Managing the clinical effects of drug-induced intestinal dysbiosis with a focus to antibiotics: Challenges and opportunities.

The term "intestinal dysbiosis" is used for indicating change(s) of the intestinal microbiota which have been associated with the development of diseases and the deterioration of disease treatments in humans. In this review, documented clinical effects of drug-induced intestinal dysbiosis are briefly presented, and methodologies which could be considered for the management of drug-induced intestinal dysbiosis based on clinical data are critically reviewed. Until relevant methodologies are optimized and/or their effectiveness to the general population is confirmed, and, since drug-induced intestinal dysbiosis refers predominantly to antibiotic-specific intestinal dysbiosis, a pharmacokinetically-based approach for mitigating the impact of antimicrobial therapy on intestinal dysbiosis is proposed.

Clinical and pathophysiological characteristics of valproate-induced pleural effusion.

INTRODUCTION: Valproic acid is a carboxylic acid derivative commonly prescribed for several types of seizure disorders or for acute manic episodes in patients with bipolar disorder. Several cases of valproate-induced pleural effusion have been reported, although the precise pathophysiological mechanism remains unknown. OBJECTIVE: To describe the presentation of pleural effusion associated with valproate use and to categorize published case reports according to clinical, immunological, and pleural effusion cell type. METHODS: PubMed/MEDLINE and Embase databases were systematically searched from January 1970 until November 2020 using the following search terms: "valproic acid" OR "valproate" OR "pleural fluid" OR "exudative effusion" OR "transudative effusion" OR "valproic lung adverse events". These searches yielded 171 references of which 135 articles were considered irrelevant, leaving 36 potentially relevant references which were carefully scrutinized. Twenty-eight cases of valproate-induced pleural effusion were identified after excluding two articles reporting five patients with lung parenchymal adverse reactions to treatment with valproic acid; two articles reporting three patients in whom the pleural effusion could not be attributed to valproic acid alone; one case discussing valproate therapy and fungal pleural effusion; and one describing a patient who suffered from severe cardiac failure. There were also two cases, in an abstract form, with pericardial and pleural effusion, but without any further informative details, and, thus, they were also excluded from this survey. EXUDATIVE EOSINOPHILIC PLEURAL EFFUSION: This was the most common type of valproate-induced pleural effusion reported in 17 out of 28 cases (60.7%), with concurrent peripheral eosinophilia in ten. Acute hypersensitivity reaction, inflammation of the pleural cavity induced by the drug, drug toxicity, and damage to mesothelial cells due to oxidants, comprise the possible pivotal mechanisms. EXUDATIVE LYMPHOCYTIC PLEURAL EFFUSION: This was reported in two cases, with concurrent pericardial effusion in one. Discontinuation of valproate led to resolution of the effusion, although the underlying pathophysiological mechanisms remain abstruse. Interestingly, a patient presented with recurrent pleural effusion characterized by transition from eosinophilic to lymphocytic predominance after readministration of valproate. TRANSUDATIVE PLEURAL EFFUSION: Three out of 28 cases (10.7%) were characterized by neutrophilic transudative pleural effusion after long-term therapy with valproate, while concurrent pericardial effusion was also noted in two. VALPROATE-INDUCED LUPUS ERYTHEMATOSUS WITH PLEURAL EFFUSION: Five patients receiving valproate therapy (17.9% out of the 28 cases) developed drug-induced lupus erythematosus with concurrent pleural effusion that was eosinophilic in three. All patients had positive antinuclear antibodies; anti-histone antibodies were positive in two. CONCLUSIONS: Valproate-induced pleural effusion is rare, but patients receiving treatment with valproic acid who develop respiratory symptoms should be examined for valproate-induced pleural effusion.

Colchicine for the treatment of COVID-19 patients: efficacy, safety, and model informed dosage regimens.

Colchicine is widely investigated for cardioprotection of COVID-19 patients since it can prevent the phenomenon of 'cytokine storm' and may reduce the complications arising from COVID-19. Despite the potentially beneficial effects of colchicine, there is no consensus on the appropriate dosage regimen and numerous schemes are currently used.In this study, simulations were performed to identify the ability of dosage regimens to attain plasma levels in CVOID-19 patients, known to be generally safe and efficacious. Since renal and hepatic impairment, as well as, drug-drug interactions have been identified to be the most significant factors increasing colchicine toxicity, the impact of these interactions was assessed in the simulations.Some dosage regimens lead to high colchicine concentrations, while others result in sub-therapeutic levels. Additional dosage schemes were proposed in this study aiming to be applied in patients with clearance insufficiency. Colchicine administration of 0.5 mg twice daily, can be considered safe and effective. In cases of clearance impairment, doses as low as 0.25 mg thrice or twice daily should be applied.Colchicine is a narrow therapeutic index drug and dosage regimens tailored to patients' needs should be designed.

Correlation between Acinetobacter baumannii Resistance and Hospital Use of Meropenem, Cefepime, and Ciprofloxacin: Time Series Analysis and Dynamic Regression Models.

Acinetobacter baumannii is one of the most difficult-to-treat pathogens worldwide, due to developed resistance. The aim of this study was to evaluate the use of widely prescribed antimicrobials and the respective resistance rates of A. baumannii, and to explore the relationship between antimicrobial use and the emergence of A. baumannii resistance in a tertiary care hospital. Monthly data on A. baumannii susceptibility rates and antimicrobial use, between January 2014 and December 2017, were analyzed using time series analysis (Autoregressive Integrated Moving Average (ARIMA) models) and dynamic regression models. Temporal correlations between meropenem, cefepime, and ciprofloxacin use and the corresponding rates of A. baumannii resistance were documented. The results of ARIMA models showed statistically significant correlation between meropenem use and the detection rate of meropenem-resistant A. baumannii with a lag of two months (p = 0.024). A positive association, with one month lag, was identified between cefepime use and cefepime-resistant A. baumannii (p = 0.028), as well as between ciprofloxacin use and its resistance (p < 0.001). The dynamic regression models offered explanation of variance for the resistance rates (R2 > 0.60). The magnitude of the effect on resistance for each antimicrobial agent differed significantly.

Optimization of hydroxychloroquine dosing scheme based on COVID-19 patients' characteristics: a review of the literature and simulations.

During the recent COVID-19 outbreak hydroxychloroquine (HCQ) has been proposed as a safe and effective therapeutic option. However, a wide variety of dosing schemes has been applied in the clinical practice and tested in clinical studies. An extended literature survey was performed investigating the pharmacokinetics, the efficacy and safety of HCQ in COVID-19 treatment. Population pharmacokinetic models were retrieved from the literature and after evaluation and assessment one was selected in order to perform simulations. The most commonly applied dosing schemes were explored for patients with different weights and different levels of HCQ clearance impairment. Model-based simulations of HCQ concentrations revealed that high initial doses followed by low and sparse doses may offer significant benefits to patients by decreasing the viral load without reaching levels considered to produce adverse effects. For instance, the dosing scheme proposed for a 70 kg adult with moderate COVID-19 symptoms would be 600 mg upon diagnosis, 400 mg after 12 h, 300 mg after 24 h, 200 mg after 36 h, followed by 200 mg BID for 4 d, followed by 200 mg OD for 5 d. Based on the results from simulations performed and the currently published knowledge regarding HCQ in COVID-19 treatment, this study provides evidence that a high loading dose followed by sparse doses could offer significant benefits to the patients.

Chloroquine dosage regimens in patients with COVID-19: Safety risks and optimization using simulations.

Currently no specific medicinal treatment exists against the new SARS-CoV2 and chloroquine is widely used, since it can decrease the length of hospital stay and improve the evolution of the associated COVID-19 pneumonia. However, several safety concerns have been raised from chloroquine use due to the lack of essential information regarding its dosing. The aim of this study is to provide a critical appraisal of the safety information regarding chloroquine treatment and to apply simulation techniques to unveil relationships between the observed serious adverse events and overdosing, as well as to propose optimized dosage regimens. The dose related adverse events of chloroquine are unveiled and maximum tolerated doses and concentration levels are quoted. Among others, treatment with chloroquine can lead to severe adverse effects like prolongation of the QT interval and cardiomyopathy. In case of chloroquine overdosing, conditions similar to those produced by SARS-CoV2, such as pulmonary oedema with respiratory insufficiency and circulatory collapse, can be observed. Co-administration of chloroquine with other drugs for the treatment of COVID-19 patients, like azithromycin, can further increase the risk of QT prolongation and cardiomyopathy. For elder patients there is a high risk for toxicity and dose reduction should be made. This study unveils the risks of some widely used dosing regimens and binds the observed serious adverse events with dosing. Based on simulations, safer alternative dosage regimens are proposed and recommendations regarding chloroquine dosing are made.

Penetration of azithromycin in experimental pleural empyema fluid.

There were no data about the extent of azithromycin penetration into the empyemic pleural fluid in humans and in experimental animals. An empyema was created via the intrapleural injection of an Escherichia coli solution into the pleural space of New Zealand white rabbits. After an empyema was verified by thoracocentesis, 24h post inoculation, azithromycin (15 mg/kg) was administered intravenously. Antibiotic levels were determined in samples of pleural fluid and blood serum, collected serially at 2, 8, 24, 48 and 72 h, after administration. Azithromycin levels were estimated using an HPLC analytical method with fluorimetric detection. Azithromycin penetrated well into the empyemic pleural fluid, exhibiting a slower onset and decline compared to the corresponding blood serum levels. Equilibration between pleural fluid and blood serum compartments seemed to occur at 2h, with peak pleural fluid levels (C(maxpf) of 0.48 microg/ml) occurring 24h post administration and decreasing thereafter. Azithromycin peak serum concentration (C(maxserum) of 0.24 microg/ml) was observed 2h after administration and, thereafter, serum antibiotic levels remained lower than the corresponding pleural fluid ones. The area under the concentration versus time curve (AUC) and terminal half-life (T(1/2)) of azithromycin was three- to six fold and twofold higher, respectively, in the pleural fluid compared to the blood serum compartment. After intravenous administration, azithromycin penetrated well into the empyemic pleural fluid, exhibiting pleural fluid levels that are inhibitory for most erythromycin-sensitive pathogens causing empyema.

Sinus fluid penetration of oral clarithromycin and azithromycin in patients with acute rhinosinusitis.

BACKGROUND: The aim of this study was to investigate the extracellular concentration and the degree of sinus fluid penetration of newer macrolides, within the first 24-48 hours of treatment in patients with acute bacterial rhinosinusitis (ABRS), choosing clarithromycin and azithromycin as model antibiotics. An open, noninterventional pharmacokinetic study was performed at a tertiary teaching hospital. METHODS: In 36 outpatients with ABRS, sinus fluid aspirates and serum samples were collected 2, 4, 6, 8, and 12 hours or 2, 6, 12, and 24 hours after the administration of three doses of oral clarithromycin, 500 mg, twice daily or two doses of oral azithromycin, 500 mg, once daily, respectively. Drug concentrations were determined in both matrices by high-performance liquid chromatography with fluorometric detection, and the pH was estimated for all sinus fluid samples. RESULTS: The average clarithromycin sinus fluid concentration was found to be significantly higher than the corresponding azithromycin concentration (2.47 mg/L versus 0.65 mg/L), while the extent of the average sinus fluid penetration, expressed by the ratio of drug concentration in tissue versus serum, was similar for both drugs (115 and 120%, respectively). CONCLUSION: In patients with ABRS, clarithromycin and azithromycin present adequate penetration into sinus fluid to eradicate erythromycin-sensitive strains of Streptococcus pneumoniae. Considering their comparative in vitro activity, the sinus fluid pH effect, and their sinus fluid penetration profile, we may conclude that among the erythromycin-resistant S. pneumoniae strains, clarithromycin might be advantageous over azithromycin in eradicating some of the low-level resistant strains.