rate. BSI etiology may change rapidly, requiring implementation of new empirical-therapy schemes.

Occurrence, presentation and treatment of candidemia

Candida is one of the most common causes of nosocomial bloodstream infections. Candidemia is not confined to hematological patients, intensive care units or abdominal surgery wards, but it is remarkably frequent in the internal medicine setting. High mortality associated with candidemia can be reduced by prompt, appropriate antifungal therapy. The epidemiology of species has been shifting toward non-albicans strains. Significant improvements in nonculture-based diagnostic methods, such as serological markers, have been made in recent years, and novel diagnostic techniques should be further studied to enable early pre-emptive therapy. Treatment guidelines indicate that echinocandins are at present the best choice for patients who are severely ill or possibly infected with fluconazole-resistant strains.

Tigecycline use in serious nosocomial infections: a drug use evaluation

BackgroundTigecycline is a novel antibiotic with activity against multidrug resistant bacteria. The aim of this study was to assess the efficacy of tigecycline use in serious hospital-acquired infections (HAI)Case presentationProspective observational study of tigecycline use was conducted in a 1500 beds university hospital. From January 1, 2007 and January 31, 2010, 207 pts were treated with tigecycline for the following indications: intra-abdominal, pneumonia, bloodstream and complicated skin and soft tissue infections and febrile neutropenia. The therapy was targeted in 130/207 (63%) and empirical in 77/207 (37%) patients. All bacteria treated were susceptible to tigecycline. Median duration of tigecycline therapy was 13 days (range, 6-28). Clinical success was obtained in 151/207 (73%) cases, with the highest success rate recorded in intra-abdominal infections [81/99 (82%)]. Microbiological success was achieved in 100/129 (78%) treated patients. Adverse clinical events were seen in 16/207 patients (7.7%):ConclusionsConsidering the lack of data on tigecycline for critically ill patients, we think that the reported data of our clinical experience despite some limitations can be useful for clinicians.

Clinical Performance of the (1,3)-β-d-Glucan Assay in Early Diagnosis of Nosocomial Candida Bloodstream Infections

ABSTRACT Microbiological diagnosis of nosocomial candidemia is negatively affected by suboptimal culture yield. Alternative methods are not fully reliable as an aid in candidemia diagnosis. Recently, the detection of (1,3)-β-d-glucan (BG) has been shown to be very promising in this setting. We carried out a prospective study on the clinical usefulness of BG detection in early diagnosis of candidemia. BG detection was performed in patients with fever unresponsive to antibacterial agents and risk factors for candidemia. BG detection was done with the Fungitell test. A total of 152 patients were included in the study; 53 were proven to have candidemia, while in 52 patients candidemia was excluded on microbiological and clinical bases. The remaining 47 patients were considered to have possible candidemia. In summary, 41 of 53 candidemia patients (77.3%), 9 of 52 patients without candidemia (17.3%), and 38 of 47 patients with possible candidemia (80.8%) were positive in the BG assay. With these results, the sensitivity and the specificity of the assay were 77% and 83%, respectively. BG levels of >160 pg/ml were highly predictive of candidemia. In 36 of 41 patients with candidemia and positive BG testing, the BG assay was performed within 48 h from when the first Candida-positive blood sample for culture was drawn, thus allowing a possible earlier start of antifungal therapy. Based on these results, the BG assay may be used as an aid in the diagnosis of nosocomial candidemia. The timing of assay performance is critical for collecting clinically useful information. However, the test results should be associated with clinical data.

Predictive Models for Identification of Hospitalized Patients Harboring KPC-Producing Klebsiella pneumoniae

ABSTRACT The production of Klebsiella pneumoniae carbapenemases (KPCs) by Enterobacteriaceae has become a significant problem in recent years. To identify factors that could predict isolation of KPC-producing K. pneumoniae (KPCKP) in clinical samples from hospitalized patients, we conducted a retrospective, matched (1:2) case-control study in five large Italian hospitals. The case cohort consisted of adult inpatients whose hospital stay included at least one documented isolation of a KPCKP strain from a clinical specimen. For each case enrolled, we randomly selected two matched controls with no KPCKP-positive cultures of any type during their hospitalization. Matching involved hospital, ward, and month/year of admission, as well as time at risk for KPCKP isolation. A subgroup analysis was also carried out to identify risk factors specifically associated with true KPCKP infection. During the study period, KPCKP was isolated from clinical samples of 657 patients; 426 of these cases appeared to be true infections. Independent predictors of KPCKP isolation were recent admission to an intensive care unit (ICU), indwelling urinary catheter, central venous catheter (CVC), and/or surgical drain, ≥2 recent hospitalizations, hematological cancer, and recent fluoroquinolone and/or carbapenem therapy. A Charlson index of ≥3, indwelling CVC, recent surgery, neutropenia, ≥2 recent hospitalizations, and recent fluoroquinolone and/or carbapenem therapy were independent risk factors for KPCKP infection. Models developed to predict KPCKP isolation and KPCKP infection displayed good predictive power, with the areas under the receiver-operating characteristic curves of 0.82 (95% confidence interval [CI], 0.80 to 0.84) and 0.82 (95% CI, 0.80 to 0.85), respectively. This study provides novel information which might be useful for the clinical management of patients harboring KPCKP and for controlling the spread of this organism.

Invasive aspergillosis : diagnosis, prophylaxis and treatment

Purpose of reviewInvasive aspergillosis is a common cause of morbidity and mortality in hematopoietic stem cells transplant recipients. Owing to its intrinsic high mortality rate, early diagnosis and treatment are critical. This review will therefore address the most important recent advances in diagnosing, preventing and treating invasive aspergillosis in hematopoietic stem cells transplant. Recent findingsThe present review will focus on therapeutic and prophylactic aspects, with particular regard to clinical use of drugs other than voriconazole (which has a well known and consolidated role for first-line therapy), combination therapy and prophylactic regimens, particularly with posaconazole. This review will also briefly deal with the clinical role of diagnostic tests such as the detection of galactomannan in body fluids other than blood, beta-D-glucan in serum and fungal DNA by PCR in body fluids. SummaryGalactomannan antigen detection is a rather reliable diagnostic test for invasive aspergillosis, particularly when a lower threshold of sensitivity is used. PCR is still to be validated. Liposomal amphotericin B at 3 mg/kg per day showed a similar efficacy in invasive aspergillosis as reported for voriconazole. Therapeutic drug monitoring of Aspergillus-active azoles should be implemented whenever possible in order to maximize the antifungal effect and minimize toxicity. Posaconazole showed to be active in prophylaxis, though its effectiveness in the global patient population is still controversial.

(1-3)-β-D-Glucan in Cerebrospinal Fluid Is Useful for the Diagnosis of Central Nervous System Fungal Infections

TO THE EDITOR—A definitive diagnosis of invasive fungal infection (IFI) remains difficult in immunocompromised hosts. Thus, fungal markers such as galacto-mannan (GM) or (1-3)-β-D-glucan (BG) are useful for the diagnosis of probable IFI in high risk patients [1]. Detection of GM in cerebrospinal fluid (CSF) has been studied and is now considered diagnostic for central nervous system (CNS) aspergillosis in high-risk patients with a compatible neurological disease [1, 2]. Serum BG, major constituent of fungi other than the Mucorales, is being used for noninvasive diagnosis of fungal infection , and has been included as micro-biological criterion for the diagnosis of probable IFI in the revised definitions of IFI of the European Organization for the Research and Treatment of Cancer/ Mycoses Study Group (EORTC/MSG) [1]. BG has been widely studied in serum, but only 1 animal study has analyzed its levels in CSF in a

Recognition of Antigenic Clusters of Candida albicans by T Lymphocytes from Human Immunodeficiency Virus-Infected Persons

The fine specificity of the cellular immune response to Candida albicans (i.e., recognition of different antigenic components) between normal controls and human immunodeficiency virus-infected patients in various stages of disease was compared. C. albicans-specific T cells, enriched by antigen stimulation and interleukin-2 expansion, were challenged with antigenic fractions of different molecular weight obtained by SDS-gel fractionation of C. albicans extracts in the presence of autologous mononuclear cells as antigen-presenting cells. Proliferative responses showed similar patterns of reactivity between controls and category A and B seropositive subjects. Category C patients with concurrent C. albicans infections did not give rise to C. albicans-specific T cell lines, confirming the T cell defect. Patients without clinically evident C. albicans infection had a low but broad reactivity pattern of C. albicans-specific T cells. These results suggest that depletion of C. albicans-specific T cells, independent of their fine specificity, occurs along with disease progression.

Galactomannan testing might be useful for early diagnosis of fusariosis.

Galactomannan (GM) is used to diagnose aspergillosis. We present a case of a hematopoietic stem cell transplantation recipient with fusariosis who received early antifungal treatment based on GM positivity. Additionally, 3 Fusarium isolates tested positive for GM. Fusarium is another mold containing GM. GM might be useful for diagnosing fusariosis in high-risk patients.