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Antibiotics and the developing intestinal microbiome, metabolome and inflammatory environment in a randomized trial of preterm infants.
Russell, JT, Lauren Ruoss, J, de la Cruz, D, Li, N, Bazacliu, C, Patton, L, McKinley, KL, Garrett, TJ, Polin, RA, Triplett, EW, et al
Scientific reports. 2021;(1):1943
Abstract
Antibiotic use in neonates can have detrimental effects on the developing gut microbiome, increasing the risk of morbidity. A majority of preterm neonates receive antibiotics after birth without clear evidence to guide this practice. Here microbiome, metabolomic, and immune marker results from the routine early antibiotic use in symptomatic preterm Neonates (REASON) study are presented. The REASON study is the first trial to randomize symptomatic preterm neonates to receive or not receive antibiotics in the first 48 h after birth. Using 16S rRNA sequencing of stool samples collected longitudinally for 91 neonates, the effect of such antibiotic use on microbiome diversity is assessed. The results illustrate that type of nutrition shapes the early infant gut microbiome. By integrating data for the gut microbiome, stool metabolites, stool immune markers, and inferred metabolic pathways, an association was discovered between Veillonella and the neurotransmitter gamma-aminobutyric acid (GABA). These results suggest early antibiotic use may impact the gut-brain axis with the potential for consequences in early life development, a finding that needs to be validated in a larger cohort.Trial Registration This project is registered at clinicaltrials.gov under the name "Antibiotic 'Dysbiosis' in Preterm Infants" with trial number NCT02784821.
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A randomized double-blinded placebo-controlled clinical trial on protective effects of pentoxifylline on gentamicin nephrotoxicity in infectious patients.
Mousavinasab, SR, Akhoundi-Meybodi, Z, Mahmoudi, L, Karimzadeh, I
Clinical and experimental nephrology. 2021;(8):844-853
Abstract
BACKGROUND AND OBJECTIVE Renal toxicity has limited gentamicin use in clinical practice. The aim of the present clinical trial was to assess the possible nephroprotective effects of pentoxifylline (PTX) against gentamicin nephrotoxicity. MATERIALS AND METHODS A multicenter, randomized, double-blind, placebo-controlled clinical trial was conducted on patients who had the indication for systemic gentamicin for at least 7 days. Sixty people were selected and randomly assigned. For patients in the intervention and control groups, 400 mg PTX sustained release tablet and placebo were given orally three times daily, respectively. Demographic, clinical, laboratory, and therapeutic information of patients were recorded. malondialdehyde (MDA) and tumor necrosis factor-alpha (TNF-α) levels in serum were measured on days 0 and 7. RESULTS The incidence of nephrotoxicity in the placebo group was 19.6 times higher than that in the PTX group (OR = 19.6, 95%CI = 3.08-114.32; P value = 0.001). The mean ± SD time onset of ATN was 4.00 ± 2.32 and 5.58 ± 1.59 days in PTX and placebo recipients, respectively (P value < 0.001). No significant differences were observed for hypokalemia, hypomagnesemia, potassium and magnesium wasting between the two groups. The mean ± SD levels of serum MDA and TNF-α at day 7 were significantly lower in the PTX compared to those in the placebo group (P value < 0.001 for both indexes). CONCLUSION The co-administration of 400 mg PTX orally three times daily along with gentamicin was both well-tolerated and effective in preventing the nephrotoxicity of gentamicin in patients with different infectious diseases.
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A 10-Year Follow-Up of a Randomized Prospective Study of 2 Treatments for Chronic Rhinosinusitis Without Nasal Polyps and Investigation of the Impact of Gastroeosophageal Reflux Disease in the Resistance to Treatment.
Lechien, JR, Debie, G, Mahillon, V, Thill, MP, Rodriguez, A, Horoi, M, Kampouridis, S, Muls, V, Saussez, S
Ear, nose, & throat journal. 2021;(5_suppl):569S-577S
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OBJECTIVES To compare the 2 long-term medical strategies in chronic rhinosinusitis without nasal polyps (CRSnNP) and to identify the role of gastroesophageal reflux disease (GERD) and Helicobacter pylori as factors of treatment failure. MATERIAL AND METHODS Fifty-seven patients with CRSnNP were randomized into 2 therapeutic groups. The first group was treated with 4 weeks of amoxicillin/clavulanate and a short course of oral steroids. The second group received 8 weeks of clarithromycin. Sinonasal Outcome Test-20 (SNOT-20) and Lund and Mackay scores were assessed at baseline and after treatment, and GERD Health-Related Quality of Life (GERD-HRQL) questionnaire was evaluated in all patients. Patients with a GERD-HRQL score >8 received esogastroscopy and H pylori detection. Patients were followed during a 10-year period for clinical course and GERD evolution. The 10-year evolution of patients was described in terms of recurrence, medical, and surgical treatments. RESULTS Thirty-seven patients completed the study; SNOT-20 and Lund and Mackay scores similarly improved in both groups. Amoxicillin/clavulanate group had significantly more adverse reactions than the clarithromycin group (P = .03). After the therapeutic course, 35% (amoxicillin/clavulanate) and 41% (clarithromycin) of patients needed functional endoscopic sinus surgery (FESS). During the long-term follow-up, 54% (amoxicillin/clavulanate) and 40% (clarithromycin) of patients had late CRSnNP recurrence; FESS was performed in less than 15% of cases of recurrence. Gastroesophageal reflux disease complaint's severity was associated with late recurrence of CRSnNP. CONCLUSION Amoxicillin/clavulanate and clarithromycin would be competitive treatments for CRSnNP. Gastroesophageal reflux disease seems to be a negative factor for treatment response and recurrence.
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The Colombian Chemoprevention Trial: 20-Year Follow-Up of a Cohort of Patients With Gastric Precancerous Lesions.
Piazuelo, MB, Bravo, LE, Mera, RM, Camargo, MC, Bravo, JC, Delgado, AG, Washington, MK, Rosero, A, Garcia, LS, Realpe, JL, et al
Gastroenterology. 2021;(4):1106-1117.e3
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BACKGROUND & AIMS Helicobacter pylori eradication and endoscopic surveillance of gastric precancerous lesions are strategies to reduce gastric cancer (GC) risk. To our knowledge, this study is the longest prospective cohort of an H pylori eradication trial in a Hispanic population. METHODS A total of 800 adults with precancerous lesions were randomized to anti-H pylori treatment or placebo. Gastric biopsy samples taken at baseline and 3, 6, 12, 16, and 20 years were assessed by our Correa histopathology score. A generalized linear mixed model with a participant-level random intercept was used to estimate the effect of H pylori status on the score over time. Logistic regression models were used to estimate progression by baseline diagnosis and to estimate GC risk by intestinal metaplasia (IM) subtype and anatomic location. RESULTS Overall, 356 individuals completed 20 years of follow-up. Anti-H pylori therapy (intention-to-treat) reduced progression of the Correa score (odds ratio [OR], 0.59; 95% confidence interval [CI], 0.38-0.93). H pylori-negative status had a beneficial effect on the score over time (P = .036). Among individuals with IM (including indefinite for dysplasia) at baseline, incidence rates per 100 person-years were 1.09 (95% CI, 0.85-1.33) for low-grade/high-grade dysplasia and 0.14 (95% CI, 0.06-0.22) for GC. Incomplete-type (vs complete-type) IM at baseline presented higher GC risk (OR, 13.4; 95% CI, 1.8-103.8). Individuals with corpus (vs antrum-restricted) IM showed an OR of 2.1 (95% CI, 0.7-6.6) for GC. CONCLUSIONS In a high-GC-risk Hispanic population, anti-H pylori therapy had a long-term beneficial effect against histologic progression. Incomplete IM is a strong predictor of GC risk.
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Effect of 3 Days of Oral Azithromycin on Young Children With Acute Diarrhea in Low-Resource Settings: A Randomized Clinical Trial.
, , Ahmed, T, Chisti, MJ, Rahman, MW, Alam, T, Ahmed, D, Parvin, I, Kabir, MF, Sazawal, S, Dhingra, P, et al
JAMA network open. 2021;(12):e2136726
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IMPORTANCE World Health Organization (WHO) guidelines do not recommend routine antibiotic use for children with acute watery diarrhea. However, recent studies suggest that a significant proportion of such episodes have a bacterial cause and are associated with mortality and growth impairment, especially among children at high risk of diarrhea-associated mortality. Expanding antibiotic use among dehydrated or undernourished children may reduce diarrhea-associated mortality and improve growth. OBJECTIVE To determine whether the addition of azithromycin to standard case management of acute nonbloody watery diarrhea for children aged 2 to 23 months who are dehydrated or undernourished could reduce mortality and improve linear growth. DESIGN, SETTING, AND PARTICIPANTS The Antibiotics for Children with Diarrhea (ABCD) trial was a multicountry, randomized, double-blind, clinical trial among 8266 high-risk children aged 2 to 23 months presenting with acute nonbloody diarrhea. Participants were recruited between July 1, 2017, and July 10, 2019, from 36 outpatient hospital departments or community health centers in a mixture of urban and rural settings in Bangladesh, India, Kenya, Malawi, Mali, Pakistan, and Tanzania. Each participant was followed up for 180 days. Primary analysis included all randomized participants by intention to treat. INTERVENTIONS Enrolled children were randomly assigned to receive either oral azithromycin, 10 mg/kg, or placebo once daily for 3 days in addition to standard WHO case management protocols for the management of acute watery diarrhea. MAIN OUTCOMES AND MEASURES Primary outcomes included all-cause mortality up to 180 days after enrollment and linear growth faltering 90 days after enrollment. RESULTS A total of 8266 children (4463 boys [54.0%]; mean [SD] age, 11.6 [5.3] months) were randomized. A total of 20 of 4133 children in the azithromycin group (0.5%) and 28 of 4135 children in the placebo group (0.7%) died (relative risk, 0.72; 95% CI, 0.40-1.27). The mean (SD) change in length-for-age z scores 90 days after enrollment was -0.16 (0.59) in the azithromycin group and -0.19 (0.60) in the placebo group (risk difference, 0.03; 95% CI, 0.01-0.06). Overall mortality was much lower than anticipated, and the trial was stopped for futility at the prespecified interim analysis. CONCLUSIONS AND RELEVANCE The study did not detect a survival benefit for children from the addition of azithromycin to standard WHO case management of acute watery diarrhea in low-resource settings. There was a small reduction in linear growth faltering in the azithromycin group, although the magnitude of this effect was not likely to be clinically significant. In low-resource settings, expansion of antibiotic use is not warranted. Adherence to current WHO case management protocols for watery diarrhea remains appropriate and should be encouraged. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT03130114.
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Rifaximin or Saccharomyces boulardii in heart failure with reduced ejection fraction: Results from the randomized GutHeart trial.
Awoyemi, A, Mayerhofer, C, Felix, AS, Hov, JR, Moscavitch, SD, Lappegård, KT, Hovland, A, Halvorsen, S, Halvorsen, B, Gregersen, I, et al
EBioMedicine. 2021;:103511
Abstract
BACKGROUND The gut microbiota represents a potential treatment target in heart failure (HF) through microbial metabolites such as trimethylamine N-oxide (TMAO) and systemic inflammation. Treatment with the probiotic yeast Saccharomyces boulardii have been suggested to improve left ventricular ejection fraction (LVEF). METHODS In a multicentre, prospective randomized open label, blinded end-point trial, we randomized patients with LVEF <40% and New York Heart Association functional class II or III, despite optimal medical therapy, to treatment (1:1:1) with the probiotic yeast Saccharomyces boulardii, the antibiotic rifaximin, or standard of care (SoC) only. The primary endpoint, the baseline-adjusted LVEF at three months, was assessed in an intention-to-treat analysis. FINDINGS We enrolled a total of 151 patients. After three months' treatment, the LVEF did not differ significantly between the SoC arm and the rifaximin arm (mean difference was -1•2 percentage points; 95% CI -3•2 - 0•7; p=0•22) or between the SoC arm and the Saccharomyces boulardii arm (mean difference -0•2 percentage points; 95% CI -2•2 - 1•9; p=0•87). We observed no significant between-group differences in changes in microbiota diversity, TMAO, or C-reactive protein. INTERPRETATION Three months' treatment with Saccharomyces boulardii or rifaximin on top of SoC had no significant effect on LVEF, microbiota diversity, or the measured biomarkers in our population with HF. FUNDING The trial was funded by the Norwegian Association for Public Health, the Blix foundation, Stein Erik Hagen's Foundation for Clinical Heart Research, Ada og Hagbart Waages humanitære og veldedige stiftelse, Alfasigma, and Biocodex.
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Efficacy of Lactiplantibacillus plantarum 299 and 299v against nosocomial oropharyngeal pathogens in vitro and as an oral prophylactic treatment in a randomized, controlled clinical trial.
Tranberg, A, Klarin, B, Johansson, J, Påhlman, LI
MicrobiologyOpen. 2021;(1):e1151
Abstract
BACKGROUND Disturbance in the oropharyngeal microbiota is common in hospitalized patients and contributes to the development of nosocomial pneumonia. Lactiplantibacillus plantarum 299 and 299v (Lp299 and Lp299v) are probiotic bacteria with beneficial effects on the human microbiome. AIM: To investigate how Lp299 and Lp299v affect the growth of nosocomial oropharyngeal pathogens in vitro and to evaluate the efficacy in vivo when these probiotics are administered prophylactically in hospitalized patients. METHODS The in vitro effect of Lp299 and Lp299v on nosocomial respiratory tract pathogens was evaluated using two methods, the co-culture and agar overlay. In the clinical study, patients were randomized to orally receive either probiotics or placebo twice daily during their hospital stay. Oropharyngeal swabs were analyzed at inclusion and every fourth day throughout hospitalization. FINDINGS All tested pathogens were completely inhibited by both Lp299 and Lp299v using the agar-overlay method. In the co-culture experiment, Lp299 and Lp299v significantly (p < 0.05) reduced the growth of all pathogens except for Enterococcus faecalis co-incubated with Lp299. In the clinical study, daily oral treatment with Lp299 and Lp299v did not influence the development of disturbed oropharyngeal microbiota or nosocomial infection. Proton pump inhibitors, antibiotics, and steroid treatment were identified as risk factors for developing disturbed oropharyngeal microbiota. CONCLUSIONS Lp299 and Lp299v inhibited pathogen growth in vitro but did not affect the oropharyngeal microbiota in vivo. The ClinicalTrials.gov Identifier for this study is NCT02303301.
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Tolerability and effectiveness of povidone-iodine or mupirocin versus saline sinus irrigations for chronic rhinosinusitis.
Lee, VS, Pottinger, PS, Davis, GE
American journal of otolaryngology. 2020;(5):102604
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OBJECTIVES The role of topical anti-infectives in acute exacerbations of chronic rhinosinusitis is controversial. Povidone-iodine is an anti-bacterial and anti-viral that is affordable and available over-the-counter and may demonstrate advantages over mupirocin as a sinus irrigation therapy. The objective was to compare povidone-iodine or mupirocin versus saline sinus irrigations for sinusitis exacerbations in post-surgery subjects as well as to assess tolerability of povidone-iodine sinus irrigations. MATERIALS AND METHODS This was a prospective single-blinded (clinician only) randomized controlled trial. Subjects were post-surgery with acute exacerbations of chronic rhinosinusitis and gram-positive bacteria on culture. They received povidone-iodine, mupirocin, or saline sinus irrigations, twice daily for 30 days. Outcomes were post-treatment culture negativity (primary) and Sinonasal Outcome Test-20 and Lund-Kennedy endoscopic score change (secondary). RESULTS Of the 62 subjects analyzed, post-treatment culture negativity rate was higher in the MUP (14/20, 70%) group compared to the PI (9/21, 43%) and SAL (9/19, 47%) groups, although this was not significant (p = 0.29). Povidone-iodine sinus irrigations at the 1% concentration were very well-tolerated, similar to saline irrigations. There were no significant differences in Sinonasal Outcome Test-20 score (povidone-iodine -0.3 [-0.6, 0.05] vs. mupirocin -0.3 [-0.7, 0.05] vs. saline -0.4 [-0.8, 0.05]; p = 0.86) or Lund-Kennedy endoscopic score (povidone-iodine -3.5 [-7, -0.5] vs. mupirocin -2 [-4, 2] vs. saline -3 [-5, 0]; p = 0.45) change. No serious adverse effects were reported. CONCLUSIONS In patients who have had prior sinus surgery with acute exacerbations of CRS and gram-positive bacteria on culture, mupirocin sinus irrigations achieved a better post-treatment culture "control" rate compared to saline and povidone-iodine. In addition, 1% povidone-iodine solution was well-tolerated as a sinus irrigation and may represent a feasible method for temporarily disinfecting the sinonasal cavity of bacteria and viruses such as COVID-19.
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A Prospective, Randomized Trial of Povidone-Iodine 0.6% and Dexamethasone 0.1% Ophthalmic Suspension for Acute Bacterial Conjunctivitis.
Ta, CN, Raizman, MB, Gross, RD, Joshi, S, Mallick, S, Wang, Y, Segal, B
American journal of ophthalmology. 2020;:56-65
Abstract
PURPOSE To evaluate the efficacy and safety of a topical ophthalmic suspension combination of povidone-iodine 0.6% (PVP-I) and dexamethasone 0.1% (DEX) for infectious and inflammatory components of bacterial conjunctivitis. DESIGN Randomized, double-masked, multicenter, phase 3 clinical trial. METHODS Subjects of all ages (those <3 months had to be full-term) with a diagnosis of bacterial conjunctivitis were randomized 3:1:3 to either PVP-I/DEX, PVP-I alone, or placebo. The primary endpoint was clinical resolution in the study eye, and the key secondary efficacy endpoint was bacterial eradication, both at the day 5 visit. Adverse events (AEs) were documented at all visits. RESULTS Overall, 753 subjects were randomized (intent-to-treat [ITT] population; PVP-I/DEX [n = 324]; PVP-I [n = 108]; placebo [n = 321]); mean and standard deviation (SD) age was 44.3 (22.9) years, and most were female (61.2%) and white (78.1%). In all treatment groups, mean treatment compliance was >98%. The modified ITT population for the efficacy analysis comprised 526 subjects. In the study eye at the day 5 visit, clinical resolution was achieved by 50.5% (111/220) subjects in the PVP-I/DEX group vs 42.8% (95/222) in the placebo group (P = .127), and bacterial eradication was achieved by 43.3% (94/217) and 46.8% (102/218), respectively (P = .500). Treatment-emergent AEs were experienced by 32.8% (106/323), 39.8% (43/108), and 19.0% (61/321) of subjects in the safety population treated with PVP-I/DEX, PVP-I, and placebo, respectively (most mild in severity). CONCLUSION In this study, PVP-I/DEX did not demonstrate additional benefit in clinical efficacy compared with placebo in subjects with bacterial conjunctivitis.
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Therapeutic Value of Vitamin D as an Adjuvant Therapy in Neonates with Sepsis.
Hagag, AA, El Frargy, MS, Houdeeb, HA
Infectious disorders drug targets. 2020;(4):440-447
Abstract
UNLABELLED Sepsis is unusual systemic reaction to an ordinary infection, and it probably represents a pattern of response by the immune system to the injury. Vitamin D is a fat-soluble steroid hormone that contributes to the maintenance of normal calcium homeostasis and skeletal mineralization. Vitamin D has an important role in the regulation of both innate and adaptive immune systems. AIM OF THE WORK The current study aimed to evaluate the therapeutic value of vitamin D supplementation as an adjuvant therapy in neonates with sepsis. SUBJECTS AND METHOD This study included 60 neonates with sepsis who were randomly divided into 2 equal groups; group I: 30 neonates with sepsis who received antibiotic only, Group II: 30 neonates with sepsis who received antibiotic therapy and vitamin D. This study also included 30 healthy neonates as a control group. For all patients and controls, serum level of 25 (OH) vitamin D and highly sensitive C reactive protein (hs-CRP) were immunoassayed. RESULTS There is no significant difference between groups I, II and controls regarding weight, gestational age, sex and mode of delivery. There were significant differences between groups I and II in sepsis score and hs-CRP after 3, 7, 10 days of treatment (p values for sepsis score were 0.009, 0.006, 0.004 respectively and for hs-CRP were 0.015, 0.001, 0.001 respectively). There was a significant difference in immature /total (I/T) ratio after 7, and 10 days of treatment (p value= 0.045, 0.025, respectively,) while there was no significant difference in immature /total (I/T) ratio after 3 days of treatment (p value = 0.624).Serum 25(OH) vitamin D levels were significantly lower in neonates with sepsis (group I and II) than the controls (p value < 0.05, while there were no significant differences between the three groups considering serum calcium and phosphorus levels (P =1.000, 1.000, respectively). Isolated organisms from blood culture in neonates with sepsis (group I and group II) were most commonly B- hemolytic streptococci, E-coli, hemophilus influenza and staphylococcus aurous. There was a significant negative correlation between hs-CRP and serum 25 (OH) vitamin in group II on entry (r = - 0.832 and P value = 0.001) and after 2 weeks (r = - 0.590 and P value = 0.021). ROC curve of specificity and sensitivity of 25 (OH) vitamin D level in prediction of early-onset neonatal sepsis showed that cutoff value of vitamin D was ≤20 ng/ml, sensitivity was 100%, specificity was 73%, positive predictive value was 73%, negative predictive value was 100% and accuracy was 87. CONCLUSION AND RECOMMENDATION Serum 25 (OH) vitamin D levels of neonates with the early onset neonatal sepsis were significantly lower than the healthy controls. Vitamin D supplementation improved sepsis score and decrease high levels of hs-CRP; this reflects the role of vitamin D as a target therapy for neonatal sepsis. Further studies are warranted to confirm the therapeutic value of vitamin D in neonatal sepsis.