High Doses Of Metronidazole Research Articles

Modulation of Iron Import and Metronidazole Resistance in Bacteroides fragilis Harboring a nimA Gene

Bacteroides fragilis is a commensal of the human gut but can also cause severe infections when reaching other body sites, especially after surgery or intestinal trauma. Bacteroides fragilis is an anaerobe innately susceptible to metronidazole, a 5-nitroimidazole drug that is prescribed against the majority of infections caused by anaerobic bacteria. In most of the cases, metronidazole treatment is effective but a fraction of B. fragilis is resistant to even very high doses of metronidazole. Metronidazole resistance is still poorly understood, but the so-called nim genes have been described as resistance determinants. They have been suggested to encode nitroreductases which reduce the nitro group of metronidazole to a non-toxic aminoimidazole. More recent research, however, showed that expression levels of nim genes are widely independent of the degree of resistance observed. In the search for an alternative model for nim-mediated metronidazole resistance, we screened a strain carrying an episomal nimA gene and its parental strain 638R without a nim gene for physiological differences. Indeed, the 638R daughter strain with the nimA gene had a far higher pyruvate-ferredoxin oxidoreductase (PFOR) activity than the parental strain. High PFOR activity was also observed in metronidazole-resistant clinical isolates, either with or without a nim gene. Moreover, the strain carrying a nimA gene fully retained PFOR activity and other enzyme activities such as thioredoxin reductase (TrxR) after resistance had been induced. In the parental strain 638R, these were lost or very strongly downregulated during the development of resistance. Further, after induction of high-level metronidazole resistance, parental strain 638R was highly susceptible to oxygen whereas the daughter strain with a nimA gene was hardly affected. Ensuing RT-qPCR measurements showed that a pathway for iron import via hemin uptake is downregulated in 638R with induced resistance but not in the resistant nimA daughter strain. We propose that nimA primes B. fragilis toward an alternative pathway of metronidazole resistance by enabling the preservation of normal iron levels in the cell.

High-dose dual therapy versus culture-based susceptibility-guided therapy as a rescue regimen for Helicobacter pylori infection: a randomized controlled trial.

Although the Maastricht VI/Florence consensus report recommended high-dose proton pump inhibitor-amoxicillin dual therapy as possible rescue therapy for Helicobacter pylori infection, clinical evidence of its efficacy was lacking. To compare the efficacy, safety, patient compliance, and cost between high-dose dual therapy (HDDT) and culture-based susceptibility-guided therapy (CB-SGT) as a rescue regimen for H. pylori infection. A single-center, open-label, randomized controlled clinical trial. In all, 146 patients with a history of eradication failure were enrolled and randomly assigned to receive HDDT or CB-SGT. HDDT consisted of esomeprazole 20 mg and amoxicillin 750 mg, both given four times per day (qid). CB-SGT consisted of esomeprazole 20 mg twice daily (bid), amoxicillin 1000 mg bid plus clarithromycin 500 mg bid, metronidazole 400 mg bid, or levofloxacin 500 mg daily (qd) for sensitive patients, in that order. For patients with triple resistance, a bismuth-containing regimen with a high dose of metronidazole was chosen, including esomeprazole 20 mg bid, bismuth 220 mg bid, amoxicillin 1000 mg bid, and metronidazole 400 mg qid. All regimens were given for 14 days. The eradication H. pylori rates achieved with HDDT in the intention-to-treat (ITT), per-protocol, and modified ITT analyses were all 84.9% [62/73, 95% confidence interval (CI): 76.5-93.9%], compared with 83.6% (61/73, 95% CI: 74.9-92.3%), 84.7% (61/72, 95% CI: 76.2-93.2%), and 84.7% (61/72, 95% CI: 76.2-93.2%) with CB-SGT, respectively. For patients with CYP2C19 polymorphisms of intermediate/poor metabolizers, the eradication rates of HDDT and CB-SGT were 90.70% (39/43, 95% CI: 77.86-97.41%) and 84.21% (32/38, 95% CI: 68.75-93.98%), respectively. The difference between groups was 6.49% (95% CI: -8.00% to 20.97%), and the non-inferiority p value was 0.0128. For patients with a treatment interval of more than 3 months, the eradication rates of the two regimens reached 88.71% (95% CI: 78.11-95.34%) and 71.97% (95% CI: 70.02-90.64%). The difference between groups was 6.74% (95% CI: -5.71% to 19.20%), with a non-inferiority p value of 0.0042. Patient adherence was high in both groups. The HDDT had a lower cost and rate of side effects (p < 0.001) compared with CB-SGT. HDDT can reach an eradication rate of 85% in treatment-experienced patients of H. pylori infection and 91% in patients with CYP2C19 polymorphisms of intermediate/poor metabolizers, with good compliance, lower side effects and costs, and less use of antibiotics. In conclusion, HDDT offers an effective rescue regimen for H. pylori infection. This clinical trial was registered at the Chinese Clinical Trail Registry (trail registration number: ChiCTR1900025044).

TREATMENT POTENTIAL OF ALOE VERA GEL IN GAIRDIA INTESTINALIS INFECTED ALBINO RATS

Aloe vera has been used as a traditional medicine in many cultures, especially Egypt, and known for its therapeutical effects with dermatitis, ulcer and burns. It has many beneficial properties as it is a powerful antioxidant, anti-inflammatory and antimicrobial agent. G. intestinalis is a waterborne parasite that causes human giardiasis. In Egypt, outbreaks commonly occur in areas where water treatment is insufficient leading to infection rates of 50% of the total population. The current treatment against G. intestinalis involves metronidazole, known as flagyl, which can induce many side effects as headache, vertigo, nausea, and a metallic taste in the mouth. Previous studies showed that high doses of metronidazole, over long periods, have mutagenic and carcinogenic effects in experimental animals. The study aims to evaluate the effect of Aloe vera in treatment of G. intestinalis in male albino rats in comparison to metronidazole. Our results showed that Aloe vera cleared the infection and reduced inflammatory cytokines in treated groups. Thus it can be used instead of metronidazole in treatment of G. intestinalis due to its anti-inflammatory properties and to avoid the undesired side effect of the metronidazole.

TREATMENT POTENTIAL OF ALOE VERA GEL IN GAIRDIA INTESTINALIS INFECTED ALBINO RATS

Aloe vera has been used as a traditional medicine in many cultures, especially Egypt, and known for its therapeutical effects with dermatitis, ulcer and burns. It has many beneficial properties as it is a powerful antioxidant, anti-inflammatory and antimicrobial agent. G. intestinalis is a waterborne parasite that causes human giardiasis. In Egypt, outbreaks commonly occur in areas where water treatment is insufficient leading to infection rates of 50% of the total population. The current treatment against G. intestinalis involves metronidazole, known as flagyl, which can induce many side effects as headache, vertigo, nausea, and a metallic taste in the mouth. Previous studies showed that high doses of metronidazole, over long periods, have mutagenic and carcinogenic effects in experimental animals. The study aims to evaluate the effect of Aloe vera in treatment of G. intestinalis in male albino rats in comparison to metronidazole. Our results showed that Aloe vera cleared the infection and reduced inflammatory cytokines in treated groups. Thus it can be used instead of metronidazole in treatment of G. intestinalis due to its anti-inflammatory properties and to avoid the undesired side effect of the metronidazole.

Bismuth improves efficacy of proton-pump inhibitor clarithromycin, metronidazole triple Helicobacter pylori therapy despite a high prevalence of antimicrobial resistance.

Helicobacter pylori (H. pylori) eradication has become increasingly difficult especially for penicillin allergy patients. To evaluate the efficacy of adding bismuth or high-dose metronidazole to an H.pylori eradication regimen containing a proton-pump inhibitor, clarithromycin, and metronidazole in patients allergic to penicillin. Pilot study in which penicillin-allergic, treatment-naive subjects were randomized (1:1) to 14-day esomeprazole (20mg q12h), clarithromycin (500mg q12h), and high dose of metronidazole (400mg q6h) with (BECM group) or without (ECM group) bismuth (600mg q12h). Eradication was confirmed by 13 C-urea breath test 6weeks after therapy. Antimicrobial susceptibility was assessed by the agar dilution method. Adverse events were recorded. Sixty-six subjects were randomized, four were lost to follow-up and eight violated the protocol. The eradication rates were 63.6% (95% CI: 47.2%-80.0%) for ECM vs 84.8% (95% CI 72.6%-97.1%) (p=.049) for BECM by intention-to-treat, 67.7% (95% CI 51.3%-84.2%) vs 90.3% (95% CI 79.9%-100%) (p=.029) by modified ITT, and 70% (95% CI 53.6%-86.4%) vs 96% (95% CI 88.3%-100%) (P=.033) by per-protocol. Metronidazole, clarithromycin, and dual-resistant rates were 74.2%, 24.2%, and 18.2%, respectively. The cure rates were significantly improved by the addition of bismuth for both clarithromycin-resistant isolates (100% vs 25%, P=.024) and metronidazole-resistant isolates (94.7% vs 63.6%, P=.043). Adverse events were reported by 45.5% of subjects in ECM group and 48.5% in the BECM group (P=.805). This prospective trial demonstrated that while high-dose metronidazole could not completely overcome metronidazole resistance, bismuth was additive and improved the overall cure rates by 21%-26%.

An In Vivo Zebrafish Model for Interrogating ROS-Mediated Pancreatic β-Cell Injury, Response, and Prevention.

It is well known that a chronic state of elevated reactive oxygen species (ROS) in pancreatic β-cells impairs their ability to release insulin in response to elevated plasma glucose. Moreover, at its extreme, unmitigated ROS drives regulated cell death. This dysfunctional state of ROS buildup can result both from genetic predisposition and environmental factors such as obesity and overnutrition. Importantly, excessive ROS buildup may underlie metabolic pathologies such as type 2 diabetes mellitus. The ability to monitor ROS dynamics in β-cells in situ and to manipulate it via genetic, pharmacological, and environmental means would accelerate the development of novel therapeutics that could abate this pathology. Currently, there is a lack of models with these attributes that are available to the field. In this study, we use a zebrafish model to demonstrate that ROS can be generated in a β-cell-specific manner using a hybrid chemical genetic approach. Using a transgenic nitroreductase-expressing zebrafish line, Tg(ins:Flag-NTR)s950, treated with the prodrug metronidazole (MTZ), we found that ROS is rapidly and explicitly generated in β-cells. Furthermore, the level of ROS generated was proportional to the dosage of prodrug added to the system. At high doses of MTZ, caspase 3 was rapidly cleaved, β-cells underwent regulated cell death, and macrophages were recruited to the islet to phagocytose the debris. Based on our findings, we propose a model for the mechanism of NTR/MTZ action in transgenic eukaryotic cells and demonstrate the robust utility of this system to model ROS-related disease pathology.

Toxic encephalopathy associated with high-dose metronidazole therapy in a dog: a case report

This case report describes an episode of acute ataxia, tremor, vertical nystagmus and progressive weakness in a mixed breed dog treated with high doses of metronidazole. Complete blood cell count, serum biochemistry, coagulation profile, blood pressure measurement, urinalysis, computed tomography of the brain and cerebrospinal fluid examination were unremarkable. Metronidazole had been administered at a dose of 65 mg/kg/day and neurotoxicity was, therefore, suspected. Drug concentrations in the patient’s serum and cerebrospinal fluid were measured using high-performance liquid chromatography and compared to control dogs. Metronidazole administration was immediately discontinued; supportive care consisted of fluid therapy and diazepam treatment. The neurological status of the patient improved rapidly within 72 h. The aim of this case report is to describe the clinical presentation of metronidazole intoxication in a mixed breed dog and to interpret the chromatographic analysis which can be a beneficial diagnostic and screening tool in dogs intoxicated with metronidazole.

Invitro activity of nitazoxanide against some metronidazole-resistant and susceptible Trichomonas vaginalis isolates.

Trichomonas vaginalis cases refractory to metronidazole (MTZ) treatment had been reported. This study aimed to the assessment of invitro metronidazole resistance among Trichomonas positive cases with treatment failure by determination of metronidazole minimal lethal concentration (MLC), and to the evaluation of the invitro efficacy of nitazoxanide (NTZ) as compared to metronidazole (MTZ) in both resistant and susceptible isolates. Drug testing was carried out by an aerobic tube assay where suspension of Trichomonas trophozoites was exposed for 24 and 48h to serial dilution of metronidazole and nitazoxanide. In refractory isolates n=30, median MLC conc. for MTZ was 100μg/ml versus 50μg/ml for NTZ (P<.0001). After 48h median MLC conc. for MTZ was 25μg/ml versus 12μg/ml for NTZ (P<.0001). NTZ against resistant isolates was twice as active as MTZ at 24h and increased to 2.5 times at 48h while in susceptible isolates, NTZ was twice as active as MTZ at both 24h and 48h. MTZ was about 8 times more active in susceptible than in resistant isolates. So, high doses of metronidazole in resistant cases will likely increase side effects. The study proved the activity of NTZ against trichomoniasis especially in cases with MTZ resistance.

A study on Nim expression in Bacteroides fragilis

Members of the genus Bacteroides, mainly Bacteroides fragilis, can cause severe disease in man, especially after intestinal perforation in the course of abdominal surgery. Treatment is based on a small number of antibiotics, including metronidazole, which has proved to be highly reliable throughout the last 40 to 50 years. Nevertheless, metronidazole resistance does occur in Bacteroides and has been mainly attributed to Nim proteins, a class of proteins with a suggested nitroreductase function. Despite the potentially high importance of Nim proteins for human health, information on the expression of nim genes in B. fragilis is still lacking. It was the aim of this study to demonstrate expression of nim genes in B. fragilis at the protein level and, furthermore, to correlate Nim levels with the magnitude of metronidazole resistance. By the application of 2D gel electrophoresis, Nim proteins could be readily identified in nim-positive strains, but their levels were not elevated to a relevant extent after induction of resistance with high doses of metronidazole. Thus, the data herein do not provide evidence for Nim proteins acting as nitroreductases using metronidazole as a substrate, because no correlation between Nim levels and levels of metronidazole resistance could be observed. Furthermore, no evidence was found that Nim proteins protect B. fragilis from metronidazole by sequestering the activated antibiotic.

Ameliorative effects of curcumin on the structural parameters of seminiferous tubules and Leydig cells in metronidazole-treated mice: A stereological approach

Metronidazole (MTZ), an anti-parasitic drug, induces negative effects on the testis. Curcumin exhibits antioxidant properties and anti-tumor properties. The aim was to evaluate negative effects of seminiferous tubules and Leydig cells by MTZ and ameliorative effects of curcumin. Balb/c mice were divided into six groups. The control, second, third, fourth and fifth, and sixth groups were administrated distilled water, high doses of MTZ (500 mg/kg/day), MTZ (500 mg/kg/day) +100 mg/kg/day curcumin, therapeutic doses of MTZ (165 mg/kg/day), MTZ (165 mg/kg/day) +100 mg/kg/day curcumin, and 100 mg/kg/day curcumin, respectively. The data revealed significant reduction in tubule volume, length and diameter and germinal epithelium height, and increase the number of Leydig cells in MTZ-treated (high or therapeutic doses) animals. Combined treatment of curcumin with high or therapeutic doses of MTZ ameliorated the increase in number of Leydig cell. Ameliorative effects of curcumin on the other above-mentioned parameters were observed in mice receiving therapeutic doses of MTZ. Leydig cell or nucleus volume and interstitial tissue volume did not show any significant difference in the MTZ-treated mice. It can be concluded that metronidazole can changes structural parameters of the tubules and number of Leydig cells and curcumin can ameliorate these effects.

Ameliorative Effects of Curcumin on the Seminiferous Epithelium in Metronidazole-Treated Mice

Metronidazole (MTZ) has negative effects on sperm analysis and testis structure. Curcumin is the principal curcuminoid found in turmeric and exhibits antitumor, anti-inflammatory, and anti-infectious activities with low toxicity. To evaluate stereological changes of seminiferous germinal epithelium by MTZ and ameliorative effects of curcumin, Balb-c mice were divided into 6 groups. The control, second, third, fourth, fifth, and sixth groups were administrated distilled water, high doses of MTZ (500 mg/kg/day), MTZ (500 mg/kg/day) + 100 mg/kg/d curcumin, therapeutic doses of MTZ (165 mg/kg/day), MTZ (165 mg/kg/day) + 100 mg/kg/day curcumin, and 100 mg/kg/day curcumin, respectively. Testis weight, testis volume, total epithelial volume, spermatocytes, and spermatid number showed a significant reduction in MTZ-treated (high or therapeutic doses) animals in comparison with the controls. Curcumin can protect spermatocytes after high or therapeutic doses of MTZ treatment. But curcumin is able to protect the other parameters only in the mice receiving therapeutic doses of MTZ. The total number of sertoli cells and spermatogonia did not show any significant difference in the mice that received MTZ. MTZ can reduce germinal epithelium volume and the number of spermatocytes and spermatids. Ameliorative effects of curcumin can mainly be observed in the mice receiving therapeutic doses of MTZ.

Treatment failure of vaginal trichomoniasis in clinical practice

We have conducted a retrospective study of treatment failure of Trichomonas vaginalis (TV) infection in a busy, urban genitourinary medicine clinic in Birmingham, UK, between 1998 and 2002. The prevalence of non-response to standard doses of metronidazole without any history of reinfection or nonadherence was 1.7% (28/1603) overall, and has significantly increased from 0.38% in 1999 to 3.5% in 2002 (P = 0.001, chi2 test). There were no associated demographic factors. The majority of patients (53% or 15/28) responded to either a repeat of standard (10/26) or higher oral dose (5/7) of metronidazole. A standardized treatment algorithm using a high dose of metronidazole may be useful in the absence of any new, efficacious non-imidazole-based TV therapy in the clinical management of persistent TV infection.