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Background Rifaximin has demonstrated efficacy and safety for diarrhea-predominant irritable bowel syndrome (IBS-D). Aim To determine the rifaximin repeat treatment effect on fecal bacterial antibiotic susceptibility. Methods Patients with IBS in Trial 3 (TARGET 3) study who responded to open-label rifaximin 550 mg three times daily for 2 weeks, with symptom recurrence within 18 weeks, were randomized to double-blind treatment: two 2-week repeat courses of rifaximin or placebo, separated by 10 weeks. Prospective stool sample collection occurred before and after open-label rifaximin, before and after the first repeat course, and at the end of the study. Susceptibility testing was performed with 11 antibiotics, including rifaximin and rifampin, using broth microdilution or agar dilution methods. Results Of 103 patients receiving open-label rifaximin, 73 received double-blind rifaximin ( n  = 37) or placebo ( n  = 36). A total of 1429 bacterial and yeast isolates were identified, of which Bacteroidaceae (36.7%) and Enterobacteriaceae (33.9%) were the most common. In the double-blind phase, Clostridium difficile was highly susceptible to rifaximin [minimum inhibitory concentration (MIC) range 0.008–1 µg/mL] and rifampin (MIC range 0.004–0.25 µg/mL). Following double-blind rifaximin treatment, Staphylococcus isolates remained susceptible to rifaximin at all visits (MIC 50 range ≤0.06–32 µg/mL). Rifaximin exposure was not associated with long-term cross-resistance of Bacteroidaceae, Enterobacteriaceae, and Enterococcaceae to rifampin or nonrifamycin antibiotics tested. Conclusions In this study, short-term repeat treatment with rifaximin has no apparent long-term effect on stool microbial susceptibility to rifaximin, rifampin, and nonrifamycin antibiotics. ClinicalTrials.gov Identifier NCT01543178.

BackgroundAmoxicillin, metronidazole, proton pump inhibitor, bismuth quadruple therapy had been shown to reliably achieve high eradication rates. The role of individual components remains undefined.AimTo identify the additional benefit/role of bismuth in amoxicillin, metronidazole, proton pump inhibitor, bismuth quadruple therapy for Helicobacter pylori (H. pylori) treatment.MethodsThis was a non-inferiority factorial design trial. Treatment-naive H. pylori-infected subjects were randomly (1:1) assigned to receive 14-day amoxicillin- and metronidazole-containing triple therapy consisting of esomeprazole 20 mg twice a day, amoxicillin 1 g, and metronidazole 400 mg both thrice daily with or without 220 mg bismuth twice a day. Six weeks after treatment, H. pylori eradication was assessed by 13C-urea breath test. Antimicrobial susceptibility was assessed by the twofold agar dilution method.ResultsFrom July 2018 to June 2019, a total of two hundred and sixteen subjects were randomized. Both therapies achieved high eradication rates. Per-protocol with bismuth = 97.9% (94/96, 95% CI 95.1–100%) and without bismuth = 94.7% (90/95, 95% CI 90.3–99.1%) (P = 0.43). Intent-to-treat analysis = 90.7% (98/108, 95% CI 85.2–96.2%) versus 88.9% (96/108, 95% CI 82.8–95.0%) with and without bismuth (P = 0.65). The two regimens were not inferior by intent-to-treat or per-protocol analyses. Metronidazole resistance did not affect the efficacy of either therapy.ConclusionNeither the presence nor absence of bismuth or metronidazole resistance reduced the effectiveness of triple therapy containing esomeprazole 20 mg twice a day, amoxicillin 1 g, and metronidazole 400 mg thrice daily in this population. The clinical trial was registered with ClinicalTrials.gov, NCT03557437.

Background Novel, rapid blood culture diagnostics can provide faster antibiotic susceptibility results (AST) compared to standard methods but their impact on clinical outcomes is unclear and not assessed in many prospective clinical trials. Methods This study is a two-arm, multicenter, multinational, prospective randomized controlled clinical trial conducted in countries with high antibiotic resistance rates including Greece, India, Israel, and Spain. Nine hundred hospitalized subjects who have blood cultures collected as part of routine clinical care with growth of Gram-negative bacilli (GNB) will be randomized 1:1 to blood culture evaluation using standard of care (SOC) AST vs. a rapid phenotypic AST method, VITEK REVEAL™ in addition to SOC AST. Subjects in both study arms will be reviewed by antibiotic stewardship clinicians who will recommend changes to antibiotic therapy, if indicated. The primary outcome is a composite three-category Desirability of Outcome Ranking (DOOR) defined using three ordered levels: alive without deleterious events, alive with at least one deleterious event, and death. Key secondary outcomes include mortality, length of stay, and time to antibiotic escalation or de-escalation within 3 days of randomization. Exploratory outcomes include a five-category DOOR, categorial agreement between VITEK REVEAL™ and SOC testing, clinician compliance with antibiotic stewardship recommendations, and desirability of treatment selection based on antibiotic spectrum, activity, and bloodstream isolate susceptibility profile (DOOR MAT). The primary analysis will be conducted on the modified intention-to-treat population. Discussion This trial will evaluate whether use of a rapid phenotypic AST method improves outcomes compared to use of conventional methods for patients with Gram-negative bloodstream infections in clinical settings with high antibiotic resistance rates. Trial registration ClinicalTrials.gov ID NCT06174649. Registered on Dec 18 2023. Protocol version Number 20-0021, version 5.0, 11-April-2024.

Background Currently, there is no agreed standard for exploring the antimicrobial activity of wound antiseptics in a phase 2/ step 2 test protocol. In the present study, a standardised in-vitro test is proposed, which allows to test potential antiseptics in a more realistically simulation of conditions found in wounds as in a suspension test. Furthermore, factors potentially influencing test results such as type of materials used as test carrier or various compositions of organic soil challenge were investigated in detail. Methods This proposed phase 2/ step 2 test method was modified on basis of the EN 14561 by drying the microbial test suspension on a metal carrier for 1 h, overlaying the test wound antiseptic, washing-off, neutralization, and dispersion at serial dilutions at the end of the required exposure time yielded reproducible, consistent test results. Results The difference between the rapid onset of the antiseptic effect of PVP-I and the delayed onset especially of polihexanide was apparent. Among surface-active antimicrobial compounds, octenidine was more effective than chlorhexidine digluconate and polihexanide, with some differences depending on the test organisms. However, octenidine and PVP-I were approximately equivalent in efficiency and microbial spectrum, while polihexanide required longer exposure times or higher concentrations for a comparable antimicrobial efficacy. Conclusion Overall, this method allowed testing and comparing differ liquid and gel based antimicrobial compounds in a standardised setting.

AimsQuinolone-containing triple therapy has been considered as the second-line therapy for eradication of Helicobacter pylori (H. pylori). At present, there are no data to show the efficacy and safety of antofloxacin-based rescue therapy for the eradication of H. pylori, and this pilot clinical trial was designed.MethodsA total of 196 patients who failed H. pylori eradication using the clarithromycin-based or metronidazole-based triple or bismuth quadruple therapy were randomly allocated to one of the following rescue eradication therapy groups: AEA group (antofloxacin 200 mg once daily, esomeprazole 20 mg + amoxicillin 1000 mg twice daily) for 14 days, or LEA group (levofloxacin 500 mg once daily, esomeprazole 20 mg + amoxicillin 1000 mg twice daily) for 14 days. The minimal inhibitory concentrations were tested by the E-test method. The gyrA mutation was analyzed by sequencing. Follow-up 13/14C-urea breath test was examined at 1 month after discontinuation.ResultsA total of 178 eligible patients were included in this study. The eradication rate was significantly higher in AEA group than in LEA group according to both ITT (87.6% vs. 68.5%; P = 0.002) and PP analyses (90.7% vs. 70.1%; P = 0.001). ITT analyses indicated that the eradication rate was significantly higher in AEA group than in LEA group with Asn87 mutation (78.9% vs. 31.3%; P = 0.005) and levofloxacin-resistant strains (76.9% vs. 44.2%; P = 0.003). Two groups exhibited similar adverse event rates (AEA 14.6% vs. LEA 20.2%, P = 0.323).ConclusionsThe findings showed that antofloxacin may be a promising candidate in rescue therapy for H. pylori eradication failure in China.

Solithromycin is a novel fluoroketolide developed in both oral and intravenous formulations to address increasing macrolide resistance in pathogens causing community-acquired bacterial pneumonia (CABP). When compared with its macrolide and ketolide predecessors, solithromycin has several structural modifications which increase its ribosomal binding and reduce its propensity to known macrolide resistance mechanisms. Solithromycin, like telithromycin, affects 50S ribosomal subunit formation and function, as well as causing frame-shift errors during translation. However, unlike telithromycin, which binds to two sites on the ribosome, solithromycin has three distinct ribosomal binding sites. Its desosamine sugar interacts at the A2058/A2059 cleft in domain V (as all macrolides do), an extended alkyl-aryl side chain interacts with base pair A752-U2609 in domain II (similar to telithromycin), and a fluorine at C-2 of solithromycin provides additional binding to the ribosome. Studies describing solithromycin activity against Streptococcus pneumoniae have reported that it does not induce erm -mediated resistance because it lacks a cladinose moiety, and that it is less susceptible than other macrolides to mef -mediated efflux due to its increased ribosomal binding and greater intrinsic activity. Solithromycin has demonstrated potent in vitro activity against the most common CABP pathogens, including macrolide-, penicillin-, and fluoroquinolone-resistant isolates of S. pneumoniae , as well as Haemophilus influenzae and atypical bacterial pathogens. Solithromycin displays multi-compartment pharmacokinetics, a large volume of distribution (>500 L), approximately 67% bioavailability when given orally, and serum protein binding of 81%. Its major metabolic pathway appears to follow cytochrome P450 (CYP) 3A4, with metabolites of solithromycin undergoing biliary excretion. Its serum half-life is approximately 6–9 h, which is sufficient for once-daily administration. Pharmacodynamic activity is best described as f AUC 0–24 /MIC (the ratio of the area under the free drug concentration–time curve from 0 to 24 h to the minimum inhibitory concentration of the isolate). Solithromycin has completed one phase II and two phase III clinical trials in patients with CABP. In the phase II trial, oral solithromycin was compared with oral levofloxacin and demonstrated similar clinical success rates in the intention-to-treat (ITT) population (84.6 vs 86.6%). Clinical success in the clinically evaluable patients group was 83.6% of patients receiving solithromycin compared with 93.1% for patients receiving levofloxacin. In SOLITAIRE-ORAL, a phase III trial which assessed patients receiving oral solithromycin or oral moxifloxacin for CABP, an equivalent (non-inferior) early clinical response in the ITT population was demonstrated for patients receiving either solithromycin (78.2%) or moxifloxacin (77.9%). In a separate phase III trial, SOLITAIRE-IV, patients receiving intravenous-to-oral solithromycin (79.3%) demonstrated non-inferiority as the primary outcome of early clinical response in the ITT population compared with patients receiving intravenous-to-oral moxifloxacin (79.7%). Overall, solithromycin has been well tolerated in clinical trials, with gastrointestinal adverse events being most common, occurring in approximately 10% of patients. Transaminase elevation occurred in 5–10% of patients and generally resolved following cessation of therapy. None of the rare serious adverse events that occurred with telithromycin (i.e., hepatotoxicity) have been noted with solithromycin, possibly due to the fact that solithromycin (unlike telithromycin) does not possess a pyridine moiety in its chemical structure, which has been implicated in inhibiting nicotinic acetylcholine receptors. Because solithromycin is a possible substrate and inhibitor of both CYP3A4 and P-glycoprotein (P-gp), it may display drug interactions similar to macrolides such as clarithromycin. Overall, the in vitro activity, clinical efficacy, tolerability, and safety profile of solithromycin demonstrated to date suggest that it continues to be a promising treatment for CABP.

Inadequate therapy in bloodstream infections is suggested to be associated with higher mortality. We evaluated the reduction in inappropriate antibiotic therapy using rapid identification and antibiotic susceptibility testing (FAST) compared to standard of care (SOC) testing in patients with bloodstream infections. The FAST method used polymerase chain reaction (PCR) for identification and to detect growth in the presence or absence of antibiotics after only 6 h. For SOC testing, the BD Phoenix system was used. Patients with blood cultures growing Staphylococcus , Streptococcus or Enterococcus species or Gram-negative rods were randomised for FAST or SOC tests. A total of 129 patients were randomised for FAST and 121 patients for the SOC group. At the time SOC results became available, 78 patients in the FAST group could have been switched to more appropriate therapy. Although FAST results were highly accurate (agreement with SOC was 94 %), they were only implemented in a minority (16) of patients. However, significantly fewer patients in the FAST group used inappropriate therapy at the time of SOC results ( p  = 0.025). The time to results in the FAST group was reduced by 15.6 h ( p  < 0.001). In the patients switched after FAST, this was done after a mean of 42.3 h compared to 61.4 h in those switched after SOC tests ( p  < 0.001). In bacteraemic patients, FAST resulted in significantly more patients using appropriate antibiotic therapy at the time SOC results were available and 15.6 h earlier than SOC tests. However, the implementation of FAST results was not optimal and no benefit on clinical outcome was shown.

Background Invasive fungal infections are a major cause of morbidity and mortality in preterm infants. The authors conducted the first prospective, randomised controlled trial of nystatin compared with fluconazole for the prevention of fungal colonisation and invasive fungal infection in very low birth weight (VLBW) neonates. Methods During a 12-month period, all VLBW neonates were assigned randomly to receive nystatin (1 ml suspension, 100 000 U/ml, every 8 h), fluconazole (3 mg/kg body weight, every third day) or placebo from birth until day 30 of life (day 45 for neonates weighing <1000 g at birth). The authors performed weekly surveillance cultures and systemic fungal susceptibility testing. Results During the study period, 278 infants (fluconazole group, n=93; nystatin group, n=94; control group, n=91) weighing <1500 g at birth were admitted. There were no differences in birth weight, gestation, gender or risk factors for fungal infection among the groups. Fungal colonisation occurred in 11.7% of the nystatin group and 10.8% of the fluconazole group, as compared with 42.9% of the control group. The incidence of invasive fungal infection was 4.3% in the nystatin group and 3.2% in the fluconazole group, as compared with 16.5% in the control group. There were no differences in fungal colonisation and invasive fungal infection between the nystatin and fluconazole groups. Conclusions Prophylactic nystatin and fluconazole reduce the incidence of colonisation and invasive fungal infection in VLBW neonates. The authors believe that nystatin is an alternative to fluconazole, because nystatin is safe, inexpensive, well tolerated and effective.

The purpose of this investigation was to assess the impact of selective reporting of antibiotic susceptibility data on the appropriateness of intended documented antibiotic prescriptions in urinary tract infections (UTIs) among residents training in general practice. We conducted a randomised-controlled case-vignette study in three French universities using a questionnaire with four UTI vignettes. In each university, residents were randomly allocated to two groups: a control group with usual full-length reporting of antibiotic susceptibility data (25 antibiotics) and an intervention group with selective reporting of antibiotic susceptibility data (2 to 4 antibiotics only). 326/611 residents (53 %) participated in the survey, 157/305 (52 %) in the intervention group and 169/306 (55 %) in the control group. For all four UTI scenarios, selective reporting of antibiotic susceptibility data significantly improved the appropriateness of antibiotic prescriptions (absolute increase ranging from 7 to 41 %, depending on the vignette). The variety of antibiotic prescriptions was reduced in the intervention group, and cephalosporins and fluoroquinolones were less often prescribed. Among 325 respondents, 124 (38 %) declared being either not really or not at all at ease with antibiotic susceptibility data, whereas 112/157 (71 %) of the residents in the intervention group declared that selective reporting of antibiotic susceptibility data made their antibiotic choice easier. Selective reporting of antibiotic susceptibility data could be a promising strategy to improve antibiotic use in UTIs, as part of a multi-faceted antibiotic stewardship programme. Microbiology laboratories should be aware that they can have a significant influence on antibiotic use.

Volunteers experimentally infected with influenza A/Texas/36/91 (H1N1) virus and treated with the neuraminidase (NA) inhibitor oseltamivir were monitored for the emergence of drugresistant variants. Two (4%) of 54 resistant viruses were detected by NA inhibition assay among last-day isolates recovered from 54 drug recipients. They bore a substitution His274Tyr in the NA. Hemagglutinin (HA) variants detected in the placebo group differed from the eggadapted inoculum virus by virtue of amino acid substitutions at residues 137, 225, or both. These variants had a higher affinity for Neu5Ac(α2–6)Gal-containing receptors, which are characteristic of human respiratory epithelium, than for Neu5Ac(α2–3)Gal-containing receptors, which are typical of chicken egg allantoic membrane. Although appearing to be more sensitive to oseltamivir in humans, the variants with increased affinity for Neu5Ac(α2–6)Gal receptors were less sensitive than the Neu5Ac(α2–3)Gal-binding variants in Madin-Darby canine kidney cells. Thus, HA affinity for receptors is an essential feature of influenza virus susceptibility to NA inhibitors, both in cell culture and in humans.