Administration Of Clarithromycin Research Articles

Pharmacokinetic Model of Drug Interaction of Tacrolimus with Combined Administration of CYP3A4 Inhibitors Voriconazole and Clarithromycin After Bone Marrow Transplantation.

A pharmacokinetic model has been developed to quantify the drug-drug interactions of tacrolimus with concentration-dependent inhibition of cytochrome P450 (CYP) 3A4 from voriconazole and clarithromycin based on the CYP3A5 and CYP2C19 genotypes. This retrospective study recruited unrelated bone marrow transplant recipients receiving oral tacrolimus concomitantly with voriconazole and clarithromycin. The published population pharmacokinetic model that implemented genotypes of CYP3A5 (tacrolimus) and CYP2C19 (voriconazole) was integrated. The tested CYP3A4 inhibition models (Sigmoid efficacy maximum [Emax], Emax, log-linear, and linear) were a function of competitive inhibition of voriconazole and mechanism-based inhibition of clarithromycin in a virtual enzyme compartment. The total tacrolimus trough concentrations were 119 points, with a median of 4.3 (range: 2.0-9.9) ng/mL (n = 3). The final model comprised the Sigmoid Emax model for voriconazole and clarithromycin, which depicted time-course alterations in tacrolimus concentration and clearance when given voriconazole and clarithromycin. These findings could facilitate the model-informed precision dosing of tacrolimus after unrelated bone marrow transplant.

Assessment of De-Escalation of Empirical Antimicrobial Therapy in Medical Wards with Recognized Prevalence of Multi-Drug-Resistant Pathogens: A Multicenter Prospective Cohort Study in Non-ICU Patients with Microbiologically Documented Infection.

Antimicrobial resistance poses a major threat to human health worldwide and the implementation of antimicrobial stewardship programs (ASPs), including antimicrobial de-escalation (ADE), is a multifaceted tool for minimizing unnecessary or inappropriate antibiotic exposure. This was a prospective observational study of 142 non-Intensive Care Unit (ICU) patients with microbiologically documented infection who were initially administered empirical antimicrobial therapy and admitted to the medical wards of 6 tertiary-care hospitals in Greece from January 2017 to December 2018. Patients were divided into two groups, the ADE and non-ADE group, based on whether ADE was applied or not, respectively. Exploratory end-points were ADE feasibility, safety and efficacy. ADE was applied in 76 patients at a median time of 4 days (IQR: 3, 5). An increased likelihood of ADE was observed in patients with urinary tract (OR: 10.04, 95% CI: 2.91, 34.57; p < 0.001), skin and soft tissue (OR: 16.28, 95% CI: 1.68, 158.08; p = 0.016) and bloodstream infections (OR: 2.52, 95% CI: 1, 6.36; p = 0.05). Factors significantly associated with higher rates of ADE were clarithromycin administration, diagnosis of urinary tract infection (UTI), isolation of E. coli, age and symptoms type on admission. Mortality was lower in the ADE group (18.4% vs. 30.3% p < 0.1) and ADE was not significantly associated with the probability of death (p = 0.432). ADE was associated with favorable clinical outcomes and can be performed even in settings with high prevalence of multi-drug resistant (MDR) pathogens without compromising safety.

Prophylactic Effect of Clarithromycin on Radiation Pneumonitis in IMRT for Lung Cancer.

To evaluate the association between prophylactic administration of clarithromycin (CAM) and the development of radiation pneumonitis (RP) in patients treated with intensity modulated radiation therapy (IMRT) for lung cancer. A total of 89 patients who underwent definitive or salvage IMRT for lung cancer were retrospectively evaluated. The median total and daily doses were 60 Gy and 2 Gy, respectively. A total of 39 patients (44%) received CAM for a median of three months after the start of IMRT. The relationship between the development of RP and certain clinical factors was analyzed. RP of Grade ≥2 was recognized in 10 (11%) patients; Grade 2 in six patients and Grade 3 in four patients. The incidence of Grade ≥2 RP was 3% (1/39) in patients treated with CAM, which was significantly lower than that of 18% (9/50) in patients without CAM. The median lung V20 and V5 in the 10 patients with RP Grade ≥2 were 24% and 46%, respectively, compared with 18% and 37% in the 79 patients with RP Grade 0-1, and the differences were significant. Durvalumab administration after IMRT was also a significant factor for RP Grade ≥2. Prophylactic administration of CAM may reduce Grade ≥2 RP in patients treated with IMRT for lung cancer. Therefore, further clinical trials are warranted.

The Features and Treatment Effects on Keratoepitheliopathy for Meibomitis-Related Keratoconjunctivitis.

Meibomitis-related keratoconjunctivitis (MRKC) is characterized by meibomitis with corneal epithelial abnormalities, and can be divided into two types: MRKC accompanied with phlyctenular keratitis, and MRKC accompanied with keratoepitheliopathy that is similar to superficial punctate keratopathy (SPK). The purpose of this retrospective study was to investigate the characteristic features of keratoepitheliopathy and treatment outcomes for MRKC. This study involved 27 eyes of 18 MRKC patients (3 males and 15 females). National Eye Institute (NEI) scores and visual acuity were compared at pre and post treatment. All subjects were treated with a small-dose administration of clarithromycin. Keratoepitheliopathy characteristic to MRKC, yet different in appearance from SPK, was noted in 24 of the 27 eyes. Fluorescein staining revealed granular epithelial lesions generally larger than SPK that coexisted with small dark spots. In 17 eyes, keratoepitheliopathy was located within the pupillary zone, and the visual acuity in 12 eyes was less than 1.0. Our findings showed significant improvement in the NEI score in MRKC (p < 0.0001) and in visual acuity (p = 0.0157) post treatment, and the characteristic features of keratoepitheliopathy in MRKC that are often associated with decreased visual acuity were elucidated. The treatment of clarithromycin was found to be effective for MRKC with keratoepitheliopathy.

Oral Clarithromycin Therapy for Perioral Dermatitis in Children: A Retrospective Case-series Study

Background: Effective treatments for pediatric periorificial dermatitis are limited. We assessed the clinical utility of oral Clarithromycin (CLR) in pediatric patients with periorificial dermatitis. Methods and Findings: A retrospective medical record review of pediatric patients with periorificial dermatitis was performed. A total of 39 pediatric patients with periorificial dermatitis received prescription of oral CLR during January 2021 and February 2023. The median age at diagnosis was 5.3 ± 3.9 years (interquartile rage 2-9). Except 8 who did not revisit the clinic and could not obtain safety data, none of 31 experienced adverse events during CLR meditation. Among 31 cases who revisited the clinic, we selected 25 cases for efficacy evaluation and excluded 6 cases who stopped medication by their own reason and/or did not take medication regularly as prescribed. Twenty-five cases included 13 females and 12 meles and average age was 6.2 ± 4.2 years (interquartile rage 2-9). Twenty-three cases achieved Complete Response (CR) by CLR: 18 achieved CR in 4 weeks and 5 achieved CR in 8 weeks. One case showed partial response (PR) by CLR and one case worsen after CLR administration with cessation of TCI. Among 23 CR cases, 7 cases (30%) had relapsed during 1.5 to 19 months after CR. All of relapse cases achieved CR by readministration of CLR. Conclusion: Oral clarithromycin is an effective and well tolerated therapeutic option for pediatric patients with periorificial dermatitis.

Plasma 6β-hydroxycortisol to cortisol ratio as a less invasive cytochrome P450 3A phenotyping method.

A less invasive evaluation method of cytochrome P450 3A (CYP3A) activity provides an important tool for personalized medicine. We aimed to clarify the usefulness of the plasma 6β-hydroxycortisol to cortisol concentration (6β-OHF/F) ratio as a minimally invasive CYP3A phenotyping method. Plasma 6β-OHF and cortisol concentrations were measured via liquid chromatography/tandem mass spectrometry. The plasma 6β-OHF/F ratio was compared with 6β-hydroxylation clearance of endogenous cortisol (CLm(6β); which we previously developed as an index of CYP3A activity) before, during and after oral contraceptive administration in 3 healthy women. The plasma 6β-OHF/F ratio was observed during oral clarithromycin administration. The plasma 6β-OHF/F ratio was also measured in 39 healthy participants. The plasma 6β-OHF/F ratio in 3 healthy women on Day 21 of starting oral contraceptive administration decreased by 39, 49 and 61% compared with Day 0. These values were similar to CLm(6β) values (43, 54 and 59%, respectively). Plasma 6β-OHF/F ratio and CLm(6β) exhibited a good correlation (r = .9053). The 6β-OHF/F ratio decreased from 0.00921 to 0.00577 only 3h following clarithromycin administration. The plasma 6β-OHF/F ratio ranged 0.00565-0.01556 in 39 healthy participants. Based on its close relationship with CLm(6β) and its decrease upon inhibition by clarithromycin, the plasma 6β-OHF/F ratio serves as an index of CYP3A activity. Using this minimally invasive index, we can identify patients with extremely low CYP3A activity before treatment initiation and optimize the initial drug dose, thereby mitigating the risk of severe adverse reactions.

Efficacy and safety of clarithromycin for patients with sepsis or septic shock: a systematic review and meta-analysis

Abstract Background Clarithromycin exerts an immunomodulatory role in several human diseases. However, whether this effect improves the prognosis in patients with sepsis remains controversial, and higher levels of clinical evidence are urgently needed. To the best of our knowledge, no meta-analysis to date has reported the clinical efficacy and safety of clarithromycin in sepsis. Methods A comprehensive literature search of PubMed, EMBASE, and the Cochrane Library was conducted up to December 31, 2022. Only randomized controlled trials comparing the clinical efficacy and safety of clarithromycin with controls among patients with sepsis or septic shock were included. Data were pooled by applying a fixed-effects model and a relative risk (RR) estimate with 95% confidence intervals (CIs) using Review Manager (version 5.3; Cochrane Collaboration, Copenhagen, Denmark). Results Three randomized controlled trials involving a total of 910 patients were included. The pooled results confirmed that clarithromycin had no beneficial effect on progression to multiple organ dysfunction syndrome (RR: 1.51; 95% CI: 1.02–2.25; P = 0.04; I 2 = 0%), 28-day mortality (RR: 1.09; 95% CI: 0.87–1.36; P = 0.46; I 2 = 0%), and 90-day mortality (RR: 0.86; 95% CI: 0.71–1.03; P = 0.10; I 2 = 81%) in patients with sepsis or septic shock. Moreover, there was no difference in other serious adverse events between patients who received clarithromycin and those in the control group (RR: 1.02; 95% CI: 0.87–1.19; P = 0.83; I 2 = 18%). Conclusion Our meta-analysis did not reveal an improvement to short-term outcomes in patients with sepsis treated with clarithromycin. However, administration of clarithromycin did not increase the risk of adverse events.

Efficacy of adjunctive topical liposomal clarithromycin on systemic Glucantime in Old World cutaneous leishmaniasis: a pilot clinical study.

Aim: This study aimed to investigate the effects of topical liposomal clarithromycin in combination with meglumine antimoniate (Glucantime®) on cutaneous leishmaniasis (CL) lesions. Methods: This pilot, randomized, double-blinded clinical trial was conducted on patients with CL lesions. Patients were randomly assigned to two groups: the first group received liposomal clarithromycin in combination with Glucantime for 28days, while the second group received Glucantime and a placebo. Afterward, patients were followed up at 1.5, 3, and 6months after treatment initiation and were evaluated for recovery time, induration, and size of the lesions. Results: Sixty patients with CL lesions were divided into two separate groups with 30 members each and were examined. Within-group analysis revealed that recovery time in the clarithromycin group was 26.65 ± 5.12days, while in the placebo group, it was 32.84 ± 24.43, which was statistically insignificant (p = 0.18). Lesion size comparison in the first and last follow-ups reduced in both groups: 7.73 ± 4.31 to 0.48 ± 0.50 in the clarithromycin group (p = 0.006) and 5.47 ± 5.83 to 0.76 ± 0.88 in the placebo group (p = 0.03). Moreover, the size of lesions in the intervention group was significantly reduced compared to that in the placebo group (p = 0.02). Recognizable induration reduction was observed in the clarithromycin group (2.60 ± 0.77 to 1.0 ± 0.00). No adverse effects attributable to clarithromycin were reported. Conclusion: The administration of liposomal clarithromycin in combination with systemic Glucantime had a significant beneficial effect on reducing lesion size in leishmaniasis. Further studies on larger populations are recommended. Systematic Review Registration: https://www.irct.ir/trial/46611.

Rapid changes of mRNA expressions of cardiac ion channels affected by Torsadogenic drugs influence susceptibility of rat hearts to arrhythmias induced by Beta-Adrenergic stimulation.

Drug-induced long QT syndrome (LQTS) and Torsades de Pointes (TdP) are serious concerns in drug development. Although rats are a useful scientific tool, their hearts, unlike larger species, usually do not respond to torsadogenic drugs. Consequently, their resistance to drug-induced arrhythmias is poorly understood. Here, we challenged rats with rapid delayed rectifier current (Ikr)-inhibiting antibiotic clarithromycin (CLA), loop diuretic furosemide (FUR) or their combination (CLA + FUR), and examined functional and molecular abnormalities after stimulation with isoproterenol. Clarithromycin and furosemide were administered orally at 12-h intervals for 7 days. To evaluate electrical instability, electrocardiography (ECG) was recorded either in vivo or ex vivo using the Langendorff-perfused heart method under basal conditions and subsequently under beta-adrenergic stimulation. Gene expression was measured using real-time quantitative PCR in left ventricular tissue. Indeed, FUR and CLA + FUR rats exhibited hypokalemia. CLA and CLA + FUR treatment resulted in drug-induced LQTS and even an episode of TdP in one CLA + FUR rat. The combined treatment dysregulated gene expression of several ion channels subunits, including KCNQ1, calcium channels and Na+/K + -ATPase subunits, while both monotherapies had no impact. The rat with recorded TdP exhibited differences in the expression of ion channel genes compared to the rest of rats within the CLA + FUR group. The ECG changes were not detected in isolated perfused hearts. Hence, we report rapid orchestration of ion channel reprogramming of hearts with QT prolongation induced by simultaneous administration of clarithromycin and furosemide in rats, which may account for their ability to avoid arrhythmias triggered by beta-adrenergic stimulation.

Plasma lipidomic analysis to investigate putative biomarkers of P-glycoprotein activity in healthy volunteers.

P-glycoprotein (P-gp) is an efflux transporter involved in the bioavailability of many drugs currently on the market. P-gp is responsible for several drug-drug interactions encountered in clinical practice leading to iatrogenic hospital admissions, especially in polypharmacy situations. ABCB1 genotyping only reflects an indirect estimate of P-gp activity. Therefore, it would be useful to identify endogenous biomarkers to determine the P-gp phenotype to predict in vivo activity prior to the initiation of treatment and to assess the effects of drugs on P-gp activity. The objective of this study was to assess changes in plasma lipidome composition among healthy volunteers selected on the basis of their ABCB1 genotype and who received clarithromycin, a known inhibitor of P-gp. Untargeted lipidomic analysis based on liquid chromatography-tandem mass spectrometry was performed before and after clarithromycin administration. Our results revealed changes in plasma levels of some ceramides (Cers) {Cer(d18:1/22:0), Cer(d18:1/22:1), and Cer(d18:1/20:0) by ~38% (p < 0.0001), 13% (p < 0.0001), and 13% (p < 0.0001), respectively} and phosphatidylcholines (PCs) {PC(17:0/14:1), PC(16:0/18:3), and PC(14:0/18:3) by ~24% (p < 0.001), 10% (p < 0.001), and 23.6% (p < 0.001)} associated with both ABCB1 genotype and clarithromycin intake. Through the examination of plasma lipids, our results highlight the relevance of untargeted lipidomics for studying in vivo P-gp activity and, more generally, to safely phenotyping transporters.

Severe cytopenia during adjuvant chemotherapy for early breast cancer in a patient with idiopathic CD4+ lymphocytopenia.

Idiopathic CD4+ lymphocytopenia (ICL) is a rare immunodeficiency disorder characterized by decreased CD4+ T-cell counts in the absence of human immunodeficiency virus (HIV) infection. Similar to HIV infection, ICL is commonly associated with acquired immunodeficiency syndrome-defining cancers, such as Kaposi sarcoma, non-Hodgkin lymphoma and cervical cancer; however, the presentation of breast cancer in a patient with ICL is rare. The current study presented the clinical course of a patient with early breast cancer and ICL. Following surgery, the patient underwent adjuvant chemotherapy comprising doxorubicin plus cyclophosphamide, followed by paclitaxel. The patient's immunodeficiency status required the prophylactic administration of clarithromycin, trimethoprim-sulfamethoxazole and valganciclovir. Throughout the course of chemotherapy, the patient experienced severe complications of febrile neutropenia, anemia, neutropenia and thrombocytopenia, and was eventually forced to discontinue anticancer chemotherapy, as the relative dose intensity (RDI) could not be maintained. Similar hematological complications and reduced RDI, leading to worse outcomes, are also common in patients with HIV infection receiving chemotherapy, suggesting that CD4+ T cell-deficient patients are prone to developing cytopenia during chemotherapy. The present study demonstrates the importance of further data accumulation in patients with ICL with cancer and the development of a methodology for maintaining the RDI.

Pharmacokinetic interaction of voriconazole and clarithromycin in Pakistani healthy male volunteers: a single dose, randomized, crossover, open-label study.

Background: Voriconazole an antifungal drug, has a potential for drug-drug interactions (DDIs) with administered drugs. Clarithromycin is a Cytochromes P450 CYP (3A4 and 2C19) enzyme inhibitor, and voriconazole is a substrate and inhibitor of these two enzymes. Being a substrate of the same enzyme for metabolism and transport, the chemical nature and pKa of both interacting drugs make these drugs better candidates for potential pharmacokinetic drug-drug interactions (PK-DDIs). This study aimed to evaluate the effect of clarithromycin on the pharmacokinetic profile of voriconazole in healthy volunteers. Methods: A single oral dose, open-label, randomized, crossover study was designed for assessing PK-DDI in healthy volunteers, consisting of 2weeks washout period. Voriconazole, either alone (2mg × 200mg, tablet, P/O) or along with clarithromycin (voriconazole 2mg × 200mg, tablet + clarithromycin 500mg, tablet, P/O), was administered to enrolled volunteers in two sequences. The blood samples (approximately 3 cc) were collected from volunteers for up to 24h. Plasma concentrations of voriconazole were analyzed by an isocratic, reversed-phase high-performance-liquid chromatography ultraviolet-visible detector (RP HPLC UV-Vis) and a non-compartmental method. Results: In the present study, when voriconazole was administered with clarithromycin versus administered alone, a significant increase in peak plasma concentration (Cmax) of voriconazole by 52% (geometric mean ratio GMR: 1.52; 90% CI 1.04, 1.55; p = 0.000) was observed. Similarly, the area under the curve from time zero to infinity (AUC0-∞) and the area under the concentration-time curve from time zero to time-t (AUC0-t) of voriconazole also significantly increased by 21% (GMR: 1.14; 90% CI 9.09, 10.02; p = 0.013), and 16% (GMR: 1.15; 90% CI 8.08, 10.02; p = 0.007), respectively. In addition, the results also showed a reduction in the apparent volume of distribution (Vd) by 23% (GMR: 0.76; 90% CI 5.00, 6.20; p = 0.051), and apparent clearance (CL) by 13% (GMR: 0.87; 90% CI 41.95, 45.73; p = 0.019) of voriconazole. Conclusion: The alterations in PK parameters of voriconazole after concomitant administration of clarithromycin are of clinical significance. Therefore, adjustments in dosage regimens are warranted. In addition, extreme caution and therapeutic drug monitoring are necessary while co-prescribing both drugs. Clinical Trial Registration: clinicalTrials.gov, Identifier NCT05380245.

Gender determinism of the effect of placenta cryoextract on the hepatotropic effects of esomeprazole, clarithromycin and metronidazole in chronic liver damage

Current regimens for the eradication of Helicobacter pylori infection include bismuth drugs, proton pump inhibitors, and a combination of 2–3 antibacterial drugs. Uncontrolled use of antibacterial agents as part of eradication schemes increases the risk of developing their unwanted drug reactions, in particular, hepatotoxicity. As a means with potentially hepatoprotective activity, our attention was drawn to placental cryoextract.&#x0D; The purpose of the study. To characterize the gender aspects of the hepatotropic action of placenta cryoextract in tetrachloromethane hepatitis with background ethanol-induced cirrhosis and liver damage by antiulcer agents.&#x0D; Materials and methods. Research was conducted on 112 male and female rats. Tetrachloromethane hepatitis with background ethanol-induced liver cirrhosis was reproduced by injecting an oil solution of CCl4 in combination with a 5.0% ethanol solution for 45 days. Modulation of the content of sex hormones was achieved by surgical ovariectomy or testectomy.&#x0D; Results and discussion. Administration of esomeprazole, clarithromycin, and metronidazole in chronic liver damage in animals without changes in hormonal status led to a statistically significant (p=0.01) 27.6% increase in the level of bilirubin in homogenates of liver tissues in female rats (78.7±4.5 mmol/l) than in males. The greatest decrease in the content of bilirubin (41.7%, p&lt;0.001) with the use of cryoextract of the placenta was noted in castrated female rats with simulated tetrachlormethone hepatitis with background ethanol-induced cirrhosis of the liver, which were injected with antiulcer agents.&#x0D; Conclusions. Administration of cryoextract of the placenta has a pronounced hepatoprotective effect in animals of both sexes. In male rats with no change in hormonal status with simulated liver injury and the administration of antiulcer drugs, placenta cryoextract therapy was more effective than in female rats, as indicated by a more than 1.6-fold decrease in the content of bilirubin in the liver homogenates of male rats (43.1%, p&lt;0.001) than in females (27.4%, p&lt;0.01).

Quantitative evaluation of Mycobacterium abscessus clinical isolate virulence using a silkworm infection model.

Mycobacterium abscessus causes chronic skin infections, lung diseases, and systemic or disseminated infections. Here we investigated whether the virulence of M. abscessus clinical isolates could be evaluated by calculating the median lethal dose (LD50) in a silkworm infection model. M. abscessus subsp. abscessus cells were injected into the silkworm hemolymph. When reared at 37˚C, the silkworms died within 2 days post-infection with M. abscessus subsp. abscessus. Viable cell numbers of M. abscessus increased in the hemolymph of silkworms injected with M. abscessus. Silkworms were not killed by injections with heat-killed M. abscessus cells. The administration of clarithromycin, an antibacterial drug used to treat the infection in humans, prolonged the survival time of silkworms injected with M. abscessus. The LD50 values of 7 clinical isolates in the silkworm infection model were differed by up to 9-fold. The Mb-17 isolate, which was identified as a virulent strain in the silkworm infection model, induced more detachment of human THP-1-derived macrophages during infection than the Mb-10 isolate. These findings suggest that the silkworm M. abscessus infection model can be used to quantitatively evaluate the virulence of M. abscessus clinical isolates in a short time period.

Гепатотропні ефекти трикомпонентної противиразкової терапії та кріоекстракту плаценти: роль статевих чинників у ліпопероксидації

The purpose of the work was to reveal the role of sex factors in the processes of lipid peroxidation (LPO) against the background of chronic ethanol-tetrachloromethane-induced liver damage and the hepatotropic effects of triple antiulcer therapy and cryopreserved placenta extract (CEP). Chronic ethanol-tetrachloromethane-induced liver damage was induced by the introduction of a CCl4 solution in combination with an ethanol solution for 45 days. The content of reactants with thiobarbituric acid (TBA-active products) and catalase activity were measured in liver homogenates. Modulation of the content of sex hormones was achieved by surgical ovariectomy or testectomy. The study showed that the combined intravenous administration of esomeprazole, clarithromycin and metronidazole to rats with chronic ethanol-tetrachloromethane-induced liver damage caused an inhibition of the antioxidant defense system, this was indicated by a statistically significant decrease in catalase activity by 38.4% and a decrease in the antioxidant-prooxidant index by 35.1%, compared with the parameters of intact rats. The most significant activation of LPO processes was noted in females against the background of chronic ethanol-tetrachloromethaneinduced liver damage and the administration of anti-ulcer drugs after ovariectomy. In this case, the content of TBAactive products was 36.1 ± 2.79 μmol/kg of tissue. It was established that in castrated females, the combined use of anti-ulcer drugs and CEP against the background of chronic ethanol-tetrachloromethane-induced liver damage leveled the activation of LPO processes, this was indicated by a statistically significant (P &lt; 0.001) 2.7 times lower content of TBA-active products in liver homogenates.

Clarithromycin-treated chronic spontaneous urticaria with the negative regulation of FcεRΙ and MRGPRX2 activation via CD300f

Mast cells (MCs) are main effector cells in chronic spontaneous urticaria (CSU). Both Fc epsilon RI (FcεRΙ)- and MAS-related G coupled receptor-X2 (MRGPRX2)-mediated MC activations affect CSU course. Leukocyte mono-immunoglobulin-like receptor 3 (CD300f) has been shown to regulate FcεRΙ activation. However, no study has verified CD300f is a target to cure CSU. Therefore this study aimed to verify whether clarithromycin (CLA) regulates FcεRΙ- and MRGPRX2-mediated MC activations via CD300f and shows therapeutic effect on CSU. The target of CLA was verification. CLA inhibited FcεRΙ- and MRGPRX2-mediated MC activations were shown in vivo and in vitro. A single-center, self-comparison study was performed, and CLA-treated CSU was investigated in 28 patients who were not sensitive to the third-generation antihistamines. Serum inflammatory mediators in patients before and after CLA administration were analyzed. CLA effectively inhibited type Ι anaphylactic reactions and pseudo-allergic reactions in mice. Moreover, CLA inhibited FcεRΙ- and MRGPRX2-mediated MC signaling pathway activation. Regulatory effects of CLA were decreased significantly after CD300f knockdown. CLA effectively alleviated the symptoms of wheal and itch and reduced serum cytokine levels in patients. CLA negatively regulated FcεRΙ- and MRGPRX2-mediated MC activation via CD300f and showed significant therapeutic effect on CSU.

Dried blood spots analysis of 6β‐hydroxycortisol and cortisol using liquid chromatography/tandem mass spectrometry for calculating 6β‐hydroxycortisol to cortisol ratio

AbstractDried blood spot (DBS) sampling is a minimally invasive method used to collect blood samples of any population for personalized medicine. We aimed to develop a sensitive and reliable analytical method for measuring 6β‐hydroxycortisol (6β‐OHF) and cortisol concentrations in DBS by liquid chromatography/tandem mass spectrometry so as to utilize DBS as a less invasive blood sampling method for calculating the ratio of 6β‐OHF/cortisol. The lower limits of quantification obtained using four DBS were 1.08 pg/50 μl for 6β‐OHF and 1.01 pg/50 μl for cortisol. The 6β‐OHF and cortisol in DBS were stable for 28 days at room temperature. The intraday and interday accuracy and precision of the method was &lt;12%. Additionally, the 6β‐OHF and cortisol in DBS were measured before, during, and after 3 days of clarithromycin administration to two of the subjects. Then, their concentration was compared in the plasma and whole blood collected simultaneously. The concentrations of 6β‐OHF and cortisol in four DBS ranged from 0.007 to 0.079 ng/50 μl and from 1.15 to 6.66 ng/50 μl, respectively. The 6β‐OHF/cortisol ratio in DBS decreased by approximately 50% on administering clarithromycin compared with that before the administration of clarithromycin. The 6β‐OHF/cortisol ratio in DBS also showed a strong correlation with that in whole blood (r = 0.9694) and plasma (r = 0.9383). This method provides high accuracy and precision for measuring 6β‐OHF and cortisol in DBS. It also allows the use of DBS instead of plasma for calculating the 6β‐OHF/cortisol ratio. The 6β‐OHF/cortisol ratio could be an index of CYP3A activity in clinical setting.

Clarithromycin Inhibits Pneumolysin Production via Downregulation of ply Gene Transcription despite Autolysis Activation.

ABSTRACTStreptococcus pneumoniae, the most common cause of community-acquired pneumonia, causes severe invasive infections, including meningitis and bacteremia. The widespread use of macrolides has been reported to increase the prevalence of macrolide-resistant S. pneumoniae (MRSP), thereby leading to treatment failure in patients with pneumococcal pneumonia. However, previous studies have demonstrated that several macrolides and lincosamides have beneficial effects on MRSP infection since they inhibit the production and release of pneumolysin, a pneumococcal pore-forming toxin released during autolysis. In this regard, we previously demonstrated that the mechanisms underlying the inhibition of pneumolysin release by erythromycin involved both the transcriptional downregulation of the gene encoding pneumolysin and the impairment of autolysis in MRSP. Here, using a cell supernatant of the culture, we have shown that clarithromycin inhibits pneumolysin release in MRSP. However, contrary to previous observations in erythromycin-treated MRSP, clarithromycin upregulated the transcription of the pneumococcal autolysis-related lytA gene and enhanced autolysis, leading to the leakage of pneumococcal DNA. On the other hand, compared to erythromycin, clarithromycin significantly downregulated the gene encoding pneumolysin. In a mouse model of MRSP pneumonia, the administration of both clarithromycin and erythromycin significantly decreased the pneumolysin protein level in bronchoalveolar lavage fluid and improved lung injury and arterial oxygen saturation without affecting bacterial load. Collectively, these in vitro and in vivo data reinforce the benefits of macrolides on the clinical outcomes of patients with pneumococcal pneumonia.IMPORTANCE Pneumolysin is a potent intracellular toxin possessing multiple functions that augment pneumococcal virulence. For over 10 years, sub-MICs of macrolides, including clarithromycin, have been recognized to decrease pneumolysin production and release from pneumococcal cells. However, this study indicates that macrolides significantly slowed pneumococcal growth, which may be related to decreased pneumolysin release recorded by previous studies. In this study, we demonstrated that clarithromycin decreases pneumolysin production through downregulation of ply gene transcription, regardless of its inhibitory activity against bacterial growth. Additionally, administration of clarithromycin resulted in the amelioration of lung injury in a mouse model of pneumonia induced by macrolide-resistant pneumococci. Therefore, therapeutic targeting of pneumolysin offers a good strategy to treat pneumococcal pneumonia.

Mycobacterium mucogenicum and Klebsiella pneumoniae Pulmonary Infection in a Patient Following Cardiac Surgery: A Case Report

Introduction: Mycobacterium mucogenicum belongs to the rapidly growing mycobacteria, and it is a rare conditional pathogen. Although recent studies suggested that the incidence of M. mucogenicum infection was increased worldwide, there are no case reports of M. mucogenicum and Klebsiella pneumoniae pulmonary infection. Case Presentation: A 32-year-old non-smoking male was diagnosed with congenital atrial septal defect and pulmonary arterial hypertension. After cardiac surgery, lung infections were observed in the patient and then rapidly developed acute respiratory distress syndrome. The cefoperazone-sulbactam, vancomycin, ceftazidime, carbapenem, tigecycline, and micafungin were used for the treatment of pulmonary infection but did not work well. Ultimately, M. mucogenicum and K. pneumoniae were identified as pathogens by using next-generation sequencing. The patient was treated successfully with the administration of clarithromycin, linezolid, tigecycline, and ceftazidime-avibactam. The clinical outcome of this patient was favorable without relapse of infection. Conclusions: This case demonstrates that M. mucogenicum pulmonary infection may result in severe outcomes. The next-generation sequencing technology is important for the identification of M. mucogenicum. Additionally, the clinicians and clinical pharmacists should remain awareness in dealing with M. mucogenicum infection to avoid delaying appropriate treatment.

In vivo evaluation of intestinal human CYP3A inhibition by macrolide antibiotics in CYP3A-humanised mice

It is important to predict drug-drug interactions via inhibition of intestinal cytochrome P450 3A (CYP3A) which is a determinant of bioavailability of orally administered CYP3A substrates. However, inhibitory effects of macrolide antibiotics on CYP3A-mediated metabolism are not entirely identical between humans and rodents. We investigated the effects of macrolide antibiotics, clarithromycin and erythromycin, on in vitro and in vivo metabolism of triazolam, a CYP3A substrate, in CYP3A-humanised mice generated by using a mouse artificial chromosome vector carrying a human CYP3A gene. Metabolic activities of triazolam were inhibited by macrolide antibiotics in liver and intestine microsomes of CYP3A-humanised mice. The area under the plasma concentration-time curve ratios of 4-hydroxytriazolam to triazolam after oral dosing of triazolam were significantly decreased by multiple administration of macrolide antibiotics. The plasma concentrations ratios of α-hydroxytriazolam and 4-hydroxytriazolam to triazolam in portal blood were significantly decreased by multiple administration of clarithromycin in CYP3A-humanised mice. These results suggest that intestinal CYP3A activity was inhibited by macrolide antibiotics in CYP3A-humanised mice in vitro and in vivo. The plasma concentrations of triazolam and its metabolites in the portal blood of CYP3A-humanised mice would be useful for direct evaluation of intestinal CYP3A-mediated drug-drug interactions.