Once-daily atazanavir/cobicistat and darunavir/cobicistat exposure over 72 h post-dose in plasma, urine and saliva: contribution to drug pharmacokinetic knowledge.

Background: We investigated the pharmacokinetics (PK) of atazanavir/cobicistat and darunavir/cobicistat once daily over 72 h following drug intake cessation in plasma, saliva and urine. Methods: Healthy volunteers received a fixed-dose combination of 300/150 mg of atazanavir/cobicistat once daily for 10 days, followed by a 10 day washout period and then a fixed-dose combination of 800/150 mg of darunavir/cobicistat once daily for 10 days. Full PK profiles were assessed for each phase for 72 h following day 10 and parameters determined to the last measurable concentration in plasma, saliva and urine by non-compartmental methods. Results: Sixteen subjects completed the study. Geometric mean (GM) terminal elimination half-life values to 72 h of atazanavir and darunavir were 6.77 and 6.35 h, respectively. All subjects had atazanavir concentrations above the suggested minimum effective concentration of 150 ng/mL 24 h post-dose and 14/16 subjects had concentrations higher than this target at 30 h post-dose (GM of 759 and 407 ng/mL, respectively). Thirteen out of 16 subjects had darunavir concentrations higher than the target of 550 ng/mL at 24 h post-dose and 5/16 subjects had concentrations higher than the target at 30 h post-dose (GM of 1033 and 382 ng/mL, respectively). Cobicistat half-life to 72 h was 4.21 h with atazanavir and 3.62 h with darunavir. GM values 24 h after the observed dose ( C 24 ) for atazanavir and darunavir were 141 and 43 ng/mL, respectively, in saliva and 24857 and 11878 ng/mL, respectively, in urine. Concentration decay in saliva/urine mirrored plasma concentrations for both drugs. Conclusions: Different concentration decay patterns were seen for atazanavir and darunavir, which may be partially explained by cobicistat half-life (longer with atazanavir than darunavir). For the first time, we also measured drug PK forgiveness in saliva and urine, which represent easier markers of adherence.

Systemic Inflammatory Response Is a Prognostic Marker in HIV-Infected Patients with Hepatocellular Carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is increasingly prevalent in people living with HIV. Systemic inflammation is a prognostic factor requiring validation in HIV-associated HCC. AIMS: Using a multi-centre database of consecutive HCC cases, we investigated the prognostic role of a panel of inflammatory markers, including neutrophil to lymphocyte ratio (NLR), using univariate and multivariate survival analyses. RESULTS: Fifty-nine patients with HIV-associated HCC secondary to hepatitis C (69%) or B virus infection (32%) were identified. The median survival was 22 months. A raised NLR independently predicted patients' survival and was correlated with advanced Barcelona Clinic Liver Cancer stage (p = 0.003) and poor performance status (p < 0.001) but not with HIV RNA or CD4 counts. CONCLUSION: Systemic inflammation, as measured by NLR, is a prognostic determinant associated with adverse pathological features of malignancy, but not coexisting HIV infection, suggesting a tumour-promoting role of the innate immune response that warrants further investigation in mechanistic studies.

Predictive models for identification of hospitalized patients harboring KPC-producing Klebsiella pneumoniae.

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.

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

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.

Identifying patients harboring extended-spectrum-beta-lactamase-producing Enterobacteriaceae on hospital admission: derivation and validation of a scoring system.

Increases in community-acquired infections caused by extended-spectrum-ß-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) ß-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 χ(2) = 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 model's potential as a guide for prescribing empirical antibiotic therapy.

A phase IV, open-label three-arm study investigating the impact of a combination of tenofovir disoproxil fumarate/emtricitabine with raltegravir or dolutegravir or elvitegravir/cobicistat on renal function in HIV-1 antiretroviral naïve patients.

Objectives: Tenofovir DF (TDF) remains one of the preferred backbone agents for naïve HIV patients starting antiretroviral treatment (ART). The impact of TDF on renal function and metabolic parameters may vary by anchor agent. We investigated the impact of TDF in combination with 3 different integrase inhibitors on tubular and glomerular function, and metabolic parameters in ART-naïve patients.Methods: Sixty patients with normal renal function were randomised (20 per arm) to TDF/emtricitabine (FTC) plus either raltegravir (RAL) (400 mg b.d.), dolutegravir (DTG) or elvitegravir/cobicistat (EVG/c) for 48 weeks.Results: 57 patients completed the study. Significant increases in RBP/creatinine ratio at week 24 were seen in all arms [RAL +4.7 µg/mmol (CI 0.43 to 8.98, p = 0.032); DTG +4.96 µg/mmol (CI 0.77 to 9.15, p = 0.021); EVG/c +6.95 µg/mmol (CI 2.53 to 11.36, p = 0.002)], although this was not sustained to week 48 in the RAL arm. Similar changes across the arms were observed for urinary α1microglobulin (RAL +6.20 mg/L, p = 0.030; DTG +6.30 mg/L, p = 0.025; EVG/c +8.15 mg/L, p = 0.003). Urinary ß2microglobulin significantly increased at week 24 with DTG and EVG/c but remained unchanged in the RAL arm. Glomerular filtration measured with CKD-EPI creatinine-cystatin C increased significantly in the RAL arm at week 24 through 48 but declined modestly in other two arms. Total and LDL cholesterol decreased in the RAL arm, but increased in the EVG/c arm, with no significant changes in the DTG arm. Weight increased significantly from baseline with DTG but not RAL or EVG/c.Conclusion: INSTIs in combination with TDF/FTC impact differently on tubular microproteinuria, eGFR, metabolic markers and weight. Use of TDF/FTC with RAL had the least tubular effects and the most favorable metabolic profile.

Carbapenemase-Producing Klebsiella pneumoniae Colonization and Infection in Solid Organ Transplant Recipients: A Single-Center, Retrospective Study.

Carbapenemase-KPC producing Klebsiella pneumoniae (CP-Kp) infection represents a serious threat to solid organ transplant (SOT). All patients admitted between 1 May 2011 and 31 August 2014 undergoing SOT were included in the retrospective study. The primary outcomes included a description of the association of enteric colonization and invasive infections by CP-Kp with one-year mortality. Secondary outcomes were the study of risk factors for colonization and invasive infections by CP-Kp. Results: A total of 5.4% (45/828) of SOT recipients had at least one positive rectal swab for CP-Kp, with most (88.9%) occurring after transplantation. 4.5% (35/828) of patients developed a CP-Kp-related invasive infection, with 68.6% (24/35) being previously colonized. The 1-year mortality was 31.1% in patients with enteric colonization with CP-Kp and, it was 51.4% among patients with CP-Kp-related invasive infections. At univariate analysis, colonization, invasive infections, sepsis, severe sepsis, and septic shock were significantly associated with 1-year mortality. At multivariate analysis, only invasive infections and the combination of sepsis, severe sepsis, or septic shock were significantly associated with 1-year mortality, whereas gastrointestinal colonization was significantly associated with survival. In this population, the 1-year mortality was significantly associated with invasive infections; otherwise, gastrointestinal colonization was not associated with increased 1-year mortality.

PC945, a Novel Inhaled Antifungal Agent, for the Treatment of Respiratory Fungal Infections.

Disease due to pulmonary Aspergillus infection remains a significant unmet need, particularly in immunocompromised patients, patients in critical care and those with underlying chronic lung diseases. To date, treatment using inhaled antifungal agents has been limited to repurposing available systemic medicines. PC945 is a novel triazole antifungal agent, a potent inhibitor of CYP51, purpose-designed to be administered via inhalation for high local lung concentrations and limited systemic exposure. In preclinical testing, PC945 is potent versus Aspergillus spp. and Candida spp. and showed two remarkable properties in preclinical studies, in vitro and in vivo. The antifungal effects against Aspergillus fumigatus accumulate on repeat dosing and improved efficacy has been demonstrated when PC945 is dosed in combination with systemic anti-fungal agents of multiple classes. Resistance to PC945 has been induced in Aspergillus fumigatus in vitro, resulting in a strain which remained susceptible to other antifungal triazoles. In healthy volunteers and asthmatics, nebulised PC945 was well tolerated, with limited systemic exposure and an apparently long lung residency time. In two lung transplant patients, PC945 treated an invasive pulmonary Aspergillus infection that had been unresponsive to multiple antifungal agents (systemic ± inhaled) without systemic side effects or detected drug-drug interactions.

Acquisition of FKS2 mutation after echinocandin treatment of infective endocarditis by Candida glabrata.

Bloodstream infections caused by non-albicans Candida species are increasing and echinocandins have been extensively used especially in patients with hemodynamic instability, previous antifungal treatment and hospital risk factors for intrinsic or acquired resistance to azoles. Candida glabrata resistance to echinocandins is reported and is generally associated with previous use of echinocandins; FKS gene mutations have been associated with a worse outcome. We report the case of a 65-year-old woman who developed candidemia and endocarditis by C. glabrata with a newly acquired FKS mutation 24 months after successful treatment of infective endocarditis by C. glabrata with a double dosage of anidulafungin (200 mg daily) followed by oral voriconazole. Driven by high echinocandin MICs the strain taken by intraoperative cultures was further analyzed in a referral microbiology laboratory, confirming the new onset of point mutation S633P of the FKS2 gene.

Pharmacogenomic influence on sepsis outcome in critically ill patients.

In infectious and inflammatory diseases, pharmacogenetics affects treatment efficacy and toxicity. Moreover, recent studies suggest its important role in predicting the clinical outcome of sepsis. Our aim was to investigate the influence of single nucleotide polymorphisms (SNPs) in genes which we supposed to be involved in linezolid elimination upon sepsis outcome. Fourteen ICU-admitted patients in therapy with intravenous linezolid (600mg q12h) were enrolled and classified into three groups: group 0 for sepsis, 1 for severe sepsis and 2 for septic shock. Genotyping for SNPs in MDR1 3435 rs1045642 C>T, 2677 rs2032582 G>T and 1236 rs1128503 C>T, MRP2 -24 rs717620 G>A and 1249 rs2273697 G>A, MRP4 *879 rs1059751 T>C and 3348 rs1751034 T>C, BCRP1 421 rs2231142 C>A and 1194+928 rs13120400 T>C, -127 rs4149170 G>A and OCT1 480 rs683369 C>G genes was done using real-time PCR allelic discrimination assay. The Mann-Whitney statistical test was used to analyse variables. MDR1 2677 (p= 0.012), MRP2 1249 (p= 0.038), MRP4 *879 (p= 0.032) and 3348 SNPs significantly influenced the sepsis score. Our study, despite its limited sample size, could be decisive for early sepsis prediction and may improve the management of critically ill patients.

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.

Candidemia, and infections by Clostridium difficile and carbapenemase-producing Enterobacteriaceae: new enteropathogenetic opportunistic syndromes?

In this paper we analyze three enteropathogenetic opportunistic infections represented by Candida spp., C. difficile and carbapenemase-producing K. pneumoniae. The common pathogenetic pathway is based on an alteration of the intestinal flora, now mainly referred as the human microbiome, with secondary opportunism for infections caused by Candida, C. difficile and carbapenemase-producing Enterobacteriaceae ("CCC"). We highlight the epidemiology, risk factors, clinical syndromes associated with the pathogens and we propose some new issues related to the epidemiology and diagnosis of candidemia, also using hierarchical cluster analysis, definitions of levels of interventions in patients colonized or infected by carbapenemase-producing bacteria. The "enteropathogenetic" opportunistic syndromes are best prevented with antimicrobial stewardship programs aiming at increasing diagnostic specificity of infectious syndromes to reduce the antimicrobial use and costs. Appropriate guidelines for infection control should also be implemented to reduce the nosocomial spread of enteropathogenetic microbes.