Nicole Pagani

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.

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.

A(H1N1)pdm09 hemagglutinin D222G and D222N variants are frequently harbored by patients requiring extracorporeal membrane oxygenation and advanced respiratory assistance for severe A(H1N1)pdm09 infection

In patients with A(H1N1)pdm09 infection, severe lung involvement requiring admission to intensive care units (ICU) has been reported. Mutations at the hemagglutinin (HA) receptor binding site (RBS) have been associated with increased virulence and disease severity, representing a potential marker of critical illness.

Pharmacokinetics of high dosage of linezolid in two morbidly obese patients

Sir, Obesity represents a major burden on healthcare as an independent risk factor for mortality in infected patients and its association with comorbidities. Adequate antimicrobial exposure is essential for treatment success, but there are few published data on the pharmacokinetics (PK) of antibiotics in obesity. Furthermore, the degree of alteration depends on several factors: degree of obesity, comorbidities and pharmacological characteristics of the drugs. In addition, the volume of distribution (V) may vary according to the amount of adipose tissue and the lipophilic properties of the antibiotic, resulting in lower serum concentrations. Linezolid is active against Gram-positive bacteria used for skin and lung infections and is a highly lipophilic molecule with a high rate of penetration into tissues. Canut et al. proposed as a PK index predictive of efficacy an AUC/MIC .100 (where AUC1⁄4area under the antimicrobial concentration–time curve for 24 h). The achievement of a Cmin ≥2 mg/L and/or AUC24 .160–200 mg.h/L was proposed as a theoretical threshold to ensure efficacy. Data reported so far show significantly lower concentrations with standard doses of linezolid in obese patients. We report here the main PK parameters in two morbidly obese patients, as defined by BMI, receiving a higher dosage of linezolid. Patient 1 was a male ,50 years old with a BMI of 72 kg/m admitted to the ICU for community-acquired pneumonia with severe sepsis. He had hypoxaemic respiratory failure and later developed methicillin-resistant Staphylococcus epidermidis bloodstream infection (BSI) with a linezolid MIC of 2 mg/L. Patient 2 was a male .60 years old with a BMI of 66 kg/m and acute hypercapnic respiratory failure, admitted to the ICU with a diagnosis of healthcare-associated pneumonia and septic shock. Bronchoalveolar lavage identified an MRSA with a linezolid MIC of 1 mg/L. Plasma concentrations of linezolid were studied at steadystate with a dose of 600 mg every 8 h intravenously by 1 h infusion. The AUC of daily (AUC0 – 24) plasma concentrations was calculated with blood samples collected before (time 0) and at 2, 4, 6 and 8 h after intravenous administration. The Cmin was defined as the concentration before the administration and the maximum plasma concentration (Cmax) as the concentration at the end of the infusion. Linezolid was determined in plasma by a UPLC–photodiode array method. PK data were analysed using Kinetica software (Thermo Scientific, Waltham, MA, USA). AUC0–24 was calculated as 3×AUC0–8. Informed consent was waived due to the clinical need for monitoring plasma levels. The main linezolid PK parameters for Patient 1 were as follows: Cmax 4.83 mg/L, Cmin 0.88 mg/L, AUC0 – 24 55.05 mg.h/L, half-life (t1/2) 3.01 h, clearance (CL) 32.70 L/h, V 141.6 L and 0.51 L/kg, AUC/MIC (MIC1⁄41 mg/L) 55.05 and AUC/MIC (MIC1⁄42 mg/L) 27.52. The main linezolid PK parameters for Patient 2 were as follows: Cmax 15.54 mg/L, Cmin 11.89 mg/L, AUC0 – 24 335.69 mg.h/L, t1/2 10.39 h, CL 5.40 L/h, V 80.98 L and 0.45 L/kg, AUC/MIC (MIC1⁄41 mg/L) 335.69 and AUC/MIC (MIC1⁄42 mg/L) 167.50. See Figure 1. There were satisfactory Cmax and Cmin only in Patient 2, whereas in Patient 1 there was an increased CL and reduced AUC. Since the PK/pharmacodynamic parameter of importance for linezolid activity is the AUC/MIC ratio, assessing changes in AUC exposure by body size is of paramount importance. Only Patient 2 had satisfactory values of AUC and AUC/MIC. Furthermore, since linezolid PK is not related to renal function, the creatinine clearance values of .120 and 40 mL/min in Patients 1 and 2, respectively, are not helpful in understanding the alteration of plasma clearance. Moreover, the observation of higher V (141.6 and 80.9 L in Patients 1 and 2, respectively, when compared with healthy volunteers (52 L) confirms the suggestion of a relationship between weight and V in determining a significant decrease of plasma exposure. Taken together, these data suggest that linezolid PK may be strongly influenced by the degree of obesity and standard doses are not sufficient, further noting that linezolid undergoes slow non-enzymatic oxidation mediated by ubiquitous reactive species in vivo.

From ESKAPE to ESCAPE, From KPC to CCC

TO THE EDITOR—Colonization and infection due to multidrug-resistant (MDR) bacteria is nowadays an important issue in nosocomial and healthcare-associated infections, as reported by several surveillance systems [1, 2]. The spread of MDR microorganisms has been linked to asymptomatic carriage by the hands of healthcare workers, contamination of hospital environment, colonization of the bowel, and use and duration of antibiotic treatments.We are currently facing newmicrobiological, infection control and clinical issues, and the epidemiologic variations observed in the last years highlighted the need of a change from the initial proposed acronym “ESKAPE” (E. faecium, S. aureus, K. pneumoniae, A. baumannii, P. aeruginosa, and Enterobacter species), to “ESCAPE” (E. faecium, S. aureus, C. difficile, A. baumannii, P. aeruginosa, and Enterobacteriaceae). The gut microbiota regulates important physiological metabolic functions of the host and can be impaired during prolonged antibiotic treatments, becoming a significant reservoir of microorganisms with a nosocomial profile of antibiotic resistance. In C. difficile infections, there is a clearly recognized causal role of a dysbiotic microbiota, suggesting that similar alterations may be favoring colonization by Klebsiella pneumoniae carbapenemase (KPC)-producing K. pneumoniae (KPCKp) or an excessive intestinal growth by Candida species, thus favoring Candida bloodstream infections. Indeed, there are reports of candidemia following C. difficile severe infections [3], and KPC-Kp bloodstream infections associated with candidemia [4]. Interestingly, in murine models of gastrointestinal candidiasis, Cole et al analyzed the impact of colonization of gastrointestinal mucosa, alterations of the normal integrity of the mucosal epithelium, and impairmentofmucosal immunity in the development of invasive candidiasis [5]. If these considerations are correct, the gastrointestinal tube is a well-recognized key player as the main reservoir for human disease by Candida species and for epidemic dissemination of MDR bacteria such as KPC-Kp and C. difficile. Accordingly, we propose that antimicrobial stewardship programs should start focusing on a “CCC” strategy, aiming at carbapenemase-producing Enterobacteriaceae, C. difficile, and Candida species. Among Enterobacteriaceae, carbapenemases are mainly seen in KPC-Kp, with increasing data comingnot only from critically ill and surgical patients but also from internal medicine wards [6]. The identification of patients colonized by KPC-Kp in different settings deserves a dedicated intervention and a major compliance of healthcare workers to simple standard hygiene procedures, such as handwashing [7]. The European guidelines on infection control issues for gramnegative bacteria highlight the scientific evidence available on prevention and isolation, including C. difficile [8]. The “CCC” acronym may help antimicrobial stewardship programs to focus on current issues and may guide physicians in remembering and acknowledging the importance of disturbances of the gastrointestinal tract, including the collateral damage due to antibiotic treatment [9]. Timely identification of at-risk patients, early treatment in symptomatic patients, and antibiotic de-escalation are urgently needed. Save the tube!

Risk factors for mortality in patients with Staphylococcus aureus bloodstream infection

In this two year retrospective analysis, we evaluated the epidemiology and risk factors for mortality of Staphylococcus aureus bloodstream infection (SaBSI). Methicillin-susceptible S. aureus (MSSA) was isolated in 84 (44.2%) and methicillin-resistant S. aureus (MRSA) in 106 episodes (55.8%). The mortality rate after 21 days was 16.4%. At univariate analysis older age, no removal of central venous catheter (CVC), prosthetic heart valves, severe sepsis, septic shock and high APACHE II score were significantly associated with mortality, whereas treatment duration > 48 hours, appropriate targeted therapy and prolonged treatment duration were significantly associated with survival. At multivariate analysis, prosthetic valves, septic shock and fever 48 hours after the diagnosis were significantly related to mortality. In this study, the mortality was associated with clinical rather than microbiological factors.

Voriconazole and atazanavir: a CYP2C19-dependent manageable drug–drug interaction

AIM To investigate the pharmacokinetics of voriconazole when administered to HIV-positive patients receiving treatment with atazanavir-containing therapies according to CYP2C19 genotype. MATERIALS & METHODS We describe four HIV-positive patients with pulmonary aspergillosis treated with voriconazole and atazanavir-based regimens (with or without ritonavir). They were managed by assessing their CYP2C19 genotype (CYP2C19*2, rs4244285, G>A, real-time PCR) and therapeutic drug monitoring (HPLC-based validation methods). RESULTS & CONCLUSION Voriconazole exposure was variable but Ctrough levels were above 1000 ng/ml in all patients; one CYP2C19 intermediate metabolizer required lower doses of voriconazole (50 mg twice daily) to obtain satisfactory drug concentrations. Atazanavir and ritonavir plasma levels were moderately reduced (area under the curve: -23 and -26%, respectively); raltegravir exposure seemed increased by voriconazole administration (area under the curve: 2.5-fold higher) in a single subject. Coadministration of atazanavir and voriconazole may be feasible in selected HIV-positive patients; therapeutic drug monitoring and CYP2C19 genotyping may optimize exposure of both drugs.

Therapeutic drug monitoring of boosted PIs in HIV-positive patients: undetectable plasma concentrations and risk of virological failure

Background Therapeutic drug monitoring (TDM) of antiretroviral drugs is performed in selected HIV-positive patients. The aim of this study was to estimate the prevalence of undetectable plasma concentrations of ritonavir and boosted PIs and to evaluate the association between those and the 48 week risk of virological failure. Methods A TDM registry study and a retrospective follow-up study were conducted. Plasma concentrations were measured through validated methods. According to PI and ritonavir concentrations, patients were stratified as adherent, partially non-adherent or non-adherent. Virological outcome was evaluated 48 weeks afterwards. Results The TDM registry study included 2468 samples collected from 723 patients (68.1% male, median age 43.5 years). Eighty-seven samples (3.5%, 74 patients) and 68 samples (2.8%, 52 patients) were in the partially non-adherent and non-adherent groups, respectively; more patients on atazanavir/ritonavir (7.9%) versus darunavir/ritonavir (2% twice daily and 1.9% once daily) and lopinavir/ritonavir (1.5%; P  <   0.001) were observed in the partially non-adherent group. Two hundred and ninety patients were included in the follow-up study (64.1% male, median age 40 years). Patients in the adherent group had a higher chance of viral control [81.9% (167/204)] versus the partially non-adherent group and the non-adherent group [71.7% (33/46) and 53.1% (17/32), respectively; P  =   0.001]. Based on multivariate analysis, baseline HIV RNA >50 copies/mL ( P  <   0.001), genotypic susceptibility score ≤2 ( P  =   0.001), lower nadir CD4 cell count ( P  =   0.003) and not being in the adherent group ( P  =   0.029) were independent predictors of HIV RNA >50 copies/mL at 48 weeks. Conclusions The measurement of PI and ritonavir plasma levels can uncover incomplete compliance with treatment; TDM may represent a useful tool for identifying patients in need of adherence-promoting interventions.

Prevention and Diagnosis of Ventilator-Associated Pneumonia: A Regional Survey in Italy

The rate of application of preventive and diagnostic strategies in the management of patients with ventilator-associated pneumonia (VAP) may be significantly different from those reported in international guidelines. We are reporting in this correspondence the results of a regional Italian survey of preventive and diagnostic strategies for the management of patients with VAP in the setting of the 24 participating ICUs of the Piedmont Intensive Care Unit Network (or PICUN). We used as the main references for discussion the results of a similar survey1 and comprehensive evidence-based clinical practice guidelines for the prevention of VAP.2 The results are shown in Table 1. In our study, there was consistent use of open and closed endotracheal suction systems and of subglottic secretion drainage. Closed suction systems are associated with lower costs, and improved safety of patients and health-care workers.2 There was a high percentage of subglottic secretion drainage, which is effective in preventing early-onset VAP, as was confirmed by a 2005 metaanalysis.3 It appears that heat and moisture

Pharmacokinetics of caspofungin increased dosage in a patient on rifampin-containing anti-tubercular treatment

Abstract We describe a patient treated with caspofungin and rifampin; after increasing the dosage of the former (70 mg/day) we observed an unexpectedly lower plasma exposure (AUC0–24 79.5 μg/ml*h vs. 108.8 μg/ml*h). Although rifampin-mediated complete enzyme induction may take longer than 2 weeks, the clinical advantage of an increased caspofungin dose deserves clinical investigation.