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Background: Invasive mechanical ventilation is the treatment of choice in COVID-19 patients when hypoxemia persists, despite maximum conventional oxygen administration. Some frail patients with severe hypoxemic respiratory failure are deemed not eligible for invasive mechanical ventilation. Objectives: To investigate whether High-flow nasal cannula (HFNC) in the wards could serve as a rescue therapy in these frail patients. Methods: This retrospective cohort study included frail COVID-19 patients admitted to the hospital between March 9th and May 1st 2020. HFNC therapy was started in the wards. The primary endpoint was the survival rate at hospital discharge. Results: Thirty-two patients with a median age of 79.0 years (74.5–83.0) and a Clinical Frailty Score of 4 out of 9 (3–6) were included. Only 6% reported HFNC tolerability issues. The overall survival rate was 25% at hospital discharge. Conclusions: This study suggests that, when preferred, HFNC in the wards could be a potential rescue therapy for respiratory failure in vulnerable COVID-19 patients.

Hypercoagulation is one of the most distinct prognostic factors of patients with COVID-19 and has been associated with arterial thrombosis and other venous thrombotic events (VTE). Bleeding complications are far less encountered. The International Society on Thrombosis and Haemostasis (ISTH) guidance advises giving prophylactic low-molecular-weight heparin (LMWH) to prevent these events, although there is evidence that the incidence remains high despite using prophylactic LMWH. We describe three cases of COVID-19 pneumonia that were admitted to our intensive care unit (ICU) and developed acute pulmonary embolisms (APE) despite high dosage prophylactic LMWH. These cases raise concerns about using prophylactic LMWH instead of therapeutic anticoagulation in severe and critically COVID-19 patients., Highlights • Hypercoagulation is one of the most distinct prognostic factors in COVID-19. • Despite prophylactic LMWH COVID-19 patients develop thrombotic complications. • Immune-thrombosis is a potential mechanism contributing to thrombotic complications.

Structured abstract for full paperBackgroundAfter recovery from COVID-19, most patients have anti-SARS-CoV-2 neutralizing antibodies. Their convalescent plasma could be an inexpensive and widely available treatment for COVID-19.MethodsThe Convalescent-plasma-for-COVID (ConCOVID) study was a randomized trial comparing convalescent plasma with standard of care therapy in patients hospitalized for COVID-19 in the Netherlands. Patients were randomized 1:1 and received 300ml of plasma with anti-SARS-CoV-2 neutralizing antibody titers of at least 1:80. The primary endpoint was day-60 mortality and key secondary endpoints were hospital stay and WHO 8-point disease severity scale improvement on day 15.ResultsThe trial was halted prematurely after 86 patients were enrolled. Although symptomatic for only 10 days (IQR 6-15) at the time of inclusion, 53 of 66 patients tested had anti-SARS-CoV-2 antibodies at baseline. A SARS-CoV-2 plaque reduction neutralization test showed neutralizing antibodies in 44 of the 56 (79%) patients tested with median titers comparable to the 115 donors (1:160 vs 1:160, p=0.40). These observations caused concerns about the potential benefit of convalescent plasma in the study population and after discussion with the data safety monitoring board, the study was discontinued. No difference in mortality (p=0.95), hospital stay (p=0.68) or day-15 disease severity (p=0.58) was observed between plasma treated patients and patients on standard of care.ConclusionMost COVID-19 patients already have high neutralizing antibody titers at hospital admission. Screening for antibodies and prioritizing convalescent plasma to risk groups with recent symptom onset will be key to identify patients that may benefit from convalescent plasma. Clinicaltrials.gov:NCT04342182

Background: In the Netherlands, access to direct-acting antivirals (DAA) against hepatitis C virus (HCV) infection has been unrestricted for chronic infection since 2015. We evaluated whether this changed the nationwide incidence of HCV primary and re-infection among HIV-positive individuals. Methods: Individuals participating in the national ATHENA HIV cohort between 2000-2018 were included. Incidence rates (IR) of HCV primary infection and re-infection were calculated per calendar year using piecewise exponential survival models. Findings: Among 22,775 individuals without prior HCV, 651 cases of HCV primary infection were documented (IR=2·9/1,000 person-years, 95%CI=2·7-3·1). The highest IR was observed in men who have sex with men (MSM) (4·5/1,000 person-years, 95%CI=4·1-4·8) and much lower among people who inject drugs (PWID) (0·8/1,000 person-years, 95%CI=0·4-1·6) and other transmission groups (0·2/1,000 person-years, 95%CI=0·1-0·4). In MSM, IR increased dramatically in 2007 (IR=8·3/1,000 person-years) and fluctuated between 4·6 and 8·6/1,000 person-years from 2008-2015. In 2016, IR declined to 2·6 cases/1,000 person-years and remained steady in 2017 and 2018 (IR=2·8 and 1·7/1,000 person-years, respectively). Among 1917 individuals with a previous HCV infection, 249 HCV re-infections were documented (IR=26·0/1,000 person-years, 95%CI=23·0-29·5). The highest IR was again observed in MSM (38·4/1,000 person-years, 95%CI=33·6-44·0) and was lower among PWID (5·5/1,000 person-years, 95%CI=2·1-14·6) and other transmission groups (9·5/1,000 person-years, 95%CI=6·7-13·5). In MSM, re-infection IRs fluctuated until 2015, reaching 51·4/1,000 person-years. In 2016, re-infection incidence declined to 37·0/1,000 person-years, followed by a further decrease in 2017 and 2018 (IR=25·1 and 15·1/1,000 person-years, respectively). Interpretation: The observed sharp decline in HCV incidence among HIV-positive MSM shortly after unrestricted DAA access suggests a “treatment-as-prevention” effect. HCV incidence was already low in PWID and other groups prior to unrestricted access. Ongoing HCV transmission is occurring in MSM, as illustrated by a declining but nonetheless high rate of reinfection, stressing the need for additional preventive measures. Funding: Dutch Ministry of Health, Welfare and Sport Conflict of Interest: BJAR reports grants from MSD and Gilead, all outside the submitted work; he hasparticipated in advisory boards organized by MSD, Gilead, Pfizer, ViiV Healthcare, Jansen Cilag, and Abbvie. EMM reports participating an advisory board of Gilead. WB reports other funds from GSK and non-financial support from Janssen, all outside the submitted work. KB reports participating in advisory boards of ViiV, Gilead, MSD and Janssen; he has received research grants form ViiV and Gilead. JS reports grants from Gilead Sciences, outside the submitted work. MP reports grants, personal fees and other funds from Gilead Sciences,Roche, MSD and Abbvie, all outside the submitted work. JA reports other funding fromGilead Sciences, Janssen-Cilag, Abbvie, BSM, and MSD, all outside the submitted work.MvdV reports grants and personal fees from Abbvie, Gilead, Johnson & Johnson, MSD, ViiV Healthcare, all outside the submitted work. All other authors report no conflicts of interest. PR reports grants from Gilead Sciences, ViiV Healthcare, and Merck & Co, and other funds from Gilead Sciences, ViiV Healthcare, Merck & Co, and Teva Pharmaceutical Industries, alloutside the submitted work. Ethical Approval: At its inception, the ATHENA cohort was approved by the institutional review boards of all participating centres. Individuals can opt out after being informed by their treating physician of the purpose of data and sample collection. Data are pseudonymized and made available to investigators in a coded form. Coded data may be used for scientific purposes without further consent. For the purpose of our analysis, only existing data have been used and therefore no additional review or consent was required.

Objectives: Voriconazole, like all other antifungals of the azole group, is potentially hepatotoxic. A large interpatient variability of liver enzyme elevations during oral or intravenous (iv) voriconazole administration is observed. This interpatient variability may be explained by differences in voriconazole metabolism because of cytochrome P450 polymorphisms. We examined the relationship between cytochrome P450 polymorphisms and hepatotoxicity in immunocompromised patients predominantly receiving oral formulations of voriconazole. Methods: In a single institution retrospective study of 86 immunocompromised patients receiving oral (n 5 74) or iv (n 5 12) voriconazole, we studied the influence of cytochrome P450 polymorphisms (CYP2C19, CYP2C9 and CYP3A5) on the maximum bilirubin and serum liver enzyme levels [alkaline phosphatase, gamma-glutamyl transpeptidase (GGT), serum aspartate aminotransferase and serum alanine aminotransferase] and their respective common toxicity criteria scores (CTC-scores). Results: Median serum bilirubin as well as the level of all other liver enzymes increased during voriconazole treatment. A decline in CTC-score was observed in zero (0%) to six (7%) patients; an increase in CTC-score was demonstrated in 36 (42%) to 54 (63%) patients. No statistically significant differences in maximum value or maximum increase of liver enzymes or CTC-score in relation to cytochrome P450 polymorphisms were observed. Only a trend towards higher maximum CTC-score of GGT for wild-type of CYP2C9 was observed (P 5 0.046). Conclusions: No significant relationship between CYP2C9, CYP2C19 or CYP3A5 polymorphisms and serum liver enzyme levels was observed in patients treated with voriconazole.

Summary Objective Renal function is profoundly influenced by thyroid status; however, this has not been studied in detail in human subjects. The purpose of the present study was to determine the relationship between renal function and thyroid status before and after treatment for hypothyroidism and hyperthyroidism, respectively. Design and patients In 37 consecutive hypothyroid and 14 hyperthyroid patients renal function as measured by plasma creatinine and glomerular filtration rate (GFR) [based on the modification of diet in renal disease (MDRD) formula] was determined before treatment and after regaining euthyroidism. Results Renal function improved significantly during treatment of hypothyroidism and decreased during treatment of hyperthyroidism. There was a strong correlation between the change in thyroid status determined as the ratio log10(fT4 post-treatment/fT4 pretreatment) and the change in renal function as a result of therapy expressed as serum creatinine (r2 = 0·81, P

The purpose of this study was to describe the nonlinear pharmacokinetics of piperacillin observed during intermittent infusion and continuous infusion by using a nonparametric population modeling approach. Data were 120 serum piperacillin concentration measurements from eight adult cystic fibrosis (CF) patients. Individual pharmacokinetic parameter estimates during intermittent infusion or continuous infusion were calculated by noncompartmental analysis and with a maximum iterative two-stage Bayesian estimator. To simultaneously describe concentration-time data during intermittent infusion and continuous infusion, nonlinear models were parameterized as two-compartment Michaelis-Menten models. Models were fit to the data with the nonparametric expectation maximization algorithm. The calculations were executed on a remote supercomputer. Nonlinear models were evaluated by log-likelihood estimates, residual plots, and R 2 values, and predictive performance was based on bias (mean weighted error [MWE]) and precision (mean weighted square error [MWSE]). A linear pharmacokinetic model could not describe combined intermittent infusion and continuous infusion data well. A good population model fit to the intermittent infusion and continuous infusion data was obtained with the constructed nonlinear models. Maximum a posteriori probability (MAP) Bayesian R 2 values for the nonlinear models were 0.96 to 0.97. Median parameter estimates for the best nonlinear model were as follows: K m , 58 ± 75 mg/liter (mean and standard deviation); V max , 1,904 ± 1,009 mg/h; volume of distribution of the central compartment, 14.1 ± 3.0 liters; k 12 , 0.63 ± 0.41 h −1 ; and k 21 , 0.37 ± 0.19 h −1 . The median bias (MWE) and precision (MWSE) values for MAP Bayesian estimation with the Michaelis-Menten model were 0.05 and 4.6 mg/liters, respectively. The developed nonlinear pharmacokinetic models can be used to optimize piperacillin therapy administered via continuous infusion in patients with CF and have distinct advantages over conventional linear models.

Antimicrobial agents may interact synergistically when both drugs are present at the infected site for an adequate period of time at sufficient concentrations. Generally speaking, the agents in the combination show different tissue distributions and pharmacokinetics. By co-encapsulation of the drugs in a drug carrier, like liposomes, parallel tissue distributions of both drugs may be ensured and drug concentrations at the site of infection may be increased. In this presentation therapeutic efficacy of liposome-co-encapsulated gentamicin (GN) and ceftazidime (CZ) will be shown in a GN-CZ-susceptible and GN-CZ-resistant Klebsiella pneumoniae-pneumonia in rats.

Combination therapy with antimicrobial agents can be used against bacteria that have reduced susceptibilities to single agents. We studied various tobramycin and ceftazidime dosing regimens against four resistant Pseudomonas aeruginosa strains in an in vitro pharmacokinetic model to determine the usability of combination therapy for the treatment of infections due to resistant bacterial strains. For the selection of an optimal dosing regimen it is necessary to determine which pharmacodynamic parameter best predicts efficacy during combination therapy and to find a simple method for susceptibility testing. An easy-to-use, previously described E-test method was evaluated as a test for susceptibility to combination therapy. That test resulted in a MIC combi , which is the MIC of, for example, tobramycin in the presence of ceftazidime. By dividing the tobramycin and ceftazidime concentration by the MIC combi at each time point during the dosing interval, fractional inhibitory concentration (FIC) curves were constructed, and from these curves new pharmacodynamic parameters for combination therapy were calculated (i.e., AUC combi , C max-combi , T >MIC-combi , and T >FICi , where AUC combi , C max-combi , T >MIC-combi , and T >FICi are the area under the FIC combi curve, the peak concentration of FIC combi , the time that the concentration of the combination is above the MIC combi , and the time above the FIC index, respectively). By stepwise multilinear regression analysis, the pharmacodynamic parameter T >FICi proved to be the best predictor of therapeutic efficacy during combination therapy with tobramycin and ceftazidime ( R 2 = 0.6821; P < 0.01). We conclude that for combination therapy with tobramycin and ceftazidime the T >FICi is the parameter best predictive of efficacy and that the E-test for susceptibility testing of combination therapy gives promising results. These new pharmacodynamic parameters for combination therapy promise to provide better insight into the rationale behind combination therapy.

The influence of half-life on the postantibiotic effect (PAE) of tobramycin against Pseudomonas aeruginosa and Staphylococcus aureus was investigated during one dosing interval. Tobramycin half-lives of 0.5 to 2.5 h were simulated in an in vitro model, and the PAE was determined by an enzymatic inactivation method at different time points, i.e., when the tobramycin concentrations were 20×, 5×, and 1× the MIC. At the time point during therapy when the tobramycin concentrations had declined to 1× the MIC, at a tobramycin half-life of 0.5 h, the times of the PAEs were approximately 0.7 and 1.7 h for P. aeruginosa and S. aureus , respectively, and the PAE disappeared completely at half-lives corresponding to those found in humans (i.e., 2 to 2.5 h). The PAE itself cannot be fully explained by the presence of free intrabacterial tobramycin or the emergence of resistant subpopulations. The explanation for the disappearance of the PAE during the dosing interval may therefore be explained by the repair of sublethal damage. Since the standard method of determining the PAE in animal models is somewhat different from the method used for measurement of the PAE in vitro, the conditions under which the PAE is measured in vivo were also simulated in the in vitro model. This resulted in PAEs longer than those found by the standard method of obtaining in vitro PAE measurements. We conclude that the PAE of tobramycin, as determined by conventional in vitro methods, has virtually no clinical importance. PAEs determined in vivo may have some clinical relevance, but they are probably primarily caused by sub-MIC effects.

Contains fulltext : 167321.PDF (Publisher’s version ) (Open Access) BACKGROUND: Approval of drugs in chronic hepatitis C is supported by registration trials. These trials might have limited generalizability through use of strict eligibility criteria. We compared effectiveness and safety of real world hepatitis C patients eligible and ineligible for registration trials. METHODS: We performed a nationwide, multicenter, retrospective cohort study of chronic hepatitis C patients treated in the real world. We applied a combined set of inclusion and exclusion criteria of registration trials to our cohort to determine eligibility. We compared effectiveness and safety in eligible vs. ineligible patients, and performed sensitivity analyses with strict criteria. Further, we used log binomial regression to assess relative risks of criteria on outcomes. RESULTS: In this cohort (n = 467) 47% of patients would have been ineligible for registration trials. Main exclusion criteria were related to hepatic decompensation and co-morbidity (cardiac disease, anemia, malignancy and neutropenia), and were associated with an increased risk for serious adverse events (RR 1.45-2.31). Ineligible patients developed significantly more serious adverse events than eligible patients (27% vs. 11%, p< 0.001). Effectiveness was decreased if strict criteria were used. CONCLUSIONS: Nearly half of real world hepatitis C patients would have been excluded from registration trials, and these patients are at increased risk to develop serious adverse events. Hepatic decompensation and co-morbidity were important exclusion criteria, and were related to toxicity. Therefore, new drugs should also be studied in these patients, to genuinely assess benefits and risk of therapy in the real world population.

Background. In human immunodeficiency virus (HIV)-infected patients, the immunogenicity of hepatitis B vaccines is impaired. The primary and secondary aims of our study were to investigate the effectiveness and compliance of 2 different vaccination regimen in an HIV-infected population. Methods. A noninferiority trial with a 10% response margin was designed. Included were patients >= 18 years old, with negative HBsAg/anti-HBc serology, and not previously vaccinated against hepatitis B. Patients were stratified according to CD4(+) cell count: 500. Participants received 10 mu g HBvaxPRO intramuscularly according to a 0-1-3 week schedule or the standard 0-4-24 week schedule. Anti-HBs levels were measured at week 28, considered protective >= 10 IU/L. Results. Modified intention to treat analysis in 761 patients was performed. Overall response difference was 50%(standard arm) versus 38.7% (accelerated arm) =11.3% (95% confidence interval [CI], [4.3, 18.3]), close to the 10% response margin. In CD4(+) cell count group 200-500 cells/mm(3), the response difference was 20.8% (95% CI [10.9, 30.7]). However, the response difference in CD4(+) cell count group >500 cells/mm(3) was -1.8% (95% CI [-13.4,+9.7]). Compliance was significantly superior with the accelerated schedule, 91.8% versus 82.7% (P 500 cells/mm(3).

In 2002 a 73-year-old woman (non-smoking, medical history of allergic rhinitis) was referred to a rheumatologist because of synovitis of the metacarpophalangeal and proximal interphalangeal joints of both hands which had slowly developed over 3 months. Late-onset rheumatoid arthritis was suspected. Morning stiffness, rheumatoid nodules, erosions of cartilage or bone, rheumatoid factor and antibodies to cyclic citrullinated peptides were absent. Prednisone (2.5–5 mg daily) and non-steroidal anti-inflammatory drugs were started. In 2004 she was referred …

Objectives: Absorption of oral voriconazole is good and in contrast to the intravenous (iv) formulation it can be given in patients with renal insufficiency. Furthermore, the acquisition costs are significantly lower. The aim of this study was to compare the incidence of hepatotoxicity in patients treated with the oral formulation of voriconazole with that in patients treated with the iv formulation. Methods: This was a retrospective observational study. A total of 35 patients with haematological disease and an invasive fungal infection were treated with oral voriconazole during the entire regimen. We compared the incidence of hepatotoxicity with that in 11 patients treated intravenously during the first week. Results: The incidence of increased liver enzymes was comparable between both groups. Voriconazole was discontinued in two patients in the oral group and one patient in the iv group because of hepatotoxicity. The incidence of liver enzyme elevations in the entire study cohort of 46 patients was higher than that previously reported in a comparable study population (P < 0.001). However, clinically significant hepatotoxicity was infrequently observed (3/46 or 6.5%). Conclusions: In 35 patients with invasive fungal infections we instituted oral voriconazole therapy from day 1 and found an incidence of hepatotoxicity comparable to 11 controls treated intravenously.

Objective An acute hepatitis C virus (HCV) infection in an HIV-positive man who had sex with men (MSM) was notified. In the period of his seroconversion he was also diagnosed with a rectal lymphogranuloma venereum (LGV) infection, and was part of a cluster of 15 LGV cases in 2003. Our aim was to investigate HCV transmission and to search for potential spread among sexual contacts and known LGV patients. Methods Our case series included the index, two recent contacts, and 14 LGV cases. They were interviewed about parenteral exposure for HCV, history of sexually transmitted diseases(STDs), sexual behaviour and drug use. Laboratory investigations included anti-HCV antibodies, HCV-polymerase chain reaction, and HCV genotyping. Results Seven out of 17 MSM recently seroconverted for HCV (41%). Three genotypes were found. Parenteral risk factors were excluded. Six out of seven had LGV proctitis coinciding with HCV seroconversion, six (86%) were HIV infected. Unprotected anal contact was practised by both HCV uninfected and infected cases. Unprotected active and passive fisting was reported by all seven HCV infected men, compared with two of nine uninfected men (P = 0.003). Non-intravenous drug use during sexual activities was common among all MSM. Numerous, often anonymous, sexual contacts in various European countries were reported. Conclusions A cluster of acute HCV infection is reported among mostly HIV-positive MSM, with multiple partners throughout Europe. Sexual techniques potentially leading to mucosal damage (fisting), concomitant STDs such as LGV and drug use seem facilitating factors for spread. Extensive case finding and partner tracing is advocated as well as targeted prevention messages.

In this study, we determined the efficacy of various dosing regimens for erythromycin and azithromycin against four pneumococci with different susceptibilities to penicillin in an in vitro pharmacokinetic model and in a mouse peritonitis model. The MIC was 0.03 μg/ml, and the 50% effective doses (determined after one dose) of both drugs were comparable for the four pneumococcal strains and were in the range of 1.83 to 6.22 mg/kg. Dosing experiments with mice, using regimens for azithromycin of one to eight doses/6 h, showed the one-dose regimen to give the best result; of the pharmacodynamic parameters tested (the maximum drug concentration in serum [ C max ], the times that the drug concentration in serum remained above the MIC and above the concentration required for maximum killing, and the area under the concentration time curve), C max was the best predictor of outcome. The bacterial counts in mouse blood or peritoneal fluid during the first 24 h after challenge were not correlated to survival of the mice. The serum concentration profiles obtained with mice for the different dosing regimens were simulated in the in vitro pharmacokinetic model. Here as well, the one-dose regimen of azithromycin showed the best result. However, the killing curves in vivo in mouse blood and peritoneal fluid and in the vitro pharmacokinetic model were not similar. The in vitro killing curves showed a decrease of 2 log 10 within 2 and 3 h for azithromycin and erythromycin, respectively, whereas the in vivo killing curves showed a bacteriostatic effect for both drugs. It is concluded that the results in terms of predictive pharmacodynamic parameters are comparable for the in vitro and in vivo models and that high initial concentrations of azithromycin favor a good outcome.

In the recent literature, cystatin C has been advocated as a new and more accurate estimate of glomerular filtration rate (GFR) (1). Cystatin C is a 13-kDa endogenous cysteine proteinase inhibitor produced by all nucleated cells at a constant rate and broken down completely in the renal tubuli (2). Cystatin C concentrations are independent of age and body weight, and there is no need for urine collection for clearance estimations. Furthermore, serum concentrations of cystatin C are not influenced by malignancy or inflammation. In contrast, the often-used serum creatinine concentration is supposedly influenced by dietary intake, renal tubular metabolism, age, and variations in muscle mass. There are also various analytical difficulties with the widely used Jaffe colorimetric assay for creatinine. A slight decrease in GFR has been found in patients with hypothyroidism, which improved significantly after treatment (3)(4)(5). We wondered whether cystatin C would also be a good marker of renal …

We read with interest the article by Villa and coworkers [1] advocating the use of cystatin C as a measure of glomerular filtration rate (GFR) in critically ill patients. However, we should like to draw attention to several flaws in this study. First, Villa and coworkers compared cystatin C with creatinine as a measure of GFR, using body surface corrected creatinine clearance as, what they call, a 'gold standard'. However, in the Discussion section of that report inulin and iothalamate clearances are mentioned as gold standards, but they were not used by these investigators. The use of body surface area corrected creatinine clearance is questionable in both obese and excessively lean individuals because the correlation between surface area and lean body mass may be lost. Both types of patients are frequently encountered in intensive care. Second, Villa and coworkers employ a cutoff of 80 ml/min to identify renal dysfunction, whereas a value of 50 ml/min is generally accepted [2]. This could have a major influence on the presented results. Third, patients with thyroid disorders or on corticosteroid therapy were excluded. Almost all patients with critical illness have low tri-iodothyronine values because of changes in thyroid hormone metabolism ('nonthyroidal illness'), thus making recognition of thyroid disorders problematic. Finally, we showed [3] that, in patients with thyroid dysfunction, cystatin C is not a suitable measure of GFR. In hypothyroidism creatinine levels are elevated but cystatin C levels are low, whereas in hyperthyroidism creatinine levels are low and cystatin C levels elevated. Taken together, we disagree with the authors that cystatin C could be used as a marker of GFR in intensive care patients.