An in vitro pharmacokinetic model mimicking human serum drug concentrations, based on a dialyzer unit, was developed to study the efficacies of continuous infusion and intermittent administration of ceftazidime over a period of 36 h. The daily dose of ceftazidime was 300 mg/liter/24 h given either as a continuous infusion or as three bolus doses. The intermittent dosing regimen yielded peak and trough concentrations after the fourth dose of 92.3 (standard deviation, 8.0) and 1.4 (standard deviation, 0.9) mg/liter, respectively. Continuous administration yielded concentrations of approximately 20 mg/liter. To study efficacy, three Pseudomonas aeruginosa strains, ATCC 27853, CF4, and CF16, were used. The MICs of ceftazidime for these strains were 1, 4, and 16 mg/liter, respectively. Strain CF16 was killed initially during both regimens and then started to regrow. At the end of the fourth dosing interval, i.e., after 32 h, viable counts showed no difference between the regimens. Strains ATCC 27853 and CF4 were killed initially during both dosing schedules, and after the first dosing interval viable counts were similar. However, after the fourth interval, there was a marked difference between bacterial counts during continuous and intermittent infusion, being 2.2 and 2.8 loglo, respectively, demonstrating a greater efficacy during continuous infusion. The results indicate that, in the absence of other factors, a sustained level of ceftazidime around or slightly above the MIC is not high enough to maintain efficacy over more than one (8-h) dosing interval. When sustained concentrations higher than four times the MIC are employed, continuous administration in this model is more efficacious than intermittent dosing.Time-kill curves for beta-lactam antibiotics against Pseudomonas aeruginosa show time-dependent killing which is maximal at relatively low concentrations (35). Concentrations much higher than the MIC contribute no extra effect. From these experiments, it can be deduced that continuous serum drug concentrations above the MIC of the antibiotic used to combat the microorganism in question should be more efficacious than declining concentrations, as observed after intermittent dosing (8, 10). During the latter regimen, concentrations fall below the MIC during part of the dosing interval. It has been shown in several animal models that continuous infusion is indeed more efficacious than intermittent dosing (14,21, 27). However, the half-life of most drugs is severely shortened in the animals studied, and conclusions regarding the pharmacodynamics in humans are difficult to make (15). For, if the shortened half-life is taken into account, the time during which the concentration is below the MIC applies for almost the entire dosing interval, which is contrary to the situation as observed in humans. This problem has, however, been partly overcome by fractional dosing to mimic human pharmacokinetics (13).In vitro simulation of human pharmacokinetics may thus give additional information with respect to kinetics of kil...

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

In a randomized clinical trial of 86 hospitalized COVID-19 patients comparing standard care to treatment with 300mL convalescent plasma containing high titers of neutralizing SARS-CoV-2 antibodies, no overall clinical benefit was observed. Using a comprehensive translational approach, we unravel the virological and immunological responses following treatment to disentangle which COVID-19 patients may benefit and should be the focus of future studies. Convalescent plasma is safe, does not improve survival, has no effect on the disease course, nor does plasma enhance viral clearance in the respiratory tract, influence SARS-CoV-2 antibody development or serum proinflammatory cytokines levels. Here, we show that the vast majority of patients already had potent neutralizing SARS-CoV-2 antibodies at hospital admission and with comparable titers to carefully selected plasma donors. This resulted in the decision to terminate the trial prematurely. Treatment with convalescent plasma should be studied early in the disease course or at least preceding autologous humoral response development.

The kidney is an important target of thyroid hormone action.

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.