Metronidazole Treatment Research Articles

A gastric ulcer: double trouble.

To the Editor, With great interest, we read the article of Marcelino et al.1 reporting forty-seven cases of Sarcina ventriculi. The article gives an extensive overview of cases describing S. ventriculi appearance, with a sudden increase in cases since 2010. They showed that S. ventriculi was identified at all ages, ranging from 1 to 87 years old, but mainly in middle-aged adults. It occurred slightly more often in women (55%). The most common symptoms were epigastric pain (51%) and nausea and vomiting (47%). However, the clinical presentation is heterogeneous, ranging from asymptomatic to life-threatening conditions.1 The presence of S. ventriculi together with Helicobacter pylori2 or after treatment and eradication of H. pylori3 has been described. We would like to add another case to the overview provided by Marcelino et al.1 Our patient, a 40-year-old male, was primarily admitted to the oncology department because of nausea and vomiting due to impaired gastric emptying by stenosis. Computed tomography (CT) scan showed signs suspicious for gastric carcinoma with lymphatic metastasis (Figure 1A). Upper GI-endoscopy showed grade-D gastroesophageal reflux disease and a large ulcer in the antrum, with signs suspicious of gastric carcinoma (Figure 1B) and gastric outlet obstruction. Biopsies were taken on three different occasions in the first two weeks of hospitalization. Figure 1 A– Thoracoabdominal CT - Coronal plane - showing an abnormal contour of the stomach due to a suspected ulcerating mass, with several enlarged lymph nodes close to the gastrohepatic ligament and around the stomach; B – Endoscopic image showing a large ulcer in the antrum of the stomach with a regular and elevated border.: Histologic examination showed chronic active inflammation, and repeatedly failed to show a malignancy. Also, a needle biopsy of an enlarged lymph node, performed by the radiologist, did not show malignancy. The patient underwent a diagnostic laparoscopy, showing no signs of malignancy. A jejunostomy tube was placed, during this procedure, permitting the patient to be properly fed. With these findings, the potential diagnosis that this was ‘just’ an ulcer caused by H. pylori became more and more probable, since the biopsies taken during upper GI-endoscopy did show H. pylori. Treatment with pantoprazole, amoxicillin and clarithromycin was started and high dose pantoprazole was continued until follow-up endoscopy. Eight weeks later, a follow-up endoscopy was performed, showing a normal esophagus, but the gastric ulcer was still present, albeit smaller in size. Again, biopsies were repeated. This time, the biopsies revealed the presence of S. ventriculi (Figure 2A), which might explain the size and severity of the gastric ulcer. Treatment with ciprofloxacin and metronidazole was started. Follow-up endoscopy 8 weeks later showed that the ulcer was still present after treatment (Figure 2B), and biopsies still showed the presence of S. ventriculi, and no signs of malignancy. Furthermore, an additional follow-up CT scan of the abdomen was performed, showing no signs of gastric cancer. Figure 2 A – Photomicrograph of the gastric biopsy showing S. ventriculi, the bacteria are typically arranged in cuboids, tetrahedral structures (arrows) (H&E, 10x); B – Endoscopic image showing a smaller ulcer in the gastric antrum after treatment for H. pylori and S. ventriculi.: There is no established standard treatment for S. ventriculi; the most commonly used regime is the combination of ciprofloxacin and metronidazole.1 After consultation of a microbiologist, the patient was started on an extended antibiotic treatment of ciprofloxacin and metronidazole for three weeks, in combination with high dose pantoprazole. The patient has not yet been subjected to a subtotal gastrectomy because his condition is improving and he can be properly fed via the jejunostomy tube. Furthermore, questions have been raised about whether performing a subtotal gastrectomy in the presence of S. ventriculi might lead to (similar) problems in the future because the bacteria is still present. After finishing the extended treatment, new evaluations will take place. This case fits in the description given by Marcelino et al., with the patient being a middle-aged adult, with symptoms of nausea and vomiting. In this case, S. ventriculi was present after the eradication of H. pylori.

Effect of topical use of solution containing ferrous ions on treatment efficacy in women with recurrent urogenital trichomoniasis

Objective. To assess effect of topical use of solution containing ferrous ions on efficacy of metronidazole therapy in women with recurrent urogenital trichomoniasis. Materials and Methods. The study enrolled 55 women aged of 20–30 years with recurrent trichomoniasis after failures of multiple standard of care regimens. All patients received oral (tablets) and intravaginal (1% gel) metronidazole therapy. Participants in the experimental group (29 women) received intravaginal therapy with a solution of ferrous ions at concentration which was determined as effective for potentiating metronidazole in a previous study. In the control group, saline solution was used. Biological samples for laboratory tests were collected prior to treatment and on treatment days 4, 8 and 22. Treatment efficacy was assessed by laboratory results (detection of T. vaginalis, leukocyte-epithelial index). Results. Concomitant use of solutions containing ferrous ions at concentration 8.96 mmol/L can increase frequency of successful treatment outcomes in recurrent trichomoniasis. T. vaginalis was detected at the end of therapy in 10.3% of patients from the experimental group and 69.2% of patients from the control group. Conclusions. The concomitant use of metronidazole and solution containing ferrous ions makes it possible to increase the efficacy of therapy for Trichomonas infection. The results of the study allow us to consider topical use of iron-containing drugs to increase metronidazole treatment efficacy in recurrent trichomoniasis.

The use of metronidazole in adult dogs with acute onset, uncomplicated, diarrhoea

PICO question
 In adult, non-geriatric, dogs with acute onset (<7 days duration) uncomplicated diarrhoea does the addition of metronidazole to a supportive care protocol such as dietary modification or probiotics (excluding other antimicrobials) reduce the time to resolution of diarrhoea compared to supportive care protocols alone?
 
 Clinical bottom line
 Category of research question
 Treatment
 The number and type of study designs reviewed
 Four studies were included in this appraisal. Two prospective, double blinded, placebo controlled clinical trials, one prospective treatment trial and one retrospective longitudinal observational study
 Strength of evidence
 Weak
 Outcomes reported
 One study found a shortened duration of clinical signs (by 1.5 days; p = 0.04) in the metronidazole treated group compared to control. However, a separate study found no significant difference between control and metronidazole groups in the regards to resolution of clinical signs.
 One study demonstrated a long standing (>28 day) negative impact of metronidazole treatment on gut microbiome with no difference in time to resolution of clinical signs when compared with faecal matter transplant
 Conclusion
 The current evidence for the superiority of metronidazole compared to supportive treatment alone is weak and at this time there is no evidence-based rationale for its use in cases of uncomplicated, acute, canine diarrhoea. Furthermore, the negative implications of metronidazole on the intestinal microbiome have been found to be long standing (>28 days as a minimum) and should not be discounted by the prescribing clinician
 
 How to apply this evidence in practice
 The application of evidence into practice should take into account multiple factors, not limited to: individual clinical expertise, patient’s circumstances and owners’ values, country, location or clinic where you work, the individual case in front of you, the availability of therapies and resources.
 Knowledge Summaries are a resource to help reinforce or inform decision making. They do not override the responsibility or judgement of the practitioner to do what is best for the animal in their care.
 

An Evaluation of Metronidazole Degradation in a Plasma-Assisted Rotating Disk Reactor Coupled with TiO2 in Aqueous Solution

Pollution involving pharmaceutical components in bodies of water is an increasingly serious environmental issue. Plasma discharge for the degradation of antibiotics is an emerging technology that may be relevant toward addressing this issue. In this work, a plasma-assisted rotating disk reactor (plasma-RDR) and a photocatalyst—namely, titanium dioxide (TiO 2 )—were coupled for the treatment of metronidazole (MNZ). Discharge uniformity was improved by the use of a rotating electrode in the plasma-RDR, which contributed to the utilization of ultraviolet (UV) light radiation in the presence of TiO 2 . The experimental results showed that the degradation efficiency of MNZ and the concentration of generated hydroxyl radicals respectively increased by 41% and 2.954 mg∙L −1 as the rotational speed increased from 0 to 500 r∙min −1 . The synergistic effect of plasma-RDR plus TiO 2 on the generation of hydroxyl radicals was evaluated. Major intermediate products were identified using three-dimensional (3D) excitation emission fluorescence matrices (EEFMs) and liquid chromatography–mass spectrometry (LC-MS), and a possible degradation pathway is proposed herein. This plasma-catalytic process has bright prospects in the field of antibiotics degradation.

Impact of Clostridioides difficile Therapy on Nosocomial Acquisition of Vancomycin-Resistant Enterococci.

Vancomycin is frequently used for the treatment of C. difficile infections (CDI). There are concerns that this might increase the risk of selecting vancomycin resistant enterococci (VRE). Here, we evaluated whether there is an increased risk of VRE acquisition following vancomycin for CDI specific treatment. Patients with CDI, metronidazole, or oral vancomycin treatment and without preexisting VRE were monitored for VRE acquisition. VRE isolates from patients with acquired and preexisting colonization were collected and subjected to whole genome sequencing. In total, 281 patients (median age 56 years, 54% of the male sex) presented with toxin positive C. difficile. Of them, 170 patients met the inclusion criteria, comprising 37 patients treated with metronidazole and 133 treated with oral vancomycin. In total, 14 patients meeting the inclusion criteria acquired VRE (vancomycin: n = 11; metronidazole: n = 3). Statistical analysis revealed no significant differences between both VRE acquisition rates. Genetic comparison of detected VRE isolates resulted in eight clusters of closely related genotypes comprising acquired and preexisting strains. Our results suggest that vancomycin and metronidazole likewise increase the risk of VRE acquisition. Genetic comparison indicates that VRE acquisition is a result of both antibiotic selection and pathogen transmission.

Cytomegalovirus colitis combined with Clostridium innocuum as a cause of lower GI bleeding in a patient with COVID-19

A 67-year-old woman who presented with fever received a diagnosis of COVID-19 infection and was admitted to the medicine ward. She had a history of hypertension and diabetes. On day 4 of hospitalization, owing to progressive dyspnea and oxygen desaturation, she received intubation and mechanical ventilator support. She received remdesivir, dexamethasone, empiric antibiotics, enoxaparin, and tocilizumab during her hospitalization. On day 24, the patient developed bloody stools, and her hemoglobin level decreased from 11.7 g/dL to 9.2 g/dL. Because of persistent bleeding, she underwent colonoscopy, which revealed colitis and ulcer bleeding at the rectum (A). CT showed wall thickening of the lower part of the rectum (B). A pathologic study of the biopsy specimen showed enlarged nuclei and viral inclusions in both the cytoplasm and the nuclei (C). Immunohistochemical stain was positive for cytomegalovirus (CMV) antigen (D). The result of a blood CMV DNA polymerase chain reaction was positive, and the diagnosis of CMV infection was confirmed. In addition, there was growth of Clostridium innocuum in the stool culture. Her bleeding subsided after ganciclovir and metronidazole treatment, and she was extubated smoothly on day 38. Here we illustrate a COVID-19 patient who presented with lower GI bleeding caused by CMV coinfection and growth of C innocuum simultaneously. Endoscopy plays a crucial role in the treatment of patients with GI bleeding. All authors disclosed no financial relationships. Commentary The healthier you are the healthier you stay; the sicker you are the sicker you get. This case reflects this axiom. This unfortunate patient experienced severe respiratory failure secondary to COVID-19 infection. Colonoscopy revealed a dramatic "punched out" ulcer, highly suggestive of a viral colitis, and indeed the patient was found to have a CMV infection. She was also found to harbor C innocuum, which, despite its name, should not be confused with C difficile. C innocuum is an anaerobic gram-positive rod that is considered to be a variant of normal gut flora. C innocuum usually behaves in a pathogenic manner in patients who are immunocompromised, as was clearly the case with this patient. C innocuum is often seen to cause illness in patients after organ transplantation, most commonly renal transplantation. Fortunately, this patient appears to have done well after aggressive therapy for her COVID-19 infection. Douglas G. Adler, MD, FASGE, GIE Senior Associate Editor, Co-Director, Center for Advanced Therapeutic Endoscopy (CATE), Porter Adventist Hospital, PEAK Gastroenterology, Denver, Colorado Mohamed O. Othman, MD, Associate Editor for Focal Points

AN ATYPICAL PRESENTATION OF LEMIERRE'S SYNDROME

TOPIC: Chest Infections TYPE: Medical Student/Resident Case Reports INTRODUCTION: Lemierre's syndrome involves recent oropharyngeal infection, clinical or radiological evidence of internal jugular vein thrombosis, and isolation of anaerobic pathogens, most commonly Fusobacterium necrophorum. We present an atypical presentation of Lemierre's syndrome. CASE PRESENTATION: A 28-year-old male with a history of left second metacarpal neck fracture status post open internal reduction and pin removal one month prior presented with malaise, chills, and hand pain. His review of systems were significant for fever, headache, sore throat, productive cough, pleuritic chest pain, and dyspnea. He was febrile, tachycardic, and hypoxic. Examination revealed edema and erythema of the left hand and wrist, tenderness to palpation, and a bounding radial pulse. Laboratory investigations revealed a white cell count of 7.7 Thou/mcL, C-reactive protein 28.65 mg/dL, lactic acid 5.1 mmol/L, and procalcitonin 74.64 ng/mL. Chest X-ray showed bibasilar infiltrates. Computed tomography (CT) of the left hand showed soft tissue edema and emphysema of the wrist, hand, and forearm. He was diagnosed with sepsis due to left upper extremity necrotizing fasciitis and underwent fasciotomy with debridement. Wound cultures had no growth. Blood cultures grew Fusobacterium necrophorum. CT angiography of the pulmonary arteries revealed septic emboli. Venous duplex of the upper extremities revealed a chronic complete thrombus of the right internal jugular vein. Transthoracic echocardiogram showed no evidence of endocarditis. The diagnosis of Lemierre's Syndrome was made. The patient was discharged on enoxaparin and metronidazole for treatment. DISCUSSION: Lemierre's syndrome was first characterized by Dr. Andre Lemierre in 1936.1 The incidence decreased significantly with widespread usage of beta-lactam antibiotics in pharyngiitis.1 Due to antibiotic stewardship, the incidence has increased.1 Our patient presented with fever, left hand pain, and concern for necrotizing fasciitis with low suspicion of Lemierre's syndrome. Upon review, he did have elements consistent with the typical presentation of Lemierre's. Fever and sore throat are predominant symptoms; late sequelae involve septic emboli to the lungs resulting in chest pain and shortness of breath.3 Despite the increase in incidence of Lemierre's syndrome since physicians began practicing antibiotic stewardship, it is still rare. It is important to keep this as a differential as the mortality is around 5% if left untreated.1 CONCLUSIONS: The incidence of Lemierre's Syndrome continues to rise with the practice of antibiotic stewardship. It is crucial to consider this potentially fatal diagnosis when the clinical picture is consistent with Lemierre's syndrome. REFERENCE #1: Karkos PD, Asrani S, Karkos CD, et al. Lemierre's syndrome: A systematic review. Laryngoscope. 2009;119(8):1552-1559. doi:10.1002/lary.20542 REFERENCE #2: Lee WS, Jean SS, Chen FL, Hsieh SM, Hsueh PR. Lemierre's syndrome: A forgotten and re-emerging infection. J Microbiol Immunol Infect. 2020;53(4):513-517. doi:10.1016/j.jmii.2020.03.027 REFERENCE #3: Olivier JB, Al-Hourani K, Bolland B. Lemierre's syndrome; a rare cause of septic arthritis. BMJ Case Rep. 2017;2017:bcr2017220110. Published 2017 May 12. doi:10.1136/bcr-2017-220110 DISCLOSURES: No relevant relationships by Mikhail de Jesus, source=Web Response no disclosure on file for Jason Jacob; No relevant relationships by Rafae Shaikh, source=Web Response No relevant relationships by Asiya Tafader, source=Web Response

Recurrent bacterial vaginosis following metronidazole treatment is associated with microbiota richness at diagnosis

Bacterial vaginosis-a condition defined by a shift from Lactobacillus dominance to a polymicrobial, anaerobic bacterial community-increases the risk of acquiring sexually transmitted infections and other complications of the female reproductive tract. Antibiotic treatment frequently fails to return the microbiome to an optimal Lactobacillus-dominated state. No criteria currently exist to identify the patients likely to experience treatment failure. We sought to identify the pretreatment community signatures associated with treatment failure through 16S ribosomal RNA gene analysis. Twenty-eight women who were enrolled in an oral metronidazole treatment trial of bacterial vaginosis were studied. Cervicovaginal lavage samples were collected before metronidazole treatment and at 7 and 30 days posttreatment. Cervicovaginal lavage DNA was amplified and sequenced using a paired-end, V4 region 2×150 MiSeq run. Of the 28 women, 25% failed to clear bacterial vaginosis; 35.7% demonstrated a transient clearance, shifting to community-type 2 (Lactobacillus iners dominant) at visit 2 only; 7.1% demonstrated a delayed clearance, reaching community-type 2 at the final visit only; and 32.1% of patients experienced sustained bacterial vaginosis clearance. Examination of the community composition and structure demonstrated that both the richness and the evenness were significantly lower for the women who experienced sustained clearance, whereas the women who failed to clear bacterial vaginosis possessed the highest median levels of richness, evenness, and diversity pretreatment. Soluble immune factors in the lower reproductive tract improved significantly following a shift from community-type 4 to a Lactobacillus-dominant microbiome, with the samples categorized as community-type 2 possessing significantly higher levels of secretory leukocyte protease inhibitor, growth-regulated alpha protein, and macrophage inflammatory protein-3 and significantly lower levels of intercellular adhesion molecule-1. Although the shifts to Lactobacillus dominance improved the markers of mucosal tissue health, these gains were only temporary among the women who experienced recurrence. Assemblies of highly diverse microbiota are associated with the enhanced resilience of bacterial vaginosis to standard metronidazole treatment. These communities may be foundational to treatment resistance or simply an indication of a well-established community made possible by canonical biofilm-forming taxa. Future studies must target the transcriptional activity of these communities under the pressure of antibiotic treatment to resolve the mechanisms of their resistance.

Temporal Changes in Vaginal Microbiota and Genital Tract Cytokines Among South African Women Treated for Bacterial Vaginosis.

The standard treatment for bacterial vaginosis (BV) with oral metronidazole is often ineffective, and recurrence rates are high among African women. BV-associated anaerobes are closely associated with genital inflammation and HIV risk, which underscores the importance of understanding the interplay between vaginal microbiota and genital inflammation in response to treatment. In this cohort study, we therefore investigated the effects of metronidazole treatment on the vaginal microbiota and genital cytokines among symptomatic South African women with BV [defined as Nugent score (NS) ≥4] using 16S rRNA gene sequencing and multiplex bead arrays. Among 56 BV-positive women, we observed short-term BV clearance (NS <4) in a proportion of women six weeks after metronidazole treatment, with more than half of these experiencing recurrence by 12 weeks post-treatment. BV treatment temporarily reduced the relative abundance of BV-associated anaerobes (particularly Gardnerella vaginalis and Atopobium vaginae) and increased lactobacilli species (mainly L. iners), resulting in significantly altered mucosal immune milieu over time. In a linear mixed model, the median concentrations of pro-inflammatory cytokines and chemokines were significantly reduced in women who cleared BV compared to pre-treatment. BV persistence and recurrence were strongly associated with mucosal cytokine profiles that may increase the risk of HIV acquisition. Concentrations of these cytokines were differentially regulated by changes in the relative abundance of BVAB1 and G. vaginalis. We conclude that metronidazole for the treatment of BV induced short-term shifts in the vaginal microbiota and mucosal cytokines, while treatment failures promoted persistent elevation of pro-inflammatory cytokine concentrations in the genital tract. These data suggest the need to improve clinical management of BV to minimize BV related reproductive risk factors.

Trichomonas vaginalis and growing concern over drug resistance: a systematic review.

In the late 90s, a sharp increase of treatment failures of Trichomonas vaginalis (TV) infections with metronidazole (MTZ) was reported, representing a problem due to limited treatment options. We proposed to review the available evidence on the frequency of MTZ resistance by TV isolates and the relationship between treatment failure and invitro resistance to MTZ. A systematic review based on the PRISMA guidelines was conducted by searching published studies in three different databases (PubMed, Scopus and Web of Science) up to December 2020. The extracted studies were uploaded to Covidence software; screening was guided based on inclusion and exclusion criteria. Additionally, different articles were included through other sources. For each article, study design, objectives, study population and key outcomes were summarized. We found 403 references from the databases and four extra studies. After duplicate removal and screening of title, abstract and full text, 27 studies were included. The selected studies were published between 1983 and 2019; all except one addressed only vaginal TV infection. We identified four major populations invitro MTZ resistance: two studies evaluated female adolescents; other two assessed HIV-positive women. Fifteen studies considered MTZ resistance in newly diagnosed vaginal TV infection. Finally, eight articles studied invitro susceptibility of isolates from women with clinical resistant trichomoniasis. High level of invitro MTZ resistance was rare; low-moderate level was described in most of the cases. Although clinical resistance to MTZ of trichomoniasis was widely reported, there was a paucity of prospective controlled studies. Our review unveiled the need to standardize susceptibility testing, to define breakpoints for detection of MTZ-resistant isolates and to correlate with clinical outcome. It is important to establish criteria to define clinical resistance to MTZ. Such a consensus would foster the development of surveillance studies about clinical and microbiological response to MTZ treatment.

Integrated Metagenomic and Transcriptomic Analyses Reveal the Dietary Dependent Recovery of Host Metabolism From Antibiotic Exposure.

The balance of gut microbiome is essential for maintaining host metabolism homeostasis. Despite widespread antibiotic use, the potential long-term detrimental consequences of antibiotics for host health are getting more and more attention. However, it remains unclear whether diet affects the post-antibiotic recovery of gut microbiome and host metabolism. In this study, through metagenomic sequencing and hepatic transcriptome analysis, we investigated the divergent impacts of short-term vancomycin (Vac), or combination of ciprofloxacin and metronidazole (CM) treatment on gut microbiome and host metabolism, as well as their recovery extent from antibiotic exposure on chow diet (CD) and high-fat diet (HFD). Our results showed that short-term Vac intervention affected insulin signaling, while CM induced more functional changes in the microbiome. However, Vac-induced long-term (45 days) changes of species were more apparent when recovered on CD than HFD. The effects of antibiotic intervention on host metabolism were long-lasting, antibiotic-specific, and diet-dependent. The number of differentially expressed gene was doubled by Vac than CM, but was comparable after recovery on CD as revealed by the hepatic transcriptomic analysis. In contrast, HFD intake during recovery could worsen the extent of post-antibiotic recovery by altering infection, immunity, and cancer-related pathways in short-term Vac-exposed rats and by shifting endocrine system-associated pathways in CM-exposed rats. Together, the presented data demonstrated the long-term recovery extent after different antibiotic exposure was diet-related, highlighting the importance of dietary management during post-antibiotic recovery.

Effect of a diet containing a mixture of soybean isoflavones and soyasaponins on contact hypersensitivity and gut microbiota in mice

AbstractDietary soybean isoflavones (SIs) and soyasaponins (SSs) individually exert inhibitory effects on contact hypersensitivity (CHS), which is an animal model of allergic contact dermatitis (ACD); however, the beneficial effects of diets containing a mixture of SIs and SSs on CHS remain unclear. Here, we investigated the CHS‐suppressive effects of diets containing a mixture of SIs and SSs at physiologically relevant doses, and the role of the gut microbiota. The diets attenuated ear swelling and reduced the number of Gr‐1‐positive cells infiltrating the auricle tissues. Ear swelling was inhibited in the SI‐ and SS‐treated mice compared to the SI‐treated mice. Compared to the CHS controls, the levels of chemokine (C‐X‐C motif) ligand 2 and triggering receptor expressed on myeloid cells‐1 (TREM‐1) were lower in the auricle tissues of SI‐ and SS‐treated mice, whereas TREM‐1 production was not suppressed in SI‐ or SS‐treated mice. In addition, vancomycin treatment had little effect on the CHS‐inhibitory activity of SI and SS diets, whereas ciprofloxacin and metronidazole treatments blocked the effects of SI and SS diets. These antibiotics exhibited differing effects on the microbiota composition deduced from the bacterial 16S ribosomal RNA gene sequences. Therefore, consuming a mixture of SIs and SSs has ACD‐preventive effects and is affected by the gut microbiota.

Risk factors for and management of metronidazole-refractory giardiasis in international travellers: A retrospective analysis

BackgroundGiardia lamblia is a common cause of diarrhoea in returning travellers. Failure of the recommended first-line treatment, metronidazole, has frequently been observed. Recommendations for treatment of metronidazole-refractory giardiasis lack clarity and evidence. MethodsWe conducted a retrospective data analysis of returned travellers with confirmed giardiasis at the Bernhard-Nocht-Clinic in Hamburg, Germany, between 2007 and 2016. ResultsWe identified 339 cases of giardiasis, mostly acquired in South Asia (n = 157). 308 patients received metronidazole as first-line treatment, leading to treatment failure in 93 cases. Statistical analysis suggested by far the highest risk of metronidazole treatment failure for travellers returning from South Asia (Odds Ratio 8.73). Second-line therapy consisted of various different therapy regimens. Combination therapy as second-line treatment seemed to be more effective than monotherapy. A repeat course of metronidazole proved to be futile. ConclusionThis study reveals a strikingly low effectiveness of metronidazole, especially in patients returning from South Asia. Second-line treatment showed inconsistency of regimens and yielded unsatisfactory results. These findings require reconsideration of treatment strategies for giardiasis. Large prospective trials are urgently needed to assess new first-line treatment options and to help implement advice for effective, agreed second-line treatment strategies. Translational projects should be created to link the understanding of resistance mechanisms with epidemiological data and clinical outcome.

P038 Microbial regulation of T-cell fate towards regulatory profiles during T-cell transfer induced colitis

Abstract Background During Inflammatory Bowel Diseases (IBD), CD4+ effector T cells are main mediators of the tissue damage. Among them, Th17 cells strongly contribute to the inflammatory response. Interestingly, our lab previously showed that Th17 cells can convert into regulatory T cells, thereby controlling inflammation. However, the forces controlling the plasticity of T cells during IBD remain largely unknown. Our aim is to understand, how CD4+ T-cell plasticity can be modulated from a pro-inflammatory towards an anti-inflammatory profile during IBD. It is currently known that both Th17 and Foxp3 Treg cells can recognize microbiota-derived antigens and that changes in the microbiota are commonly observed in IBD. We hypothesize that the microbiota is a key candidate to modulate T-cell plasticity. Methods T-cell transfer mouse IBD model was performed by transferring CD4+ naïve T-cells into Rag1 -/- receptors. To study Th17 T-cell plasticity, we used as donors IL-17A Fate-mapping mice. These mice comprise of an IL-17ACRE/R26fl/fl YFP construct where the cells that previously expressed IL-17A turn into YFP+ cells. Ciprofloxacin and metronidazole, two antibiotics commonly given to IBD patients, were used to treat the mice. Stool microbiota composition was analysed longitudinally by 16S rRNA amplicon sequencing. Colitis development was evaluated by colonoscopy. CD4+ T cells were isolated from the colon and reporter expression was analysed by Flow Cytometry. Results After T-cell transfer colitis induction, ciprofloxacin and metronidazole treatment alleviated gut inflammation, as determined by weight loss (p=0.005), colitis score (p=0.004) and colon length (p=0.01). Antibiotic treatment increased the relative abundance of bacteria previously associated with beneficial IBD outcomes (e.g. Bifidobacterium). Interestingly, colonic CD4+ T-cells showed an increased conversion from Th17 towards a Foxp3+ Treg profile (Foxp3ExTh17) (p=0.03). Conclusion The conversion of CD4+ effector T cells into Treg cells is a promising approach to counteract inflammation in IBD patients. We showed that antibiotic treatment not only correlates with a relative expansion of beneficial bacteria, but perhaps most interesting, with an increased conversion of effector Th17 cells towards Foxp3+ Treg cells in the colon. Altogether, these data support the manipulation of the microbiota as a tool to revert intestinal inflammation in IBD patients.

Outcome of concurrent treatment with a-CTLA4 and metronidazole in murine model of colon adenocarcinoma.

e14566 Background: Immune checkpoint blockade (ICB) therapy transformed clinical oncology by inducing durable responses and increasing survival rates in many types of cancers. However, ICB is effective in only in a subset of patients. Recent studies delineated the role of gut microbiome as both a biomarker and a therapeutic in ICB responsiveness. We aimed to increase understanding of the microbiome-immune system axis in ICB therapy by using antibiotics to knock out certain components of gut microbiome. Methods: We treated MC38 colon adenocarcinoma-bearing mice with a widely-used antibiotic, metronidazole, that is effective against anaerobic and protozoal infections including Clostridioides difficile – a major mediator of colitis. Metronidazole was administered via oral gavage or mixed in drinking water before and after tumor injections. Mice received twice weekly treatment with a-CTLA4 ICB. Results: Metronidazole treatment alone slowed the growth rate of MC38 tumors, consistent with the current literature regarding colon cancer murine models. When metronidazole treatment was combined with a-CTLA4 therapy, we found ̃90% complete tumor regression. In the metronidazole and a-CTLA4 combination group, we also observed an increase in the number of CD103+ type 1 conventional dendritic cells (cDC1s) in colon lamina propria, which suggests enhanced antigen sampling from lumen. Also, in the mesenteric lymph nodes (mLN), we detected upregulation of CD80 and CD86 co-stimulatory molecule expression on CX3CR1+ antigen presenting cells. Multiplex analysis of colon cytokines and colon pathology evaluation was comparable among groups, which implies a non-inflammatory environment in colon. Analysis of tumor-draining lymph nodes eight days after tumor injections showed higher expression of CD86 on CD103+ cDC1s implying superior anti-tumor immunity. 16S rRNA gene sequencing analysis of fecal samples revealed loss of Lachnospiraceae and enrichment of Bifidobacteriaceae and Sutterellaceae families in metronidazole-treated mice. Conclusions: Shifting microbiome composition with metronidazole treatment elicits a favorable anti-tumor immune response to a-CTLA4 treatment in murine colon adenocarcinoma.

Differences in Vaginal Microbiota, Host Transcriptome, and Proteins in Women With Bacterial Vaginosis Are Associated With Metronidazole Treatment Response.

Bacterial vaginosis (BV) treatment failures and recurrences are common. To identify features associated with treatment response, we compared vaginal microbiota and host ectocervical transcriptome before and after oral metronidazole therapy. Women with BV (Bronx, New York and Thika, Kenya) received 7 days of oral metronidazole at enrollment (day 0) and underwent genital tract sampling of microbiome (16S ribosomal RNA gene sequencing), transcriptome (RNAseq), and immune mediator concentrations on day 0, 15, and 35. Bronx participants were more likely than Thika participants to clinically respond to metronidazole (19/20 vs 10/18, respectively, P = .0067) and by changes in microbiota composition and diversity. After dichotomizing the cohort into responders and nonresponders by change in α-diversity between day 35 and day 0, we identified that transcription differences associated with chemokine signaling (q = 0.002) and immune system process (q = 2.5 × 10-8) that differentiated responders from nonresponders were present at enrollment. Responders had significantly lower levels of CXCL9 in cervicovaginal lavage on day 0 (P < .007), and concentrations of CXCL9, CXCL10, and monocyte chemoattractant protein 1 increased significantly between day 0 and day 35 in responders vs nonresponders. Response to metronidazole is characterized by significant changes in chemokines and related transcripts, suggesting that treatments that promote these pathways may prove beneficial.

AYURVEDA APPROACH IN THE MANAGEMENT OF TRICHOMONAL VAGINITIS WITH SPECIAL REFERENCE TO KAPHAJA YONIVYAPADA - A REVIEW

Trichomonal vaginitis is a common sexually transmitted infection that can cause vaginitis, cervicitis and urethritis. Persistent and recurrent infections are frequent in women, potentially due to the lack of routine screening recommendations for this pathogen, chronic nature of some infections and drug resistance. Modern treatment involves the use of systemic and local antibiotics which create a number of inconveniences during their usage. There are few alternative treatment options for persons with a metronidazole allergy or treatment failure. Ayurveda provides many alternatives and can prove a boon to the ailing humanity not only by curing the disease but also by preventing their recurrences. In Ayurvedic texts, various conditions giving rise to white discharge per vaginum had been described. The signs and symptoms of Shleshmala Yonivyapada are more or less similar to Trichomonal vaginitis. In recent decades, numerous efforts have been made to select, extract, and find the mechanism of plant compounds against pathogens of sexually transmitted diseases. In this article, management of Trichomonas vaginitis reviewed through an Ayurvedic text is elaborated in detail. Keywords Ayurveda, Kaphaja Yonivyapada, Trichomonal vaginitis, Yonistrava

Investigating the efficacy and safety of metronidazole during pregnancy; A systematic review and meta-analysis.

ObjectiveWe aimed to review and analyze studies focusing on the efficacy of metronidazole in reducing the risk of preterm birth and the safety of metronidazole taking into account the different doses, duration of treatment and routes of administration.Study designsEmbase, Cochrane Library and PubMed were searched up to 29 July 2019 to identify studies assessing metronidazole exposure during pregnancy. Additional studies were identified from reference lists of retrieved papers. Measured outcomes were preterm births (<37 weeks of gestation) and associated delivery outcomes such as spontaneous abortions (≤ 20 weeks of gestation), stillbirths (≥20 weeks of gestation) and low birth weight (<2500 g) irrespective of the period of exposure and major malformations after first-trimester exposure. Overall effect estimates for RCTs and observational studies were calculated using the random-effects model and pooled using Risk Ratios (RR) and Odds Ratios (OR) respectively. ROB-2 and ROBINS-I tool were used to assess Risk of Bias for RCTs and observational studies, respectively.ResultsTwenty-four studies (17 observational studies and 7 RCTs) were selected. Pooled RR was 1.10 (95 % CI 0.78–1.55; n = 7; I2 = 72 %) for preterm birth. Subgroup analysis found RR 1.67; 95 % CI 1.07–2.62; n = 3; I² = 32 %) for treatment duration of ≤3 days among women with a previous preterm delivery. Pooled OR for spontaneous abortion was 1.72 (95 % CI 1.40–2.12; n = 5; I2 = 72 %) and 1.15 (95 % CI 0.98–1.34; n = 12; I2 = 25 %) for major malformations. After exclusion of studies with critical risk of bias, pooled OR were 1.7 (1.42–2.04; n = 3; I2 = 19 %) and 1.13 (0.93–1.36; n = 9; I2 = 28 %) respectively. Among several specific malformations analyzed, only congenital hydrocephaly was significantly increased at 4.06 (95 % CI 1.75–9.42; n = 2; I² = 0%).ConclusionsData do not confirm the efficacy of metronidazole in reducing the risk of preterm birth and associated delivery outcomes. Further research is required to confirm the effect of high dose and short duration of metronidazole treatment on preterm birth among the high-risk group. Regarding the increased odds of spontaneous abortion, RCTs are required to assess the role of the underlying infection. The need for further studies to confirm the risk of congenital hydrocephaly is paramount.

The effect of oral Metronidazole on the vaginal microbiome of patients with recurrent bacterial vaginosis: A pilot investigational study

Bacterial vaginosis (BV) is the most common vaginal problem in reproductive-age women. Recurrent BV, defined as having at least three BV episodes in one year, causes significant psychological distress and can prove challenging to resolve. Using 16S rRNA sequencing, we characterized the vaginal microbiome of 63 women aged 18–40 years. We compared the vaginal microbiome of 17 patients presenting with an acute episode of recurrent BV to 46 healthy controls. The effect of oral Metronidazole treatment on the vaginal microbiome of the recurrent BV patients was analyzed 7–10 days and 30–40 days after the completed the standard 7-day oral twice-a-day Metronidazole treatment regimen. Beta diversity (unweighted UniFrac distances) of recurrent BV patients’ vaginal microbiome differed significantly from healthy controls (p = 0.01). Compared to controls, Mycoplasma, Veillonella, and Sneathia genera were more dominant in the recurrent BV cohort, while Lactobacilleacae was less abundant. After one week of oral Metronidazole treatment, recurrent BV patients’ vaginal microbiome was significantly altered [alpha diversity, p = 0.005; beta diversity, p = 0.03], and there was an increase in healthy commensals such as Lactobacillaceae. However, these changes were not sustained one month after treatment. Our findings show that the vaginal microbiome of recurrent BV patients differs from healthy controls, and that Metronidazole as monotherapy may be insufficient treatment for recurrent BV, as it only alters the vaginal microbiome temporarily. Future investigations into alternative therapies that restore a healthy vaginal microbiome are necessary.

Gardnerella Vaginalis Associated Bacterial Vaginosis: A Review Article

Introduction: Gardnerella vaginalis is associated with bacterial vaginosis. Bacterial vaginosis (bacterial vaginosis = BV) is a clinical syndrome due to replacement of Lactobacillus spp. producing hydrogen peroxidase (H2O2) in normal vagina with high concentrations of anaerobic bacteria (eg Bacteroides spp., Mobiluncus spp.), this clinical syndrome also has other names, namely Haemophilus vaginalis vaginitis, nonspecific vaginitis or Gardnerella vaginalis vaginitis. Because the cause of BV is bacteria which are normal vaginal flora, BV is referred to as an endogenous infection in the female reproductive tract. Previous published research on BV has shown disagreements about transmission through sexual contact. Post-puberty women without sexual experience experience BV less frequently than those who have sexual experience. However, longitudinal cohort studies provide evidence that women who have new sexual partners or have multiple sexual partners have an increased incidence of BV.The likelihood that a woman has BV has a 20-fold increase in risk if her partner has BV. This raises the suggestion that it is possible that BV can be transmitted through sexual contact. However, there was no association between the incidence of BV with smoking habits, a history of abnormal Pap smears, menstruation, and menarche. Aim of this article is to review gardnerella vaginalis infection in bacterial vaginosis. Discussion: The presence of sexually transmitted diseases can also increase the risk of bacterial vaginosis. The normal vaginal ecosystem is a complex aspect. Lactobacillius is the dominant bacterial species (normal flora) in the vagina of women of childbearing age, but there are also other bacteria, namely aerobic and anaerobic bacteria. At the time BV appears, there is an overgrowth of some bacterial species which are normally present in low concentrations. Therefore, BV is categorized as an endogenous infection of the female reproductive tract.. Women with positive G. vaginalis cultures do not need routine therapy, unless they have BV symptomatically. All women with symptomatic BV require treatment, including pregnant women. Treatment of BV in pregnant women is to relieve signs and symptoms of vaginal infection, reduce the risk of infectious complications that accompany BV during pregnancy, and decrease other risk factors. Several studies using placebo have shown that treatment of sexual partners of women with BV does not improve clinical outcome of BV or decrease recurrence. Conclusion: BV has a favorable prognosis, and spontaneous improvement is reported in over one-third of cases. With the treatment of metronidazole and clindamycin gave a high cure rate (84 - 96%).Prevention needs to be done to minimize the actions that can be taken to prevent bacterial vaginosis.