Silvia Corcione

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.

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.

Mortality in patients with early- or late-onset candidaemia

Objectives Although candidaemia is a well-known complication of hospital stay and has a crude mortality of ∼40%, few data are available for episodes diagnosed within 10 days after hospital admission. In this paper, we compared the risk factors for mortality according to the onset of candidaemia. Methods This was a retrospective study of hospitalized patients with early-onset candidaemia (EOC; ≤10 days) or late-onset candidaemia (LOC; >10 days) to identify any distinct clinical characteristics and risk factors for 30 day mortality in two Italian academic centres. Results A total of 779 patients were included in the study: 183 EOC and 596 LOC. Mortality was significantly lower in EOC (71/183, 38.8% versus 283/596, 47.5%, P = 0.03). In EOC, multivariate analysis showed that inadequate initial antifungal therapy (IIAT) (P = 0.005, OR 3.02, 95% CI 1.40–6.51), Candida albicans aetiology (P = 0.02, OR 2.17, 95% CI 1.11–4.26) and older age (P < 0.001, OR 1.05, 95% CI 1.02–1.07) were independent risk factors for mortality. In LOC, liver disease (P = 0.003, OR 2.46, 95% CI 1.36–4.43), IIAT (P = 0.002, OR 2.01, 95% CI 1.28–3.15) and older age (P < 0.001, OR 1.03, 95% CI 1.02–1.04) were independently associated with a fatal outcome, while treatment with caspofungin was associated with survival (P < 0.001, OR 0.42, 95% CI 0.26–0.67). Conclusions EOC has different clinical characteristics and risk factors for mortality compared with LOC. Although EOC mortality is significantly lower, the rate of inappropriate antifungal treatment is higher. Treatment with caspofungin is significantly associated with survival in patients with LOC. Efforts are needed to improve the diagnosis and treatment of EOC.

Development and validation of a new UPLC-PDA method to quantify linezolid in plasma and in dried plasma spots

Linezolid is an oxazolidinone antibiotic used for the treatment of pneumonia and uncomplicated and complicated skin and soft tissues infections caused by Gram positive bacteria. It is also used as second line agent in multi-drug resistant tuberculosis. Therapeutic drug monitoring (TDM) of linezolid represents a valid tool in clinical practice to optimize therapy, especially in critically ill patients. Spreading of TDM is mainly limited by high costs shipment and lack of laboratories that offer a TDM service. To overcome these problems, the use of dried plasma spots or dried blood spots is increasing. The aim of this work was to develop and validate a new chromatographic method to analyze linezolid in plasma and in dried plasma spots and to evaluate the correlation between the two extraction methods. Linezolid extraction from plasma and from dried plasma spots was obtained using acetonitrile. Quinoxaline was used as internal standard. Analysis was performed by an ultra performance liquid chromatography (UPLC) system coupled with photo diode array (PDA) detector, at 254nm. Both analytical methods were linear (r(2)>0.999) over the calibration range of 30-0.117mg/L. Limit of quantification and limit of detection were 0.117mg/L and 0.058mg/L, respectively. Intra and inter-day precision (R.S.D.%) and accuracy (%) were <15%. Long term stability of linezolid in dried plasma spots showed absence of degradation at room temperature (20-25°C) and at 4°C, for at least one month. Linear regression analysis confirmed that the two methods of extraction have good correlation. Thus they are suited for TDM of linezolid and for pharmacokinetic studies.

Clinical epidemiology in Italian Registry of Infective Endocarditis (RIEI): Focus on age, intravascular devices and enterococci.

INTRODUCTION The epidemiology of infective endocarditis (IE) is changing due to a number of factors, including aging and health related comorbidities and medical procedures. The aim of this study is to describe the main clinical, epidemiologic and etiologic changes of IE from a large database in Italy. METHODS We prospectively collected episodes of IE in 17 Italian centers from July 2007 to December 2010. RESULTS We enrolled 677 patients with definite IE, of which 24% health-care associated. Patients were male (73%) with a median age of 62 years (IQR: 49-74) and 61% had several comorbidities. One hundred and twenty-eight (19%) patients had prosthetic left side IE, 391 (58%) native left side IE, 94 (14%) device-related IE and 54 (8%) right side IE. A predisposing cardiopathy was present in 50%, while odontoiatric and non odontoiatric procedures were reported in 5% and 21% of patients respectively. Symptoms were usually atypical and precocious. The prevalent etiology was represented by Staphylococcus aureus (27%) followed by coagulase-negative staphylococci (CNS, 21%), Streptococcus viridans (15%) and enterococci (14%). CNS and enterococci were relatively more frequent in patients with intravascular devices and prosthesis and S. viridans in left native valve. Diagnosis was made by transthoracic and transesophageal echocardiography in 62% and 94% of cases, respectively. The in-hospital mortality was 14% and 1-year mortality was 21%. CONCLUSION The epidemiology is changing in Italy, where IE more often affects older patients with comorbidities and intravascular devices, with an acute onset and including a high frequency of enterococci. There were few preceding odontoiatric procedures.

A 30-years Review on Pharmacokinetics of Antibiotics: Is the Right Time for Pharmacogenetics?

Drug bioavailability may vary greatly amongst individuals, affecting both efficacy and toxicity: in humans, genetic variations account for a relevant proportion of such variability. In the last decade the use of pharmacogenetics in clinical practice, as a tool to individualize treatment, has shown a different degree of diffusion in various clinical fields. In the field of infectious diseases, several studies identified a great number of associations between host genetic polymor-phisms and responses to antiretroviral therapy. For example, in patients treated with abacavir the screening for HLA-B*5701 before starting treatment is routine clinical practice and standard of care for all patients; efavirenz plasma levels are influenced by single nucleotide polymorphism (SNP) CYP2B6-516G> T (rs3745274). Regarding antibiotics, many studies investigated drug transporters involved in antibiotic bioavailability, especially for fluoroquinolones, cephalosporins, and antituberculars. To date, few data are available about pharmacogenetics of recently developed antibiotics such as tigecycline, daptomycin or linezolid. Considering the effect of SNPs in gene coding for proteins involved in antibiotics bioavailability, few data have been published. Increasing knowledge in the field of antibiotic pharmacogenetics could be useful to explain the high drug inter-patients variability and to individualize therapy. In this paper we reported an overview of pharmacokinetics, pharmacodynamics, and pharmacogenetics of antibiotics to underline the importance of an integrated approach in choosing the right dosage in clinical practice.

Critical issues for Klebsiella pneumoniae KPC-carbapenemase producing K. pneumoniae infections: a critical agenda

The wide dissemination of carbapenemase producing K. pneumoniae (KPC-Kp) has caused a public health crisis of global dimensions, due to the serious infections in hospitalized patients associated with high mortality. In 2014, we aim to review clinical data on KPC-Kp at a time when a pro-active strategy (combating the problem before it is established) is no longer useful, focusing on epidemiology, patient risk profile, infection control, digestive tract colonization and treatment issues such as the role of carbapenems or carbapenem sparing strategies, colistin and resistance, dual carbapenem administration and the role of tigecycline. All these issues are illustrated prospectively to provide a forum for a Consensus strategy when not only intensive care units but also medical and surgical wards are affected by the epidemics.

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!

Anidulafungin for Candida glabrata Infective Endocarditis

Sir, we briefly report on a patient with infective endocarditis (IE) by Candida glabrata treated with double-dosage of anidulafungin.…