Population Pharmacokinetics of Remdesivir and GS-441524 in Hospitalized COVID-19 Patients.

The objective of this study was to describe the population pharmacokinetics of remdesivir and GS-441524 in hospitalized coronavirus disease 2019 (COVID-19) patients. A prospective observational pharmacokinetic study was performed in non-critically ill hospitalized COVID-19 patients with hypoxemia. For evaluation of the plasma concentrations of remdesivir and its metabolite GS-441524, samples were collected on the first day of therapy. A nonlinear mixed-effects model was developed to describe the pharmacokinetics and identify potential covariates that explain variability. Alternative dosing regimens were evaluated using Monte Carlo simulations. Seventeen patients were included. Remdesivir and GS-441524 pharmacokinetics were best described by a one-compartment model. The estimated glomerular filtration rate (eGFR) on GS-441524 clearance was identified as a clinically relevant covariate. The interindividual variability in clearance and volume of distribution for both remdesivir and GS-441524 was high (remdesivir, 38.9% and 47.9%, respectively; GS-441525, 47.4% and 42.9%, respectively). The estimated elimination half-life for remdesivir was 0.48 h, and that for GS-441524 was 26.6 h. The probability of target attainment (PTA) of the in vitro 50% effective concentration (EC50) for GS-441524 in plasma can be improved by shortening the dose interval of remdesivir and thereby increasing the total daily dose (PTA, 51.4% versus 94.7%). In patients with reduced renal function, the metabolite GS-441524 accumulates. A population pharmacokinetic model for remdesivir and GS-441524 in COVID-19 patients was developed. Remdesivir showed highly variable pharmacokinetics. The elimination half-life of remdesivir in COVID-19 patients is short, and the clearance of GS-441524 is dependent on the eGFR. Alternative dosing regimens aimed at optimizing the remdesivir and GS-441524 concentrations may improve the effectiveness of remdesivir treatment in COVID-19 patients.

Evaluating imipenem + cilastatin + relebactam for the treatment of complicated urinary tract infections.

INTRODUCTION: The addition of the ß-lactamase inhibitor relebactam to imipenem restores the antibacterial activity against the majority of multidrug resistant Gram-negative bacteria. Complicated urinary tract infections (UTIs) are predominantly caused by Gram-negative uropathogens. The rise in antibiotic resistance, including to carbapenems, is an increasing challenge in daily practice. AREAS COVERED: In the current review, the use of imipenem/relebactam in complicated UTI is evaluated by discussing its chemistry, pharmacokinetics/dynamics, microbiology, safety, and clinical efficacy. The authors also provide their expert perspectives onto its use and its future place in the treatment armamentarium. EXPERT OPINION: With respect to complicated UTI, it should be noted that, to our knowledge, there are no data yet upon the clinical efficacy of imipenem/relebactam in patients with severe urosepsis or men with suspected prostatitis. Further studies upon these specific groups of UTI patients are needed including additional pharmacokinetic studies upon its tissue penetration of the prostate which is currently unknown. However, in our opinion, imipenem/relebactam can be used in complicated UTI when other treatment options are limited.

Ticking off diagnoses of abdominal pain: early neuroborreliosis with radiculopathy.

Lyme disease (LD) is the most common tick-borne illness. The diagnosis of LD is difficult because of the great variation in clinical manifestations. Although abdominal pain is generally not considered a sign of LD, in this case report we describe a patient with unexplained severe abdominal pain that eventually turned out to be LD due to radiculopathy. Since the incidence of LD is rising it is important to realise that severe abdominal pain could be the first clinical manifestation of early neuroborreliosis.

[Clioquinol use for Dientamoeba fragilis infections is questionable]. / Clioquinol voor Dientamoeba fragilis-infectie discutabel.

Clioquinol is used for treatment of amoebiasis and infection with Dientamoeba fragilis. In a guideline of the Dutch Working Party on Antibiotic Policy, clioquinol is recommended as a first-choice treatment for Dientamoeba fragilis. This drug, however, is associated with subacute myelo-optico-neuropathy (SMON). It was withdrawn from the market worldwide in 1985 by manufacturer Ciba-Geigy. Although the Dutch Medicines Evaluation Board has registered no products for systemic use of clioquinol since then, the drug is available as a pharmacy-compounded drug and the last few years the use of clioquinol in the Netherlands has risen again. The Netherlands Pharmacovigilance Centre Lareb has received a growing number of reports of adverse drug reactions (ADRs) associated with the use of clioquinol, including nervous system disorder ADRs occurring at recommended dosages. Therefore, we debate the use of clioquinol as a first-choice treatment option for Dientamoeba fragilis.

[Fosfomycin, an old antibiotic with new possibilities]. / Fosfomycine, een oud antibioticum met nieuwe mogelijkheden.

- Fosfomycin is a broad-spectrum antibiotic agent used orally for uncomplicated cystitis. The intravenous form of administration has recently been authorised in the Netherlands.- Thanks to its broad spectrum and extensive tissue penetration, fosfomycin offers possibilities for the treatment of infections in different organs.- Infections with multidrug-resistant bacteria pose a significant threat to public health. Many of these multidrug-resistant bacteria are sensitive to fosfomycin, which means fosfomycin may be an option for the treatment of infections with multidrug-resistant bacteria. - There is a lack of knowledge about the pharmacological properties of fosfomycin to establish a good dosing schedule. Knowledge is also lacking about the safety of fosfomycin and the extent of its tolerability in the treatment of different infections. - More research is needed before fosfomycin can be used in the battle against multidrug-resistant bacteria.

Life-threatening acute lung injury after gamma butyrolactone ingestion.

We describe a case of a 44-year-old woman with a borderline personality disorder and chronic gamma- butyrolactone (GBL) use who presented with progressive dyspnoea and an altered mental status. A high anion gap metabolic acidosis and acute lung injury was diagnosed. We hypothesise this was caused by GBL. In this case report we describe the diagnostic process and possible pathophysiological mechanisms that may have led to this life-threatening condition.

Prognostic value of pro-adrenomedullin, procalcitonin and C-reactive protein in predicting outcome of febrile urinary tract infection.

Bacterial infections such as febrile urinary tract infection (fUTI) may run a complicated course that is difficult to foretell on clinical evaluation only. Because the conventional biomarkers erythrocyte sedimentation rate (ESR), leucocyte count, C-reactive protein (CRP) and procalcitonin (PCT) have a limited role in the prediction of a complicated course of disease, a new biomarker-plasma midregional pro-adrenomedullin (MR-proADM)-was evaluated in patients with f UTI. We conducted a prospective multicentre cohort study including consecutive patients with f UTI at 35 primary-care centres and eight emergency departments. Clinical and microbiological data were collected and plasma biomarker levels were measured at presentation to the physician. Survival was assessed after 30 days. Of 494 fUTI patients, median age was 67 (interquartile range 49-78) years, 40% were male; two-thirds of them had significant co-existing medical conditions. Median MR-proADM level was 1.42 (interquartile range 0.67-1.57) nM; significantly elevated MR-proADM levels were measured in patients with bacteraemia, those admitted to the intensive care unit, and in 30-day and 90-day non-survivors, compared with patients without these characteristics. The diagnostic accuracy for predicting 30-day mortality in fUTI, reflected by the area-under-the-curve of receiver operating characteristics were: MR-proADM 0.83 (95% CI 0.71-0.94), PCT 0.71 (95% CI 0.56-0.85); whereas CRP, ESR and leucocyte count lacked diagnostic value in this respect. This study shows that MR-proADM assessed on first contact predicts a complicated course of disease and 30-day mortality in patients with fUTI and in this respect has a higher discriminating accuracy than the currently available biomarkers ESR, CRP, PCT and leucocyte count.

Predicting the need for radiologic imaging in adults with febrile urinary tract infection.

BACKGROUND: Radiologic evaluation of adults with febrile urinary tract infection (UTI) is frequently performed to exclude urological disorders. This study aims to develop a clinical rule predicting need for radiologic imaging. METHODS: We conducted a prospective, observational study including consecutive adults with febrile UTI at 8 emergency departments (EDs) in the Netherlands. Outcomes of ultrasounds and computed tomographs of the urinary tract were classified as "urgent urological disorder" (pyonephrosis or abscess), "nonurgent urologic disorder," "normal," and "incidental nonurological findings." Urgent and nonurgent urologic disorders were classified as "clinically relevant radiologic findings." The data of 5 EDs were used as the derivation cohort, and 3 EDs served as the validation cohort. RESULTS: Three hundred forty-six patients were included in the derivation cohort. Radiologic imaging was performed for 245 patients (71%). A prediction rule was derived, being the presence of a history of urolithiasis, a urine pH ≥7.0, and/or renal insufficiency (estimated glomerular filtration rate, ≤40 mL/min/1.73 m(3)). This rule predicts clinically relevant radiologic findings with a negative predictive value (NPV) of 93% and positive predictive value (PPV) of 24% and urgent urological disorders with an NPV of 99% and a PPV of 10%. In the validation cohort (n = 131), the NPV and PPV for clinically relevant radiologic findings were 89% and 20%, respectively; for urgent urological disorders, the values were 100% and 11%, respectively. Potential reduction of radiologic imaging by implementing the prediction rule was 40%. CONCLUSIONS: Radiologic imaging can selectively be applied in adults with febrile UTI without loss of clinically relevant information by using a simple clinical prediction rule.

Intravesical gentamicin for recurrent urinary tract infection in patients with intermittent bladder catheterisation.

Clean intermittent catheterisation (CIC) of the bladder is used to imitate normal bladder emptying in patients with bladder dysfunction. CIC is associated with urinary tract infection (UTI) that may be difficult to treat in the case of antimicrobial resistance. The aim of this study was to establish the effect and safety of intravesical gentamicin treatment in such settings. In 2009, intravesical gentamicin treatment was started in selected patients. Here we describe our experience with two patients treated until March 2010. Two patients using CIC suffering recurrent UTI with multiresistant Escherichia coli were treated with daily administration of 80 mg intravesical gentamicin. On treatment they appeared asymptomatic. During 8- and 9-month follow-up they were free of UTI, urine cultures were negative and there were no side effects. A systematic review was conducted through searches of PubMed and other databases. Clinical trials that met the eligibility criteria and displayed the efficacy or safety of intravesical aminoglycoside treatment in patients using CIC were studied. Study selection was performed by two independent reviewers. Eight studies were included for review. Owing to study heterogeneity, a meta-analysis could not be performed. Of four controlled studies using neomycin or kanamycin, two demonstrated a significant reduction in bacteriuria, whilst two other trials did not. One case series on neomycin/polymyxin showed that the majority of patients still developed bacteriuria. Three case series using gentamicin all pointed towards a significant reduction in bacteriuria and UTIs. There were no clinically relevant side effects reported but follow-up in all studies was limited. Although data are limited, intravesical treatment with gentamicin might be a reasonable treatment option in selected patients practicing CIC who suffer recurrent UTIs with highly resistant microorganisms.

Prospective cohort study of acute pyelonephritis in adults: safety of triage towards home based oral antimicrobial treatment.

OBJECTIVE: Home-based treatment of acute pyelonephritis (AP) is generally reserved for young non-pregnant women who lack co-morbidity. This study, focusing on the elderly and patients with co-morbidity, evaluates the Dutch primary care guideline that recommends referral to hospital only in case of suspected deterioration to severe sepsis or failure of antibiotic treatment, irrespective of patient's age, sex or co-morbidity. METHODS: A prospective observational cohort study including consecutive non-pregnant adults with AP. Clinical and microbiological outcome measures of non-referred patients from 35 primary health care centres (PHC) were compared to patients referred to two affiliating emergency departments (EDs). RESULTS: Of 395 evaluable patients, 153 were treated by PHCs and 242 referred to EDs. The median age was 63years [IQR 43-77], 34% were male, 58% had co-morbidity; all comparable between the PHC and ED group. Referred ED patients were more likely to have signs of sepsis and to have been pre-treated with antibiotics. Bacteraemia was present in 10% of patients in the PHC group and 27% in the ED group (RR 2.83; 95% CI: 1.64-4.86, p<0.001). Eight (5%) PHC patients were admitted during outpatient treatment but otherwise no major complications occurred. Clinical failure rates at 30days were similar between PHC patients and ED patients; 9% and 10% respectively. Mortality rates of PHC patients versus ED patients were 1% versus 5% at 30days (p=0.058) and 1% versus 7% at 90days (p=0.007). Complicated outcome occurred in 6% of the PHC patients versus 12% in the patients referred to ED (p=0.067). CONCLUSION: In a health care system with a well-organized primary care system and clear guideline, the outcome of adults with acute pyelonephritis, including men, the elderly and patients with co-morbidity, selected for oral antibiotic treatment at home did not lead to major complications.

Risk factors and time delay associated with cardiac device infections: Leiden device registry.

AIMS: A nested case-control study of 75 patients with cardiac device infections (CDI) and 75 matched controls was conducted to evaluate time course, risk factors, culture results and frequency of CDI. METHODS AND RESULTS: CDI occurred in 75/3410 (2.2%) device implantation and revision procedures, performed between 2000 and 2007. The time delay between device procedure and infection ranged from 0 to 64 months (mean 14 (SD 16)), 21 patients (28%) had an early infection (<1 month), 26 (35%) a late infection (1-12 months) and 28 (37%) a delayed infection (>12 months). Of interest, 18 (24%) patients presented with an infection >24 months after the device-related procedure. Time delay until infection was significantly shorter when cultures were positive for micro-organisms compared to negative cultures (8 (12) vs 18 (18) months, p = 0.03). Pocket cultures in delayed infections remained more often negative (61% vs 23%, p = 0.01). Independent CDI risk factors were: device revision (odds ratio (OR) 3.67; 95% confidence interval (CI), 1.51 to 8.96), renal dysfunction defined as glomerular filtration rate <60 ml/min (OR 4.64; CI, 1.48 to 14.62) and oral anticoagulation use (OR 2.83; CI 1.20 to 6.68). CONCLUSION: CDI occurred in 2.2% of device procedures, with 24% occurring more than two years after the device-related procedure. Renal dysfunction, device revisions and oral anticoagulation are potent risk factors for CDI.

[Community-acquired Staphylococcus aureus pneumonia following influenza and the choice of empirical antibiotic treatment]. / Thuis opgelopen pneumonie door Staphylococcus aureus na influenza en de keuze voor empirische antibiotische behandeling.

A 30-year-old man presented with community-acquired pneumonia (CAP), directly following influenza. Sputum Gram stain confirmed Staphylococcus aureus pneumonia. Initial empirical antimicrobial therapy did not cover S. aureus. The isolated S. aureus strain contained genes encoding exotoxins, such as Panton-Valentine leukocidin (PVL). This exotoxin is associated with high mortality and methicillin resistance, but in this patient the strain was susceptible to methicillin. The patient died. In the Netherlands the risk of methicillin resistance in PVL-positive S. aureus CAP is low but real. This should be taken into account when selecting empirical treatment, which can include the combination of flucloxacillin and rifampicin. This case report illustrates the difficulty in predicting the causative agent in CAP and highlights the usefulness of the sputum Gram stain. Moreover, clinical awareness and recognition of S. aureus CAP remains essential to the early initiation of directed therapy.

Treating proteinuria in a diabetic patient despite hyperkalaemia due to hyporeninaemic hypoaldosteronism.

Diabetes mellitus is a common cause of hyporeninaemic hypoaldosteronism that might result in significant hyperkalaemia. We describe a patient with diabetic nephropathy and proteinuria who developed a remarkable hyperkalaemia on treatment with an angiotensin-receptor blocker. The management of hyperkalaemia and the pathophysiological background of hyporeninaemic hypoaldosteronism are discussed.

A mediastinal mass: Graves' disease related thymic hyperplasia.

A 35-year-old woman presented with symptoms of pulmonary embolism and thyrotoxicosis. Computed tomography of the chest ruled out pulmonary embolism but showed an incidental mediastinal mass. Graves' disease was confirmed and the mediastinal mass was ascribed to associating thymic hyperplasia. Treatment of Graves' thyrotoxicosis resulted in a spontaneous shrinkage of the mediastinal mass. Although it is relatively unknown, thymic hyperplasia is a normal and reversible manifestation of Graves' disease.