Butyrate administration strengthens the intestinal epithelium and improves intestinal dysbiosis in a cholestasis fibrosis model.

AIM: Intestinal dysfunction in cirrhosis patients is linked to death by bacterial infections. Currently, there is no effective therapy for this complication. This study aims to evaluate butyrate, a novel postbiotic, on the intestinal inflammatory response, tight junction proteins and the microbiota in the cholestasis model. METHODS AND RESULTS: Wistar rats underwent 15 days of bile duct ligation (BDL). We administered butyrate at a concentration of 1%. The BDL group did not receive treatment. The results showed that butyrate could significantly reduce pro-inflammatory cytokines (IL-17A, IFN-γ, TNF-α) in the ileum and colon while promoting IL-10 expression in the colon. Moreover, it significantly promotes tight junction protein (cld-1, occludin and ZO-1) expression in the ileum. A similar effect was observed in the colon except for ZO-1. Additionally, butyrate limited taxa diversity loss and promoted probiotic genera expansion such as Lachnospira, Prevotella and Lactobacillus. The increase in Turicibacter and Clostridiaceae distinguished the BDL group. CONCLUSIONS: Butyrate is effective in regulating the inflammatory response, tight junction proteins and limits bacterial diversity loss. SIGNIFICANCE AND IMPACT OF THE STUDY: This research reveals that butyrate could represent an interesting postbiotic metabolomic intervention for intestinal epithelium dysfunction in liver disease.

The effect of protease inhibitor-based dual antiretroviral regimens on CD4/CD8 ratio during the first year of therapy in ART-naïve patients with HIV-infection.

OBJECTIVES: To assess the effect of protease inhibitor (PI)-based dual therapy on CD4/CD8 ratio during the first year of therapy in antiretroviral therapy (ART)-naïve patients using data from randomized controlled clinical trials. METHODS: We pooled data from the GARDEL and ANDES studies, both randomized controlled clinical trials that recruited ART-naïve people living with HIV and randomly assigned them to receive PI-based dual therapy (DT) or triple therapy (TT) aiming to compare viral efficacy. We compared median CD4/CD8 ratios and the proportion of patients with CD4/CD8 ratio > 1 at 48 weeks after ART initiation in both treatment arms using the Mann-Whitney U-test and the χ2 test. We performed subgroup analysis for patients > 50 years old, with baseline CD4 counts ≤ 200 cells/µL, viral load > 100 000 HIV RNA copies/mL, and ritonavir-boosted lopinavir-based therapy. RESULTS: We analysed data from 571 patients: 292 on DT and 279 on TT. No differences were observed in CD4/CD8 ratio (0.632 vs. 0.617, P = 0.729) or in the proportion of patients with CD4/CD8 ratio > 1 (17.9% vs. 19.3%, P = 0.678) 48 weeks after ART initiation. Subgroup analysis showed no further differences. CONCLUSION: The impact of PI-based DT regimens on the CD4/CD8 ratio during the first year of treatment for ART-naïve patients is similar to that of TT.

Week 96 results of the randomized, multicentre Maraviroc Switch (MARCH) study.

OBJECTIVES: The Maraviroc Switch (MARCH) study week 48 data demonstrated that maraviroc, a chemokine receptor-5 (CCR5) inhibitor, was a safe and effective switch for the ritonavir-boosted protease inhibitor (PI/r) component of a two nucleos(t)ide reverse transcriptase inhibitor [N(t)RTI] plus PI/r-based antiretroviral regimen in patients with R5-tropic virus. Here we report the durability of this finding. METHODS: MARCH, an international, multicentre, randomized, 96-week open-label switch study, enrolled HIV-1-infected adults with R5-tropic virus who were stable (> 24 weeks) and virologically suppressed [plasma viral load (pVL) < 50 HIV-1 RNA copies/mL]. Participants were randomized to continue their current PI/r-based regimen (PI/r) or to switch to MVC plus two N(t)RTIs (MVC) (1:2 randomization). The primary endpoint was the difference in the proportion with pVL < 200 copies/mL at 96 weeks. The switch arm was defined as noninferior if the lower limit of the 95% confidence interval (CI) for the difference was < -12% in the intention-to-treat (ITT) population. Safety endpoints (the difference in the mean change from baseline or a comparison of proportions) were analysed as key secondary endpoints. RESULTS: Eighty-two (PI/r) and 156 (MVC) participants were randomized and included in the ITT analysis; 71 (87%) and 130 (83%) were in follow-up and on therapy at week 96. At week 96, 89.0% and 90.4% in the PI/r and MVC arms, respectively, had pVL < 50 copies/mL (95% CI -6.6, 10.2). Moreover, in those switching away from PI/r, there were significant reductions in mean total cholesterol (differences 0.31 mmol/L; P = 0.02) and triglycerides (difference 0.44 mmol/L; P < 0.001). Changes in CD4 T-cell count, renal function, and serious and nonserious adverse events were similar in the two arms. CONCLUSIONS: MVC as a switch for a PI/r is safe and effective at maintaining virological suppression while having significant lipid benefits over 96 weeks.

Lipid profiles for nevirapine vs. atazanavir/ritonavir, both combined with tenofovir disoproxil fumarate and emtricitabine over 48 weeks, in treatment-naïve HIV-1-infected patients (the ARTEN study).

OBJECTIVES: Dyslipidaemic effects of antiretrovirals (ARVs) may contribute to increased cardiovascular risk (CR) in HIV-1-infected patients. The ARTEN (atazanavir/ritonavir on a background of tenofovir and emtricitabine vs. nevirapine on the same background, in naïve HIV-1-infected patients) study compared prospectively ritonavir-boosted atazanavir (ATZ/r) 300 mg/100 mg once daily (qd) with immediate release nevirapine (NVP) 200 mg twice daily or 400 mg qd, each combined with fixed-dose tenofovir 300 mg/emtricitabine 200 mg qd in 569 ARV-naïve HIV-1-infected patients. Lipid profiles and CR from baseline to week 48 are reported. METHODS: Changes from baseline to week 48 in fasting plasma levels of total cholesterol (TC), high-density lipoprotein cholesterol (HDL-c), low-density lipoprotein cholesterol (LDL-c), TC:HDL-c ratio, apolipoprotein A1 (ApoA1), apolipoprotein B (ApoB) and total triglycerides (TG) were determined. The Framingham algorithm was used to estimate CR. Analysis was by intention-to-treat (ITT) with last observation carried forward (LOCF) for missing data. RESULTS: At week 48, NVP treatment resulted in significantly greater mean increases from baseline in TC (24.4 vs. 19.6 mg/dL; P=0.038), HDL-c (9.7 vs. 3.9 mg/dL; P<0.0001), LDL-c (15.0 vs. 10.4 mg/dL; P=0.011) and ApoA1 (0.18 vs. 0.08 g/L; P<0.0001) but not ApoB (0.02 vs. 0.02 g/L) compared with ATZ/r treatment. ATZ/r use was associated with higher mean TG increases (27.80 vs. 0.02 mg/dL; P=0.0001). Significantly greater mean decreases in TC:HDL-c and ApoB/ApoA ratios were observed with NVP vs. ATZ/r (P=0.0001 and P=0.008, respectively). Framingham CR scores were low and comparable between the arms, with only a slight mean increase from baseline to week 48 of 0.70 for NVP and 0.80 for ATZ/r [difference -0.069; 95% confidence interval (CI) -0.61 to 0.46; P=0.80]. CONCLUSIONS: In ARV-naïve patients with low CR at the outset, NVP showed a potentially less atherogenic lipid profile compared with ATZ/r.

Comparison of the safety and efficacy of lomefloxacin and trimethoprim/sulfamethoxazole in the treatment of uncomplicated urinary tract infections: results from a multicenter study.

Lomefloxacin, a new difluorinated quinolone, and trimethoprim/sulfamethoxazole (TMP/SMX) were compared in the treatment of adults with uncomplicated urinary tract infections. The study was conducted as a multicenter, controlled, prospectively randomized, single-blind study in five countries (Argentina, Belgium, Brazil, Mexico, and Venezuela). A total of 254 patients were enrolled: 129 in the lomefloxacin group and 125 in the TMP/SMX group. Patients received either 400 mg lomefloxacin orally once daily or 160 mg/800 mg TMP/SMX orally twice daily for 7-10 days. Escherichia coli and Proteus mirabilis were the pathogens most frequently isolated. At 5-9 days post-therapy, satisfactory bacteriologic results were noted in 98.4% of patients treated with lomefloxacin and in 95.8% of patients in the TMP/SMX group (p = 0.2153). Clinical success 5-9 days post-therapy was noted in 99.2% of patients in the lomefloxacin group and in 98.3% of patients in the TMP/SMX group (p = 0.5138). Adverse events probably related to treatment occurred in 6% of those treated with lomefloxacin and in 7% of patients treated with TMP/SMX. Once-daily oral lomefloxacin is a well-tolerated and effective treatment of uncomplicated urinary tract infections caused by susceptible pathogens.

Comparison of the safety and efficacy of lomefloxacin and amoxicillin in the treatment of acute exacerbations of chronic bronchitis: Results from a Latin American multicenter study.

The aim of this study was to compare the safety and efficacy of lomefloxacin, a new difluornated quinolone, with those of amoxicillin in the treatment of acute exacerbations of chronic bronchitis caused by Gram-negative bacteria. The study was conducted as a multicenter, randomized, single-blind comparison in four countries (Argentina, Colombia, Mexico and Venezuela). In total, 163 evaluable patients were assessed-82 in the lomefloxacin group and 81 in the amoxicillin group. Patients received oral therapy with either 40 mg lomefloxacin once daily or 500 mg amoxicillin three times daily for 10 days. The most frequent bacterial pathogens isolated included: Haemophilus influenzae, Moraxella catarrhalis, Pseudomonas aeruginosa and Klebsiella pneumoniae. The overall clinical success rates (cure plus improvement) were 93.9% in the lomefloxacin group and 81.5% in the amoxicillin group. The eradication rate was 81.7% in the lomefloxacin group and 75.3% in the amoxicillin group. Most of the clinical and bacteriological failures in both groups were associated with P. aeruginosa in baseline sputum cultures. In conclusion, once-daily lomefloxacin is a safe and effective treatment for acute exacerbations of chronic bronchitis caused by Gram-negative pathogens.

Safety and efficacy of lomefloxacin and cefaclor in the treatment of skin and skin structure infections.

The purpose of this study was to compare the safety and efficacy of lomefloxacin with that of cefaclor in the treatment of adult secondary bacterial skin and skin structure infections. The study was conducted as a randomized, single-blind comparison. Eighty patients enrolled in the study, of which 74 were evaluable: 37 patients in the lomefloxacin group and 37 in the cefaclor group. Patients received either 400 mg of lomefloxacin orally once daily or 250 mg of cefaclor orally three times daily for 12 days. The most frequent pathogens isolated included Staphylococcus aureus, Streptococcus pyogenes, coagulase-negative staphylococci, and Escherichia coli. The clinical response was similar in both groups (89.1%). The bacteriologic eradication rate was 100% in the lomefloxacin group and 94.5% in the cefaclor group. Adverse events were minimal. Once-daily lomefloxacin is a safe and effective treatment for secondary bacterial skin and skin structure infections caused by susceptible pathogens.

Quinolones in the treatment of Salmonella carriers.

Infections caused by Salmonella typhi are commonly followed by a chronic carrier state despite positive clinical and initial bacteriologic responses. The use of primary antibiotics like chloramphenicol, ampicillin, and trimethoprim-sulfamethoxazole has several major drawbacks, including in some instances the failure to prevent the carrier state. The appearance worldwide of strains with multiple resistance to the most commonly used regimens has prompted the search for new forms of therapy. Among the agents studied have been third-generation cephalosporins and quinolones, which are active in vitro against bacterial enteropathogens like S. typhi. Resolution of chronic carriage of S. typhi and other salmonellae is difficult, and regimens commonly fail (including those that combine antibiotic administration with removal of the gallbladder). In addition to being active in vitro against Salmonella species, the newer quinolones adequately penetrate the intestinal lumen, liver, bile, and gallbladder. Initial experience with norfloxacin and ciprofloxacin in oral treatment of the chronic S. typhi carrier state in adults has been promising.

Once-daily azithromycin in the treatment of adult skin and skin-structure infections.

The aim of this prospective, blinded, randomized study was to demonstrate the efficacy and safety of oral azithromycin and dicloxacillin in the treatment of adults with acute skin and skin-structure infections. Sixty-two patients were included in the intent-to-treat group and 60 were evaluable for analysis. Azithromycin was given as a 500 mg once-daily dose for three days and dicloxacillin as 250 mg qid for seven days. Isolated pathogens included primarily Staphylococcus aureus, Streptococcus spp., and coagulase-negative staphylococci. Clinical resolution was 83.3% in the azithromycin group and 83.9% in the dicloxacillin group, with bacteriological eradication of 90.0% in the azithromycin group and 87.1% in the dicloxacillin group. Persistence of infection was recorded in one patient in the dicloxacillin group and superinfection in one patient in the azithromycin group. Azithromycin appears to be a safe and effective antibiotic for the treatment of adult patients with acute skin and skin-structure infections.