Chiara Simona Cardellino

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.

Relationship between the early Boceprevir-S isomer plasma concentrations and the onset of breakthrough during HCV genotype 1 triple therapy

In a prospective cohort of 18 patients treated with boceprevir, we examined the role of boceprevir plasma concentration at the onset of breakthrough during the treatment. Nine patients experienced breakthrough during therapy. The resistance patterns were as follows: S122S/R, I132V, T54A/I132V, V156S/I170A, V36M/T54S/R155K, V36M/R155K and T54/R155K. Boceprevir-S isomer (SCH 534128) median concentration in patients with breakthrough was 48.3 ng/mL (interquartile range 43-58 ng/mL); in others, it was significantly (p 0.019) higher: 151 ng/mL. Low boceprevir plasma concentration can lead to virologic resistance; therapeutic drug monitoring should be used to prevent the onset of viral breakthrough during triple-regimen therapy with boceprevir.

Telaprevir-S isomer enhances ribavirin exposure and the ribavirin-related haemolytic anaemia in a concentration-dependent manner

The standard-of-care for the treatment of genotype-1 chronic hepatitis C is based on the combination of direct acting antivirals, such as boceprevir and telaprevir, with ribavirin and pegylated-interferon alfa. These triple regimens give a higher response rate than dual therapy, but on the other hand show a more than 10% higher rate of anaemia. Not enough focus has been given to the interaction between telaprevir and RBV. In this work, we aimed to study and deepen this relationship by comparing ribavirin plasma and intra-erythrocytic concentrations at one month of triple and dual therapy (17 vs. 119 patients). Moreover, we determined telaprevir isomers concentrations and tested them for correlation with ribavirin concentrations and haemoglobin loss at one month of treatment. Finally, all drugs concentration data were tested for their correlation with the renal function during treatment. The comparisons of ribavirin concentration and toxicity data were repeated on a sub-group of 9 patients who had been treated 1 year before with dual therapy and then re-treated with triple therapy. The observed ribavirin plasma and intra-erythrocytic concentrations in triple therapy were significantly higher compared to dual therapy, both in whole group and sub-group comparison. Ribavirin concentrations were significantly correlated to the haemoglobin loss and telaprevir-S isomer concentrations (r(2)=0.317 P(value)=0.023 and r(2)=0.388 P(value)=0.008, respectively). Renal function had a significant decrease from the baseline value, but was not significantly correlated with drugs concentrations. These results highlight for the first time that, in the context of triple therapy with telaprevir, ribavirin exposure is related to the telaprevir-S isomer plasma concentration. We conclude that the addition of telaprevir to the dual therapy increases ribavirin exposure and haemoglobin loss: this effect could probably be managed through the therapeutic drug monitoring of ribavirin and telaprevir-S concentrations.

Healthcare-Associated Klebsiella pneumoniae carbapenemase Producing K. pneumoniae Bloodstream Infection: The Time Has Come

TO THE EDITOR—Klebsiella pneumoniae carbapenemase (KPC)–producing K. pneumoniae (KPC-Kp) has reached a worldwide diffusion, and the associated mortality rate of infected patients is ranging from 45% to 56% [1]. Several risk factors for mortality were identified in patients with KPC-Kp bloodstream infection (KPC-Kp BSI), such as the severity of the underlying disease or the delay in administration of appropriate therapy [2, 3]. Usually KPC-Kp infections arise in patients with prolonged hospital stay and have been previously treated with antibiotics [3]. We report on patients with KPC-Kp BSI diagnosed within 5 days after hospital admission [4]. The mortality was evaluated at 21 days after the first positive blood cultures, and appropriate treatment has been considered as the administration for ≥48 hours of an antibiotic with in vitro activity [5]. Eighteen patients with healthcareassociated KPC-Kp BSI were studied (Table 1). The majority of patients were men (11 [61%]), had a mean age of 63 years (standard deviation [SD], 14), had a previous admission in the 6 months before BSI onset (13 [72%]), or underwent surgery during the hospital stay (13 [72%]). Ten patients (56%) were in a medical ward at the time of diagnosis. The median time between hospital admission and KPC-Kp BSI was 3 days (SD, 1 day), and the mean Acute Physiology and Chronic Health Evaluation II (APACHE II) score was 16 (range, 3–36). Five patients were colonized by KPC-Kp before KPC-Kp BSI. The comorbidities more frequently reported were malignancy (5 [36%]), chronic renal failure (4 [29%]), hepatopathy (3 [17%]), and cardiovascular disease (3 [17%]). After a median of 2 days (SD, 1 day), the empiric antibiotic treatment was changed and all patients were appropriately treated, mostly with combination therapy, according to the in vitro sensitivity. The overall mortality was 22% (4 patients). At univariate analysis the mortality was significantly associated with liver disease (P = .031), chronic renal failure (P = .047), and high APACHE II score (P = .01). The survival was associated with appropriate treatment administered for ≥48 hours. Usually, KPC-Kp BSI infections are diagnosed a median of 28–37 days after hospital admission [6–8]. In this study we report for the first time 18 patients with KPC-Kp BSI within 5 days after hospital admission, which had a very low crude mortality rate (22%) compared with 45% in the above-mentioned patients with nosocomial KPC-Kp BSI infections [6–8]. The pathogenesis of KPC-Kp BSI infection seems to be consistent with a multistep process where comorbidities, host factors, and prolonged antibiotic pressure contribute to the invasion of Table 1. Main Clinical Characteristics of Patients With Healthcare-Associated Klebsiella pneumoniae Carbapenemase Bloodstream Infection

Treatment with daclatasvir and sofosbuvir for 24 weeks without ribavirin in cirrhotic patients who failed first-generation protease inhibitors

BackgroundTreatment of patients with chronic hepatitis C who failed the triple therapy with first generation of protease inhibitors is not still defined. The combined use of sofosbuvir (SOF) and daclatasvir (DCV) seems to be promising due to higher genetic barrier, good tolerance and effectiveness.MethodsWe described the treatment with this drug combination in a real-life cohort of 20 cirrhotic patients with genotype 1 who failed the triple therapy.Results18 of them (90%) with Child–Pugh A, 11 (55%) with genotype 1a, 17 (85%) with more than 1 and 8 (40%) with more than 2 previous failed treatment; all patients had at baseline NS3 resistance-associated variants related to triple therapy failure. RBV was not administered due to anemia in previous treatments. The sustained virological response was 100%.ConclusionTreatment with SOF + DCV without RBV for 24 weeks is safe and effective in cirrhotic patients who failed triple therapy with the first generation of protease inhibitors.

Vitamin D pathway gene polymorphisms as predictors of hepatitis C virus-related mixed cryoglobulinemia.

Mixed cryoglobulinemia (MC) is the most frequent extrahepatic hepatitis C virus (HCV) complication. Vitamin D is a modulator of several biological processes, including immune and skeletal systems and MC presence and systemic vasculitis were associated independently with low levels of vitamin D. Considering the impact of vitamin D, we aimed to evaluate the role of some single nucleotide polymorphisms (SNPs) of vitamin D pathway genes in the prediction of MC in HCV patients treated with pegylated interferon and ribavirin. We investigated SNPs in IL-28B, CYP27B1, CYP27A1, CYP24A1, VDBP, and VDR genes through real-time PCR. VDR gene SNPs were related to baseline viral load: VDR BsmI AA (P=0.018), TaqI CC (P=0.009), and ApaI AA (P=0.004) showed a lower baseline HCV count. Among vitamin D pathway gene polymorphisms, VDR FokI T>C was a factor associated with the presence of MC in the study population (P=0.011): related to C allele carriers (TT vs. TC/CC), we obtained a P-value of 0.003. In the logistic regression analysis to assess which demographic, clinical, or genetic factors could predict the presence of cryoglobulin, the TT/CC IL-28B rs8099917/rs12979860 haplotype [P<0.001; odds ratio (OR) 3.516 (1.951–6.336)], baseline viral load [P<0.001; OR 1.000 (0.999–1.001)], and VDR FokI TC/CC genotypes [0.044; OR 0.463 (0.218–0.981)] remained in the final regression model. These data could help physicians identify patients with a higher probability of developing MC extrahepatic complications.

Different HBsAg decline after 3 years of therapy with entecavir in patients affected by chronic hepatitis B HBeAg-negative and genotype A, D and E

The role of measurement of hepatitis B “s” antigen (HBsAg) during the therapy with oral nucleos(t)ide analogues is still debatable. The HBsAg declines after 3 years of therapy with entecavir (ETV) was investigated among patients affected by hepatitis B virus (HBV), e antigen (HBeAg)‐negative and genotypes A, D and E. A prospective cohort of 123 patients was enrolled consecutively from April 2007 to May 2010 with at least 3 years of treatment with ETV. Patients with chronic HBV infection, HBeAg‐negative, naive for previous treatment and with virological response to ETV were included in the study. HBsAg level and HBV‐DNA were tested every 3 months during the first year of treatment, then every 6 months for a time of at least 3 years. After 3 years, HBsAg decline was 0.77 log IU/ml, 0.65 log IU/ml, 0.45 respectively; A versus D (P = 0.012), A versus E (P < 0.001), D versus E (P < 0.001). In the multivariate linear regression analysis only the HBV genotype was predictive of HBsAg decline after 3 years of treatment (P < 0.001). The expected time to HBsAg loss was 15.6 years for the A genotype, 17 years for D, 24.6 years for E (P < 0.001). The treatment with ETV leads the different kinetics in HBsAg decline among genotypes A, D and E; the expected time of HBsAg loss was significantly higher in E genotype compared to A and D genotype. J. Med. Virol. 86:1845–1850, 2014.

Treatment with PEG-IFN and ribavirin in patients with chronic hepatitis C, low grade of hepatic fibrosis, genotype 1 and 4 and favorable IFNL3 genotype: A pharmacogenetic prospective study

The new direct-acting antivirals agents (DAAs) rapidly changed the treatment approach in chronic hepatitis C (CHC); however, the interferon (IFN)-free therapies availability is currently different in some countries, due to higher costs of these drugs. Naïve treated patients, who are not eligible for IFN-free therapies, could be selected for standard dual treatment with pegylated (PEG)-IFN and ribavirin (RBV), through IFN lambda 3 gene polymorphisms and fibrosis stage evaluation. Inclusion criteria were: naïve treated CHC patients with GT1 or GT4, without major contraindication to PEG-IFN or RBV, with fibrosis stage F0-F2 and IFNL3 rs8099917/rs12979860 TT/CC genotypes. 65 patients were included in the study. Overall SVR was observed in 50 patients (76.9%); SVR rates among different genotypes were as follows: 15 with GT1a (71.4%), 27 with GT1b (79.4%) and 8 for GT4 (80%). The RBV cutoff at 2weeks of 1800ng/mL, predictor of RVR, was determined (p=0.003; sensibility=60.4%, specificity=88.2%, positive predictive value=88.9%, negative predictive value=100%). In multivariate analysis, factors significantly associated with treatment failure were living alone condition (OR=4.302; 95%IC=1.254-16.257; p=0.034) and RBV plasma level <1800ng/mL at 2weeks (OR=4.970; 95%IC=1.405-17.565; p=0.009). Considering a pharmacogenetic-guided approach, dual therapy with PEG-IFN and RBV can be considered a reliable option for patients ineligible for IFN-free treatments, who are motivated and well informed about all the aspects related to PEG-IFN administration.

Effect of ABCC2 and ABCG2 Gene Polymorphisms and CSF-to-Serum Albumin Ratio on Ceftriaxone Plasma and Cerebrospinal Fluid Concentrations

We measured ceftriaxone pharmacokinetics in patients’ plasma and cerebrospinal fluid (CSF) and assessed the influence of biometric, demographic, genetic (ABCB1, ABCC2, ABCB11, ABCG2, and SLCO1A2 polymorphisms) and pathological features. Adult patients with signs and symptoms of central nervous system infections, receiving intravenous ceftriaxone, were enrolled. Ceftriaxone plasma and CSF concentrations were measured by high‐precision liquid chromatographic methods; allelic discrimination was performed by real‐time polymerase chain reaction. Forty‐three patients were included: median ceftriaxone maximal concentration was 15,713 ng/mL in plasma and 3512 ng/mL in CSF with a CSF‐to‐plasma ratio of 0.3. ABCC2 1249 rs2273697 (P = .027) and ABCG2 1194+928 rs13120400 (P = .015) variants were significantly associated with CSF concentrations and CSF‐to‐plasma ratios. At linear regression analysis, CSF‐to‐serum albumin ratio was an independent predictor of ceftriaxone CSF concentrations (P = .001; also in those with intact blood‐brain barrier: P = .031) and CSF‐to‐plasma ratio (P = .001; also in those with blood‐brain barrier impairment: P = .040). We here report the role of transporters’ genetic variants as well as of blood‐brain barrier permeability in predicting ceftriaxone exposure in the central nervous system.