Real-life study on the pharmacokinetic of remdesivir in ICU patients admitted for severe COVID-19 pneumonia.

Remdesivir is one of the most encouraging treatments against SARS-CoV-2 infection. After intravenous infusion, RDV is rapidly metabolized (t1/2 = 1 h) within the cells to its active adenosine triphosphate analogue form (GS-443902) and then it can be found in plasma in its nucleoside analogue form (GS-441524). In this real-life study, we describe the remdesivir and GS-441524 concentrations at three time points in nine ICU patients, through a validated ultra-high-performance liquid chromatography tandem mass spectrometry (UHPLC-MS/MS) method. The observed data confirmed the very rapid conversion of RDV to its metabolite and the quite long half-life of GS-441524. The mean Cmin , Cmax and AUC0-24 , were < 0.24 ng/mL and 122.3 ng/mL, 2637.3 ng/mL and 157.8 ng/mL, and 5171.2 ng*h/mL and 3676.5 ng*h/ml, respectively, for RDV and GS-441524. Three out of nine patients achieved a Cmax  > 2610 ng/mL and 140 ng/mL and AUC0-24  > 1560 ng*h/mL and 2230 ng*h/mL for RDV and GS-441524, respectively. The mean t1/2 value for GS-441524 was 26.3 h. Despite the low number of patients, these data can represent an interesting preliminary report on the variability of RDV and GS-441524 concentrations in a real-life ICU setting.

Carbapenem-sparing strategy: carbapenemase, treatment, and stewardship.

PURPOSE OF REVIEW: describing the current role of carbapenems and carbapenem-sparing strategies in the setting of antimicrobial stewardship programs. RECENT FINDINGS: sparing carbapenems with other drugs appears to be an interesting perspective for a variety of reasons in the current context of the multidrug-resistant (MDR) pandemic. Specific algorithms should also be precisely investigated to define better how to spare carbapenems within empiric and targeted regimens, with combination treatment or monotherapies, aiming at the best use of the new drugs and improving de-escalation as soon as possible for most of the patients. SUMMARY: stewardship programs may be useful in reducing probable misuse and overuse of antibiotics, which has probably contributed to the emergence of carbapenem-resistant bacteria worldwide. The proposal of carbapenem-sparing strategies has then generated substantial scientific debate and, overall, the concept of sparing these drugs is well advocated together with judicious use of novel drugs, appropriate measures of infection control and prevention as well as in stewardship programs to curb the spread of MDR and XDR-strains in healthcare facilities.

Pharmacogenetics of the anti-HCV drug sofosbuvir: a preliminary study.

Background: Sofosbuvir is a potent nucleotide HCV NS5B polymerase inhibitor that is also a P-glycoprotein (encoded by the ABCB1 gene) and breast cancer resistance protein (encoded by the ABCG2 gene) substrate. Concerning previous anti-HCV therapies, pharmacogenetics had a significant impact, particularly considering the association of interleukin28B polymorphisms with dual-therapy (ribavirin + pegylated IFN) outcomes. Objectives: In this work, we investigated the association between sofosbuvir and its prevalent metabolite (GS-331007) plasma concentrations at 1 month of therapy and genetic variants (SNPs) in genes encoding transporters and nuclear factors (ABCB1, ABCG2 and HNF4α) related to sofosbuvir transport. Patients and methods: Allelic discrimination was performed through real-time PCR, whereas plasma concentrations were evaluated through liquid chromatography. One hundred and thirteen patients were enrolled. Results: Sofosbuvir concentrations were below the limit of quantification since the drug was converted into its GS-331007 metabolite. ABCB1 2677 G>T (P = 0.044) and HNF4α 975 C>G (P = 0.049) SNPs were associated with GS-331007 metabolite plasma concentrations. In linear multivariate analysis, liver stiffness, insulin resistance, baseline haemoglobin and haematocrit and SNPs in the ABCB1 gene (3435 CT/TT and 1236 TT genotypes) were significant predictors of GS-331007 concentrations. Furthermore, we performed sub-analyses considering the anti-HCV concomitant drug and HCV genotype, identifying specific polymorphisms associated with GS-331007 plasma concentrations: ABCB1 3435 C>T and HNF4α975 C>G in patients treated with daclatasvir, ABCB1 2677 G>T with ledipasvir and ABCB1 3435 C>T, ABCB1 2677 G>T, ABCG2 421 C>A and ABCG2 1194 + 928 C>A with ribavirin. Conclusions: In this study we suggested sofosbuvir GS-331007 metabolite plasma levels were affected by variants in the ABCB1 and HNFα genes.

Daclatasvir Plasma Levels in a Cohort of Patients with Hepatitis C Virus Infection Taking Methadone: A Prospective Analysis.

Backround: The effect of methadone (MET) during therapy with novel direct-acting antiviral agents is still not fully understood. Currently, no data are available about the influence of MET on daclatasvir (DCV) plasma levels in patients affected by chronic hepatitis C (CHC). The aim of this study was to assess the DCV plasma concentrations in patients treated with sofosbuvir (SOF) plus DCV, with or without ribavirin (RBV) and with or without MET. METHODS: In this analysis, 47 patients were included, treated consecutively with SOF + DCV ± RBV for 24 weeks, from May to October 2015; 22 (46.8%) received MET substitutive therapy. RESULTS AND CONCLUSION: We found a significant difference in DCV levels at 2 weeks and 1 month: 150 ng/mL in patients without MET and 313 ng/mL with MET at 2 weeks (p < 0.001), 149 and 279 ng/mL at 1 month (p = 0.006). DCV levels were lower in cirrhotic patients (p < 0.001); among cirrhotic patients we also evidenced higher DCV concentrations in patients receiving MET at 2 weeks, 1 and 2 months (p < 0.001, p = 0.005, and p = 0.031, respectively). In multivariate analysis, the only predictive factor associated with DCV plasma levels was the presence of MET. The reason for this increased DCV exposure is unclear; on the clinical side, we have not observed significant adverse events related to the reduction or increase of MET plasma levels. The administration of MET in patients with advanced fibrosis or cirrhosis leads to an early increase of DCV plasma level without significant clinical effects or toxicity.

Influence of ABCB11 and HNF4α genes on daclatasvir plasma concentration: preliminary pharmacogenetic data from the Kineti-C study.

Background: Daclatasvir is an inhibitor of HCV non-structural 5A protein and is a P-glycoprotein substrate. Pharmacogenetics has had a great impact on previous anti-HCV therapies, particularly considering the association of IL-28B polymorphisms with dual therapy outcome. Objectives: We investigated the association between daclatasvir plasma concentrations at 2 weeks and 1 month of therapy and genetic variants (SNPs) in genes encoding transporters and nuclear factors (ABCB1, ABCB11 and HNF4α). Patients and methods: Allelic discrimination was achieved through real-time PCR, whereas plasma concentrations were evaluated through LC-MS/MS. Results: Fifty-two patients were analysed, all enrolled in the Kineti-C study. HNF4α 975 C > G polymorphism was found to be associated with the daclatasvir plasma concentrations at 2 weeks (P = 0.009) and 1 month of therapy (P = 0.006). Linear regression analysis suggested that, at 2 weeks of therapy, age, baseline BMI and haematocrit were significant predictors of daclatasvir concentrations, whereas at 1 month of therapy ABCB111131 CC and HNF4α CG/GG genotypes were significant predictors of daclatasvir concentrations. Conclusions: These are the first and preliminary results from our clinical study focusing on daclatasvir pharmacogenetics, showing that this approach could have a role in the era of new anti-HCV therapies.

Epidemiology and Risk Factors for Nosocomial Infections in Left Ventricular Assist Device Recipients.

Left ventricular assist devices (LVADs) have been increasingly used as a valid option to improve the prognosis and reduce the symptoms of end-stage heart failure. However, long-term complications, mostly infections and coagulation disorders, are frequent. We described the epidemiology and risk factors for nosocomial infections (NIs) in a cohort of adult patients who underwent continuous-flow LVAD implant between January 2010 and December 2017 in Turin, Italy. Secondary outcomes were the prevalence of multidrug-resistant (MDR) bacteria and mortality. Results: Overall, 64 LVADs were implanted. A total of 32 (50%) patients experienced at least one episode of NI, with a total of 46 infectious events. VAD-related infections occurred in 22 patients (68.8%). Non VAD-related NIs occurred in 12 patients (37.5%), mainly low respiratory tract infections. Length of intensive care unit admission was a risk factor for NI (OR 1.224, 95%CI; 1.049, 1.429). Gram-negative bacilli were responsible for 58.8% of VAD-related infections and 79.5% of non-VAD related infections. In sixteen patients (50%), at least one episode of infection was related to an MDR strain. INTERMACS class and length of MV were independent risk factors for NIs by MDR strains (respectively, OR 2.12, 95%CI: 1.08, 6.80; p = 0.02 and OR 1.46, 95%CI: 1.07, 5.52, p = 0.047). In-hospital mortality was 6.3%. No differences in mortality were observed between infected and non-infected patients (p = 0.61) even when caused by MDR strains (p = 0.143). Conclusion: the rate of nosocomial infections in LVAD patients is associated with the length of ICU admission, and the etiology of nosocomial infection after LVAD implant is mainly due to GNB, including a high rate of MDR strains, especially KPC-KP and MDR PA.

Predictors of mortality in patients with COVID-19 infection in different health-care settings: A retrospective analysis from a CORACLE study group.

BACKGROUND: Despite the large number of hospitalized patients affected by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, few data are available about risk factors and mortality in subjects with nosocomially acquired respiratory infection of Coronavirus Disease 2019 (COVID-19). METHODS: We retrospectively evaluated in a multicentric study -during the pre-vaccination era-all patients admitted with confirmed diagnosis of nosocomial COVID-19 (NC). Patients were classified according to provenance: hospital-acquired NC or long-term care (LTC) facilities. RESULTS: Among overall 1047 patients evaluated with COVID-19, 137 had a confirmed diagnosis of NC (13%). 78 (56.9%) patients had hospital-acquired NC and 59 (43%) had LTC NC. Overall mortality was 35.8%, in hospital-acquired NC 24.4%, in LTC NC 50.8% (p < 0.001) (Log Rank test: p = 0.001). Timing of diagnosis was significantly different between hospital acquired and LTC NC (3.5 vs 10 days, p < 0.001). In multivariate analysis age, intensive-care unit admission, LTC provenance and sepsis were significant predictors of mortality in patients with NC infection. CONCLUSION: Patients with NC are at higher risk of mortality (especially for LTC NC) and required preventive strategies, early diagnosis, and treatment to avoid COVID-19 cluster.

Nosocomial Infections in Adult Patients Supported by Extracorporeal Membrane Oxygenation in a Cardiac Intensive Care Unit.

The use of venoarterial (VA) extracorporeal membrane oxygenation therapy (ECMO) in patients admitted to cardiac intensive care units (CICU) has increased. Data regarding infections in this population are scarce. In this retrospective study, we analyzed the risk factors, outcome, and predictors of in-hospital mortality due to nosocomial infections in patients with ECMO admitted to a single coronary intensive care unit between July 2013 and March 2019 treated with VA-ECMO for >48 h. From 69 patients treated with VA-ECMO >48 h, (median age 58 years), 29 (42.0%) patients developed 34 episodes of infections with an infection rate of 0.92/1000 ECMO days. The most frequent were ventilator-associated pneumonia (57.6%), tracheobronchitis (9.1%), bloodstream infections (9.1%), skin and soft tissue infections (9.1%), and cytomegalovirus reactivation (9.1%). In-hospital mortality was 47.8%, but no association with nosocomial infections was found (p = 0.75). The number of days on ECMO (OR 1.14, 95% CI 1.01-1.30, p = 0.029) and noninfectious complications were higher in the infected patients (OR: 3.8 95% CI = 1.05-14.1). A higher baseline creatinine value (OR: 8.2 95% CI = 1.12-60.2) and higher blood lactate level at 4 h after ECMO initiation (OR: 2.0 95% CI = 1.23-3.29) were significant and independent risk factors for mortality. Conclusions: Nosocomial infections in medical patients treated with VA-ECMO are very frequent, mostly Gram-negative respiratory infections. Preventive measures could play an important role for these patients.

Temocillin: Applications in Antimicrobial Stewardship as a Potential Carbapenem-Sparing Antibiotic.

Temocillin is an old antibiotic, but given its particular characteristics, it may be a suitable alternative to carbapenems for treating infections due to ESBL-producing Enterobacterales and uncomplicated UTI due to KPC-producers. In this narrative review, the main research question was to summarize current evidence on temocillin and its uses in infectious diseases. A search was run on PubMed using the terms ('Temocillin' [Mesh]) AND ('Infection' [Mesh]). Current knowledge regarding temocillin in urinary tract infection, blood-stream infections, pneumonia, intra-abdominal infections, central nervous system infections, skin and soft tissues infections, surgical sites infections and osteoarticular Infections were summarized. Temocillin retain a favourable profile on microbiota and risk of Clostridioides difficile infections and could be an option for treating outpatients. Temocillin may be a valuable tool to treat susceptible pathogens and for which a carbapenem could be spared. Other advantages in temocillin use are that it is well-tolerated; it is associated with a low rate of C. difficile infections; it is active against ESBL, AmpC, and KPC-producing Enterobacterales; and it can be used in the OPAT clinical setting.

Beta Lactams Plus Daptomycin Combination Therapy for Infective Endocarditis: An Italian National Survey (BADAS).

BACKGROUND: infective endocarditis (IE) remains a severe disease frequently encountered in clinical practice and often requiring interdisciplinary medical and surgical management. This national survey aims to describe the clinical prescribing habits of the use of daptomycin in the setting of IE and the possible role for combination therapy with beta-lactams. METHODS: The study was a cross-sectional internet-based questionnaire survey on therapy with daptomycin. The questionnaire was designed with closed-ended questions and distributed using the SurveyMonkey® platform between October 2019 to December 2020. RESULTS: 55 clinicians from twelve Italians regions joined the questionnaire. The survey reported use of daptomycin as first-line choice in 31.48% of cases and as the first-line anti-MRSA agent in 44.44%. The empiric use of daptomycin was stated in the high suspicion of MRSA rather than MSSA, enterococcal or streptococcal IE. The rationale of daptomycin for the empirical treatment of native and prosthetic valve IE was mostly the possibility of administering an aminoglycoside-sparing combination regimen, high bacterial killing rate and high clinical efficacy. CONCLUSIONS: In conclusion, in selected patients, daptomycin could be a feasible option for the treatment of infective endocarditis in line with data from the European registry of daptomycin.

Clinical and microbiological characteristics of bloodstream infections caused by Enterococcus spp. within internal medicine wards: a two-year single-centre experience.

Enterococcal bloodstream infections (E-BSI) constitute the second cause of Gram-positive bacterial BSI in Europe with a high rate of in-hospital mortality. Furthermore, E-BSI treatment is still challenging because of intrinsic and acquired antibiotic resistances. We conducted a retrospective, 2-year, observational, single-centre study to evaluate clinical outcome and risk factors for E-BSI mortality in internal medicine wards. 201patients with E-BSI were included in the analysis. Infection rate was 2.4/1000 days of hospital admission. Most E-BSI were hospital acquired (78.1%). The median age was 68 years. Charlson Comorbidity Index, adjusted for age, was 5 (range 4-6). Patients with E-BSI frequently had at least one invasive device, predominantly a central venous (73%) or a bladder catheter (61.7%). Enterococcus faecium accounted for 47.94% of E-BSI (resistance rate to ampicillin or vancomycin was 22.2 and 23.3%, respectively) and Enterococcus faecalis for 52.08% (resistance rate to ampicillin or vancomycin was 3.1 and 2.2%, respectively). Among all E-BSI, 25% of patients received appropriate therapy. In total, 59% of E-BSI underwent echocardiography. At the multivariate analysis, resistance to vancomycin (OR 2.09, p = 0.025), sepsis (OR 2.57, p = 0.003) and septic shock (OR 3.82, p = 0.004) was a predictor of mortality. No difference in 28-day survival was observed between appropriate or inappropriate treatment, except for endocarditis. However, E-BSI sources in clinical practices are not always properly investigated, including the rule-out of intracardiac vegetations. We did not demonstrate a difference in mortality for inappropriate therapy in the absence of endocarditis in comorbid patients with a long history of medicalization.

Meropenem/Vaborbactam and Cefiderocol as Combination or Monotherapy to Treat Multi-Drug Resistant Gram-Negative Infections: A Regional Cross-Sectional Survey from Piedmont Infectious Disease Unit Network (PIDUN).

Meropenem/vaborbactam (MV) and cefiderocol were recently approved by the Food and Drug Administration and European Medicines Agency and are among the most promising antibacterial in treatment regimens against multi-drug resistant (MDR) gram-negative bacilli. A survey with close-ended questions was proposed to infectious disease (ID) and intensive care unit (ICU) physicians of Piedmont and Valle d'Aosta Region's hospitals. The aim was to collect data about habits and prescriptions of cefiderocol and MV. Twenty-three physicians (11 ID specialists and 12 anesthesiologists) in 13 Italian hospitals took part in the survey. Both cefiderocol and MV were mostly used as target therapy after a previous treatment failure and after ID specialist consult. The most frequent MDR pathogen in hospitals was Klebsiella pneumoniae carbapenemase-producing bacteria (KPC), followed by P. aeruginosa and A. baumannii. MDRs were more frequently isolated in ICU. In conclusion, cefiderocol was used in empiric regimens when A.baumannii was suspected, while MV was more used in suspect of KPC. MV and cefiderocol can be the first option in empiric treatment for critically ill patients in settings with high risk of MDR. The treatment should then be followed by rapid de-escalation when microbiological results are available.

Pharmacokinetic of Cefiderocol in Critically Ill Patients Receiving Renal Replacement Therapy: A Case Series.

Background: Cefiderocol is a novel parenteral siderophore cephalosporin, demonstrating enhanced activity against multidrug-resistant (MDR) Gram-negative bacteria and difficult-to-treat Acinetobacter baumannii (DTR-AB). Plasma-free trough concentration (fCtrough) over the minimum inhibitory concentration (MIC) was reported as the best pharmacokinetic parameter to describe the microbiological efficacy of cefiderocol. Materials and methods: We retrospectively described the pharmacokinetic and pharmacodynamic profile of three critically ill patients admitted to the intensive care unit, receiving cefiderocol under compassionate use to treat severe DTR-AB infections while undergoing continuous venovenous haemofiltration. Cefiderocol was administrated at a dosage of 2 g every 8 h infused over 3 h. Therapeutic drug monitoring (TDM) was assessed at the steady state. Cthrough was evaluated by assuming a plasma protein binding of 58.0%. The fCmin/MIC was calculated assuming a cefiderocol MIC equal to the PK-PD breakpoint of susceptibility ≤ 2. The association between the PK/PD parameters and microbiological outcome was assessed. Results: fCtrough/MIC were >12 in 2 patients and 2.9 in the 1 who rapidly recovered from renal failure. Microbiological cure occurred in 3/3 of patients. None of the 3 patients died within 30 days. Conclusions: A cefiderocol dosage of 2 g q8 h in critically ill patients with AKI undergoing CVVH may bring about a very high plasma concentration, corresponding to essentially 100% free time over the MIC for DTR-AB.

Ten Years of KPC-Kp Bloodstream Infections Experience: Impact of Early Appropriate Empirical Therapy on Mortality.

Background. In K. pneumoniae KPC (KPC-Kp) bloodstream infections (BSI), INCREMENT CPE score >7, Charlson Comorbidity Index (CCI) ≥3 and septic shock are recognized predictors of mortality, with a possible beneficial effect of combination therapy in seriously ill patients. Materials and Methods. We conducted a ten-year retrospective study including all KPC-Kp BSI in patients ≥18 years of age with the aim to evaluate the characteristics and impact of appropriate empirical therapy, either monotherapy or combination therapy, and targeted therapy on mortality. Appropriate therapy was defined as at least one active antimicrobial agent with in vitro activity against KPC-kp demonstrated by susceptibility testing, administered within 48 h from blood culture collection. Results. The median age of the 435 analyzed patients was 66.09 years (IQR 54.87−73.98). The median CCI was 4. KPC-Kp colonization was present in 324 patients (74.48%). The probable origin of the KPC-Kp BSI was not identified in 136 patients (31.26%), whereas in 120 (27.59%) patients, it was CVC-related, and in 118 (27.13%), it was respiratory. Source control was achieved in 87 patients (72.5%) with CVC-related KPC-Kp BSI. The twenty-eight-day survival was 70.45% for empirical monotherapy, 63.88% for empirical combination therapy and 57.05% for targeted therapy (p = 0.0399). A probable source of KPC-Kp BSI other than urinary, CVC or abdominal [aHR 1.64 (IC 1.15−2.34) p = 0.006] and deferred targeted therapy [HR 1.67 (IC 1.12−2.51), p= 0.013] emerged as predictors of mortality, whereas source control [HR 0.62 (IC 0.44−0.86), p = 0.005] and ceftazidime/avibactam administration in empirical therapy [aHR 0.37 (IC 0.20−0.68) p = 0.002] appeared as protective factors. Discussion. These data underline the importance of source control together with timing appropriateness in the early start of empirical therapy over the choice of monotherapy or combination therapy and the use of ceftazidime/avibactam against KPC-Kp BSI.

The Diagnostic Relevance of ß-D-Glucan for Candidemia within Internal Medicine Wards.

Candidemia diagnosis is based on the combination of clinical, microbiological and laboratory data. We aimed to evaluate performances and accuracy of (1,3)-ß-D-glucan (BDG) at various cut-offs in internal medicine patients. An observational retrospective−prospective study was performed. Patients with at least two determinations of BDG and paired, associated blood cultures within ±48 h were considered. A total of 140 patients were included: 26 with Candida spp. blood-stream infections (BSI) and 114 without candidemia. Patients with candidemia were older and had higher BDG values, need of parenteral nutrition, higher colonization by Candida in more than one site, presence of percutaneous gastrostomy and higher Candida or Charlson scores. BDG maintained the best compromise between sensitivity, specificity and optimal negative predictive value was 150 pg/mL. BDG values at cut-off of 150 pg/mL increase the strength of association between BDG and development of candidemia (Odds Ratio­OR 5.58; CI 2.48−12.53 vs. OR 1.06; CI 1.003−1.008). Analyzing BDG > 150 pg/mL along with Candida score > 2 and Charlson score > 4, the strength of the association amongst BDG, clinical scores and development of candidemia is increased. The overall clinical evaluation with the help of scores that consider BDG values > 150 pg/mL, Candida score > 2 and Charlson score > 4 in combination seems to predict better the need of antifungal empiric treatment.

Testosterone as a Biomarker of Adverse Clinical Outcomes in SARS-CoV-2 Pneumonia.

Background: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may affect testicles. Lower testosterone levels have been associated with worse clinical outcomes and higher mortality. Our objective was to evaluate the hypothalamic−pituitary−gonadal axis of men admitted with SARS-CoV-2 pneumonia and its link with the pneumonia-treatment intensification. Short-term changes in hormonal parameters were also assessed. Methods: Men admitted with SARS-CoV-2 pneumonia were recruited in two different hospitals in Piedmont, Italy. In all patients, the assessment of total testosterone (TT), calculated free testosterone (cFT), gonadotropins, inhibin B (InhB), and other biochemical evaluations were performed at admission (T0) and before discharge (T1). Through a review of medical records, clinical history was recorded, including data on pneumonia severity. Results: Thirty-five men (median age 64 [58−74] years) were recruited. Lower TT and cFT levels at T0 were associated with CPAP therapy (p = 0.045 and 0.028, respectively), even after adjusting for age and PaO2/FIO2 ratio in a multivariable analysis. In those discharged alive, lower TT and cFT levels were associated with longer hospital stay (p < 0.01). TT, cFT, and InhB were below the normal range at T0 and significantly increased at T1 (TT 1.98 [1.30−2.72] vs. 2.53 [1.28−3.37] ng/mL, p = 0.038; cFT (0.0441 [0.0256−0.0742] vs. 0.0702 [0.0314−0.0778] ng/mL, p = 0.046; InhB 60.75 [25.35−88.02] vs. 77.05 [51.15−134.50], p < 0.01). Conclusions: Both TT and cFT levels are associated with adverse clinical outcomes in men admitted with SARS-CoV-2 pneumonia. As TT, cFT and InhB levels increase before discharge, short-term functional recovery of steroidogenesis and an indirect improvement of spermatozoa functional status could be hypothesized.

Factors Influencing the Intracellular Concentrations of the Sofosbuvir Metabolite GS-331007 (in PBMCs) at 30 Days of Therapy.

Sofosbuvir (SOF) is an HCV NS5B polymerase inhibitor, and GS-331007 is its major metabolite. The aim of this study was to investigate whether clinical and pharmacological factors could influence GS-331007 intracellular (IC) concentrations in peripheral blood mononuclear cells (PBMCs) associated with a sustained virological response in patients treated with SOF and ribavirin (RBV). Drug levels were analyzed using liquid chromatography at different days of therapy, whereas variants in genes encoding transporters and nuclear factors were investigated using real-time PCR. This study enrolled 245 patients treated with SOF; 245 samples were analyzed for pharmacogenetics and 50 were analyzed for IC pharmacokinetics. The GS-331007 IC concentration at 30 days was associated with its plasma concentration determinate at 30, 60 and 90 days of SOF-therapy and with daclatasvir concentrations at 7 days of therapy. No genetic polymorphism affected IC exposure. In linear multivariate analysis, ledipasvir treatment, baseline albumin and estimated glomerular filtration rate were significant predictors of IC exposure. This study presents data on an IC evaluation in a cohort of patients treated with SOF, also considering pharmacogenetics. These results could be useful for regions where SOF-RBV treatment is considered the standard of care; moreover, they could further deepen the knowledge of IC exposure for similar drugs in the future.

Antibiotic De-escalation Experience in the Setting of Emergency Department: A Retrospective, Observational Study.

BACKGROUND: Antimicrobial de-escalation (ADE) is a part of antimicrobial stewardship strategies aiming to minimize unnecessary or inappropriate antibiotic exposure to decrease the rate of antimicrobial resistance. Information regarding the effectiveness and safety of ADE in the setting of emergency medicine wards (EMW) is lacking. METHODS: Adult patients admitted to EMW and receiving empiric antimicrobial treatment were retrospectively studied. The primary outcome was the rate and timing of ADE. Secondary outcomes included factors associated with early ADE, length of stay, and in-hospital mortality. RESULTS: A total of 336 patients were studied. An initial regimen combining two agents was prescribed in 54.8%. Ureidopenicillins and carbapenems were the most frequently empiric treatment prescribed (25.1% and 13.6%). The rate of the appropriateness of prescribing was 58.3%. De-escalation was performed in 111 (33%) patients. Patients received a successful de-escalation on day 2 (21%), 3 (23%), and 5 (56%). The overall in-hospital mortality was 21%, and it was significantly lower among the de-escalation group than the continuation group (16% vs 25% p = 0.003). In multivariate analysis, de-escalation strategies as well as appropriate empiric and targeted therapy were associated with reduced mortality. CONCLUSIONS: ADE appears safe and effective in the setting of EMWs despite that further research is warranted to confirm these findings.

The Manifesto of Pharmacoenosis: Merging HIV Pharmacology into Pathocoenosis and Syndemics in Developing Countries.

Pathocoenosis and syndemics theories have emerged in the last decades meeting the frequent need of better understanding interconnections and reciprocal influences that coexistent communicable and non-communicable diseases play in a specific population. Nevertheless, the attention to pharmacokinetic and pharmacodynamics interactions of co-administered drugs for co-present diseases is to date limitedly paid to alert against detrimental pharmacological combos. Low and middle-income countries are plagued by the highest burden of HIV, tuberculosis, malaria, and helminthiasis, and they are experiencing an alarming rise in non-communicable disorders. In these settings, co-infections and comorbidities are common, but no tailored prescribing nor clinical trials are used to assess and exploit existing opportunities for the simultaneous and potentially synergistic treatment of intertwined diseases. Pharmacoenosis is the set of interactions that take place within a host as well as within a population due to the compresence of two or more diseases and their respective treatments. This framework should pilot integrated health programmes and routine clinical practice to face drug-drug interaction issues, avoiding negative co-administrations but also exploiting potential favourable ones to make the best out of the worst situations; still, to date, guiding data on the latter possibility is limited. Therefore, in this narrative review, we have briefly described both detrimental and favourable physiopathological interactions between HIV and other common co-occurring pathologies (malaria, tuberculosis, helminths, and cardiovascular disorders), and we have presented examples of advantageous potential pharmacological interactions among the drugs prescribed for these diseases from a pharmacokinetics, pharmacodynamics, and pharmacogenetics standpoint.