New Agents Are Coming, and So Is the Resistance.

Antimicrobial resistance is a global threat that requires urgent attention to slow the spread of resistant pathogens. The United States Centers for Disease Control and Prevention (CDC) has emphasized clinician-driven antimicrobial stewardship approaches including the reporting and proper documentation of antimicrobial usage and resistance. Additional efforts have targeted the development of new antimicrobial agents, but narrow profit margins have hindered manufacturers from investing in novel antimicrobials for clinical use and therefore the production of new antibiotics has decreased. In order to combat this, both antimicrobial drug discovery processes and healthcare reimbursement programs must be improved. Without action, this poses a high probability to culminate in a deadly post-antibiotic era. This review will highlight some of the global health challenges faced both today and in the future. Furthermore, the new Infectious Diseases Society of America (IDSA) guidelines for resistant Gram-negative pathogens will be discussed. This includes new antimicrobial agents which have gained or are likely to gain FDA approval. Emphasis will be placed on which human pathogens each of these agents cover, as well as how these new agents could be utilized in clinical practice.

Assessment of Prophylactic Antibiotic Coverage in Culture-positive Traumatic Open Fractures.

Guidelines provide varying recommendations for the prophylactic antimicrobial treatment of open fractures. This single-center, retrospective cohort study was conducted to determine how well an institutional prophylactic antibiotic protocol covered pathogens associated with open fractures. The authors included adult trauma patients with one or more open fractures and a positive culture from the site of the open fracture, and compared outcomes between patients who were covered by prophylactic antibiotics with patients not covered by prophylactic antibiotics. Of 957 patients evaluated, 75 were included, with 40 patients (53%) covered by the prophylactic antibiotics received. Multidrug-resistant pathogens were isolated in 23 (58%) patients covered versus 26 (74%) patients not covered (p = 0.128). The median time to positive culture was less in patients not covered by initial antibiotics compared with those who were covered (30.2 vs. 102.1 days; p = 0.003). Over half of the patients developed cultures with pathogens that were covered by their initial antibiotic prophylaxis. (Journal of Surgical Orthopaedic Advances 33(2):084-087, 2024).

Antifungal resistance, combinations and pipeline: oh my!

Invasive fungal infections are a strong contributor to healthcare costs, morbidity and mortality, especially amongst hospitalized patients. Historically, Candida was responsible for approximately 15% of all nosocomial bloodstream infections. In the past 10 years, the epidemiology of Candida species has altered, with increasing prevalence of resistant species. With rising fungal resistance, especially in Candida spp., the demand for novel antifungal therapies has exponentially increased over the last decade. Newer antifungal agents have become an attractive option for patients needing long-term therapy for infections or those requiring antifungal prophylaxis. Despite advances in coverage of non-Candida pathogens with newer agents, clinical scenarios involving multidrug-resistant fungal pathogens continue to arise in practice. Combination antifungal therapy can lead to a host of side-effects, some of which can be drug limiting. Additional antifungal therapies with enhanced fungal spectrum of activity and decreased rates of adverse effects are warranted. Fosmanogepix, ibrexafungerp, olorofim and rezafungin may help fill some of these gaps in the antifungal armamentarium. This article is part of the Challenges and strategies in the management of invasive fungal infections Special Issue: https://www.drugsincontext.com/special_issues/challenges-and-strategies-in-the-management-of-invasive-fungal-infections.

Local anaesthetic for pain post rubber band ligation of haemorrhoids: a prospective, single-blinded randomised controlled trial.

BACKGROUND: Rubber band ligation (RBL) is a widely accepted intervention for the treatment of haemorrhoids. However, post procedure pain is a common complaint. The aim of this study was to determine whether the addition of local anaesthetic (LA) to the haemorrhoid pedicle base, post RBL, aids in reducing early post-procedure pain. Additionally, to compare perceived perianal numbness, oral analgesia usage and total consumption, and adverse events. METHODS: This study was a prospective, single-blinded randomised controlled trial. Patients were recruited from colorectal clinics in two Australian hospitals between 2018-2019. Patients randomised to the intervention (LA) group received 2mls bupivacaine 0.5% with adrenaline 1:200,000 to each haemorrhoid base. Patients in the control group were not administered LA. Pain scores were recorded over 48 h using visual analogue scales. Analgesia consumption was documented and other secondary objectives were recorded dichotomously (yes/no). RESULTS: At 1 h post-procedure, patient reported pain scores were significantly lower in the LA group compared to the control group (p = 0.04). There were no significant differences in pain scores between the groups at 4, 24 or 48 h. Additionally, there were no significant differences between groups with respect to oral analgesia usage, perianal numbness or adverse events. CONCLUSIONS: LA to the haemorrhoid pedicle post RBL may significantly reduce early post procedure pain without any increased risk of adverse effects.

Evaluation of an Antifungal Stewardship Initiative Targeting Micafungin at an Academic Medical Center.

Delays in the treatment of proven invasive fungal disease have been shown to be harmful. However, empiric treatment for all patients at risk of infection has not demonstrated benefit. This study evaluates the effects of a micafungin stewardship initiative on the duration of therapy and clinical outcomes at the University of Mississippi Medical Center in Jackson, Mississippi. This single-center quasi-experiment evaluated patients who received micafungin. Adult inpatients who received at least one treatment dose of micafungin in the pre-intervention (1 October 2020 to 30 September 2021) or post-intervention (1 October 2021 to 30 April 2022) groups were included. Patients were placed on micafungin for prophylaxis and those who required definitive micafungin therapy were excluded. An algorithm was used to provide real-time recommendations in order to assess change in the treatment days of micafungin therapy. A total of 282 patients were included (141 pre-group versus 141 post-group). Over 80% of the patients included in the study were in an intensive care unit, and other baseline characteristics were similar. The median number of treatment days with micafungin was 4 [IQR 3-6] in the pre-group and 3 [IQR 2-6] in the post-group (p = 0.005). Other endpoints, such as time to discontinuation or de-escalation, hospital mortality, and hospital length of stay, were not significantly different between the groups. An antifungal stewardship initiative can be an effective way to decrease unnecessary empiric antifungal therapy for patients who are at risk of invasive fugal disease.

Approach to fever in patients with neutropenia: a review of diagnosis and management.

Febrile neutropenia (FN) is associated with mortality rates as high as 40%, highlighting the importance of appropriate clinical management in this patient population. The morbidity and mortality of FN can be attributed largely to infectious processes, with specific concern for infections caused by pathogens with antimicrobial resistance. Expeditious identification of responsible pathogens and subsequent initiation of empiric antimicrobial therapy is imperative. There are four commonly used guidelines, which have variable recommendations for empiric therapy in these populations. All agree that changes could be made once patients are stable and/or with an absolute neutrophil count (ANC) over 500 cells/mcL. Diagnostic advances have the potential to improve knowledge of pathogens responsible for FN and decrease time to results. In addition, more recent data show that rapid de-escalation or discontinuation of empiric therapy, regardless of ANC, may reduce days of therapy, adverse effects, and cost, without affecting clinical outcomes. Antimicrobial and diagnostic stewardship should be performed to identify, utilize, and respond to appropriate rapid diagnostic tests that will aid in the definitive management of this population.

Cannabidiol oxidation product HU-331 is a potential anticancer cannabinoid-quinone: a narrative review.

Cannabidiol and related cannabinoids are under exploration for the treatment of a number of disease states. The cannabinoid-quinone HU-331 has been studied as a potential anticancer therapeutic. Previous studies provide evidence that HU-331 displays anticancer activity without some of the known adverse events associated with traditional anticancer agents. In this brief review, we will explore the literature related to the activity of HU-331 in purified systems, cancer cell lines, and animal models. For example, HU-331 displays inhibitory activity against human topoisomerase IIα, a known anticancer drug target. Further, in multiple cell model systems, the IC50 value for HU-331 was less than 10 µM. In addition, mouse model systems demonstrate the ability of HU-331 to shrink tumors without causing cardiotoxicity. In addition, we will briefly review the activity of some key analogs and derivatives of HU-331 for various disease states. Taken together, the published studies support further exploration of HU-331 for the treatment of cancer and possibly other disease states.

Efficacy of postoperative oral metronidazole for haemorrhoidectomy pain: a randomized double-blind, placebo-controlled trial.

AIM: The aim of this work was to examine the efficacy of oral metronidazole in reducing posthaemorrhoidectomy pain versus placebo. METHOD: Forty patients were randomized to either metronidazole and standard care or placebo and standard care (21 metronidazole, 19 placebo) in a double-blinded, randomized controlled trial. The main outcome measure was posthaemorrhoidectomy pain scores over 21 days, measured on a 10-point Likert scale. RESULTS: There were no significant differences between groups with regards to age, gender, smoking status, self-reported general health or quality of life, haemorrhoid-related pain, haemorrhoid-related impact on quality of life, reported satisfaction with surgery, experience of surgery, median overall pain score or likelihood of recommending surgery to others. For reported median worst pain scores and defaecation-related pain, a trend to significance was identified between groups on days 16 and 18-21, with the metronidazole group reporting less pain. However, these differences were not significant when prespecified Bonferroni correction criteria were used. Using multilevel mixed effects modelling, the impact of time on median worst pain score was identified to be highly significant (P < 0.0001) whereas treatment allocation (placebo versus metronidazole) did not significantly affect the improvement in patients' reported pain (P = 0.8837). CONCLUSION: Our data do not support the hypothesis that postoperative metronidazole has a clinically meaningful effect on posthaemorrhoidectomy pain. This study adds to the previous literature, and implies that it should not be routinely used as an adjunct to analgesia.

Clarifying the Mechanism of Copper(II) α-(N)-Heterocyclic Thiosemicarbazone Complexes on DNA Topoisomerase IIα and IIß.

Topoisomerase II is a nuclear enzyme involved in the maintenance of DNA and is an effective anticancer drug target. However, several clinical topoisomerase II-targeted agents display significant off-target toxicities and adverse events. Thus, it is important to continue characterizing compounds with activity against topoisomerase II. We previously analyzed α-(N)-heterocyclic thiosemicarbazone copper(II) complexes against human topoisomerase IIα (TOP2A), but humans also express topoisomerase IIß (TOP2B), which has distinct functional roles. Therefore, we examined two α-(N)-heterocyclic thiosemicarbazone copper [Cu(II)] complexes for activity against TOP2B in a purified system. The Cu(II) complexes, Cu(APY-ETSC)Cl and Cu(BZP-ETSC)Cl, were examined using plasmid DNA cleavage, supercoiled DNA relaxation, enzyme inactivation, protein cross-linking, DNA ligation, and ATP hydrolysis assays with TOP2B to determine whether these compounds act similarly against both enzymes. Both of the Cu(II) thiosemicarbazone (Cu-TSC) complexes we tested disrupted the function of TOP2B in a way similar to the effect on TOP2A. In particular, TOP2B DNA cleavage activity is increased in the presence of these compounds, while the relaxation and ATPase activities are inhibited. Further, both Cu-TSCs stabilize the N-terminal DNA clamp of TOP2A and TOP2B and rapidly inactivate TOP2B when the compounds are present before DNA. Our data provide evidence that the Cu-TSC complexes we tested utilize a similar mechanism against both isoforms of the enzyme. This mechanism may involve interaction with the ATPase domain of TOP2A and TOP2B outside of the ATP binding pocket. Additionally, these data support a model of TOP2 function where the ATPase domain communicates with the DNA cleavage/ligation domain.

Efficacy of cyclic sacral nerve stimulation for faecal incontinence.

BACKGROUND: Sacral nerve stimulation (SNS) is an established treatment option for faecal incontinence. Cyclic stimulation will improve the longevity of the implanted stimulator, but little is known about its efficacy. The aim of this retrospective clinical study was to assess the efficacy of cyclic SNS for faecal incontinence. METHODS: Sixty-three patients underwent percutaneous nerve evaluation (PNE) test with a 2-week period of continuous SNS. The PNE test was deemed positive in 42 patients (67 %) who underwent implantation with permanent stimulator. All 42 patients were initially stimulated in a cyclic manner with stimulation for 20 s followed by 8 s without. During follow-up, the stimulator was explanted in 2 patients and permanently turned off in one due to the loss of effect. A postal questionnaire including the Wexner score, a general quality of life (Qol) score, and a bowel habit diary was distributed to 39 patients. RESULTS: The questionnaire was returned by 29/39 (74 %) of the patients. Median duration of follow-up was 16 (range 3-34) months. The Wexner score and the general QoL score were significantly improved compared to pre-treatment values. Some 18 patients (62 %) were still treated with cyclic stimulation at follow-up, reporting more frequent episodes of urgency without incontinence (p = 0.020) compared to symptoms during the PNE test. Patients who had changed to continuous stimulation due to a suboptimal effect during follow-up reported more frequent episodes of urgency with incontinence (p = 0.034), minor soiling (p = 0.045) and days wearing pads (p = 0.027) compared with symptoms during the PNE test. CONCLUSIONS: Cyclic stimulation seems effective for most patients treated with SNS for faecal incontinence.

Postoperative recurrence of Crohn's disease: impact of endoscopic monitoring and treatment step-up.

AIM: Eighty per cent of patients with Crohn's disease require surgery, of whom 70% will require a further operation. Recurrence occurs at the anastomosis. Although often recommended, the impact of postoperative colonoscopy and treatment adjustment is unknown. METHOD: Patients with a bowel resection over a 10-year period were reviewed and comparison made between those who did and did not have a postoperative colonoscopy within 1 year of surgery, and those who did or did not have a step-up in drug therapy. RESULTS: Of 222 patients operated on, 136 (65 men, mean age 33 years, mean disease duration 8 years, median follow-up 4 years) were studied. Of 70 patients with and 66 without postoperative colonoscopy, clinical recurrence occurred in 49% and 48% (NS) and further surgery in 9% and 5% (NS). Eighty-nine per cent of colonoscoped patients had a decision based on the colonoscopic findings: of these, 24% had a step-up of drug therapy [antibiotics (n =10), aminosalicylates (n=2), thiopurine (n=5), methotrexate (n=1)] and 76% had no step-up in drug therapy. In colonoscoped patients clinical recurrence occurred in 9 (60%) of 15 patients with, and 23 (49%) of 47 without step-up and surgical recurrence in 2 (13%) of 15 and 4 (9%) of 47 (NS). CONCLUSION: Clinical recurrence occurs in a majority of patients soon after surgery. In this cohort, there was no clinical benefit from colonoscopy or increased drug therapy within 1 year after operation. However, the response to the endoscopic findings was not standardized and immunosuppressive therapy was uncommon. Standardizing timing of colonoscopy and drug therapy, including more intense therapy, may improve outcome, although this remains to be proven.

Faecal diversion in the management of perianal Crohn's disease.

AIM: Severe perianal Crohn's disease remains an uncommon but important indication for faecal diversion (FD). The advent of biological therapy such as infliximab for Crohn's disease is considered to have improved the outcome for these patients. The aim of this study was to assess the outcome of patients undergoing FD for perianal Crohn's disease and the impact of biological therapy (infliximab). METHOD: Retrospective chart review was undertaken of patients who underwent FD for management of perianal Crohn's disease at two tertiary centres between 1990 and 2007. Patient demographics, disease extent and use of biological therapy were recorded. Subsequent surgery was assessed. The impact of infliximab on rates of proctocolectomy and restoration of intestinal continuity was assessed. RESULTS: Twenty-one patients (one male, 20 female), median age 34 years (range 21-67 years), underwent FD for perianal Crohn's disease. At a median follow-up time of 22 months (range 4-121 months), four patients had undergone stoma closure, 11 had had proctocolectomy and six had a stoma in situ. The effects of the procedure on severity of perianal disease were no effect in four (19%), temporary improvement in six (29%), initial improvement with later plateau in seven (33%) and healing in four patients (19%). Eleven patients (52%) received infliximab. In this group, four underwent proctocolectomy and two had intestinal continuity restored. This was not significantly different from the noninfliximab group. CONCLUSION: Patients undergoing FD for perianal Crohn's disease have <20% likelihood of restoration of intestinal continuity. This is not improved with biological therapy.

Enterocutaneous fistula: a single-centre experience.

BACKGROUND: Enterocutaneous fistulae (ECFs) present a difficult management problem and can cause significant morbidity. The aim of the study was to assess the outcome of these patients. METHODS: A retrospective chart review of all patients with ECF managed at a tertiary centre between 1996 and 2006 was performed. Demographic, management and outcome data including ECF closure, morbidity and mortality were recorded. RESULTS: A total of 33 patients (17 male) were identified with ECF (median age: 63 years, range: 27-84). The primary aetiology was Crohn's (30%), anastomotic leak (24%), iatrogenic (18%), mesh (6%), neoplasia (6%) and other (16%). Definitive surgery was undertaken in 21 (64%) at a median of 6.4 months (0.4-72 range) following presentation. Twenty percent of patients required emergency surgical intervention and 5 patients required preoperative total parenteral nutrition (TPN). Surgical management was formal resection and reanastomosis in all patients, with a mean operative time of 4.75 h (standard deviation = 1.8). The median hospital stay for the operative group was 19 days (7-85). Four patients required post-operative TPN with one patient requiring home TPN. Fistula closure rate was 97% (operative group: 21 out of 21; non-operative group: 11 out of 12). Mean follow-up was 37.3 months (0.5-217). Six (19%) operative patients developed fistula recurrence. There were two deaths at 2 and 5 months (fistula aetiology malignant colonic fistula and radiation enteritis, respectively). CONCLUSION: Patients with ECF can be treated with low morbidity and low recurrence rate in a multidisciplinary setting. We believe that patients with ECF should be referred to specialist units for management.

Substance P and vasoactive intestinal peptide are reduced in right transverse colon in pediatric slow-transit constipation.

BACKGROUND: Slow-transit constipation (STC) is recognized in children but the etiology is unknown. Abnormalities in substance P (SP), vasoactive intestinal peptide (VIP) and nitric oxide (NO) have been implicated. The density of nerve fibers in circular muscle containing these transmitters was examined in colon from children with STC and compared to other pediatric and adult samples. METHODS: Fluorescence immunohistochemistry using antibodies to NO synthase (NOS), VIP and SP was performed on colonic biopsies (transverse and sigmoid colon) from 33 adults with colorectal cancer, 11 children with normal colonic transit and anorectal retention (NAR) and 51 with chronic constipation and slow motility in the proximal colon (STC). The percentage area of nerve fibers in circular muscle containing each transmitter was quantified in confocal images. KEY RESULTS: In colon circular muscle, the percentage area of nerve fibers containing NOS > VIP > SP (6 : 2 : 1). Pediatric groups had a higher density of nerve fibers than adults. In pediatric samples, there were no regional differences in NOS and VIP, while SP nerve fiber density was higher in sigmoid than proximal colon. STC children had lower SP and VIP nerve fiber density in the proximal colon than NAR children. Twenty-three percent of STC children had low SP nerve fiber density. CONCLUSIONS & INFERENCES: There are age-related reductions in nerve fiber density in human colon circular muscle. NOS and VIP do not show regional variations, while SP nerve fiber density is higher in distal colon. 1/3 of pediatric STC patients have low SP or VIP nerve fiber density in proximal colon.

Decrease in nerve fibre density in human sigmoid colon circular muscle occurs with growth but not aging.

BACKGROUND: Studies in animals suggest that enteric neurons decrease in density or number with increasing age. Neurons containing nitric oxide (NO), vasoactive intestinal peptide (VIP) and Substance P (SP) have been implicated. In human large intestine, NO-utilizing neurons decrease during childhood or early adulthood but it is not known if the innervation of the muscle changes. This study examined the density of nerve fibres containing these transmitters in sigmoid colon circular muscle from children and adults. METHODS: Fluorescence immunohistochemistry using antibodies to neuronal NO synthase (nNOS), VIP and SP was performed on sigmoid colon from 18 adults with colorectal cancer, two children with familial adenomatous polyposis, and normal colon from nine children with Hirschsprung's disease. The percentage area of immunoreactive (IR) nerve fibres containing each transmitter in circular muscle was quantified in confocal images. KEY RESULTS: In the adult sigmoid colon circular muscle, the percentage area of nerve fibres containing nNOS>VIP>SP (6 : 2 : 1). Paediatric groups had significantly higher percentage area of nerve fibres containing nNOS, VIP or SP-IR than adults, with the decrease in nerve fibre density occurring from birth to 30 years. Circular muscle thickness increased between 12 and 30 years. Total nerve fibre area remained constant, while the muscle increased in thickness. CONCLUSIONS & INFERENCES: In human sigmoid colon circular muscle, there are reductions in nNOS-, VIP- and SP-IR nerve fibre density with growth from newborn to late adolescence but little further change with aging. The reduction in nerve density is due to an increase in circular muscle thickness rather than a loss of nerve fibres.

Treatment of left-sided colonic emergencies: a comparison of US, UK and Australian surgeons.

BACKGROUND: This study sought to identify and compare the current practice of surgeons in Australia, the UK and the US when presented with a left-sided colonic emergency. METHODS: Questionnaires were posted to 500 US, 500 UK and 500 Australian surgeons. Demographic data were collected regarding the surgeon's age and surgical interest, as well as their preferred method of managing left-sided colonic emergencies (namely obstruction and perforation in stable and unstable patients). The results were analysed using the chi-squared test. RESULTS: Completed questionnaires were received from 224 UK surgeons (45%), 180 US surgeons (36%) and 259 Australian surgeons (52%). All the US surgeons had an interest in gastrointestinal surgery, while 31% of the UK surgeons and 22% of Australian surgeons had an interest in colorectal surgery. In a haemodynamically stable patient with a good anaesthetic risk presenting with a complete sigmoid obstruction, significantly more UK (84%) and Australian surgeons (70%) would perform a resection and anastomosis than US surgeons (54%, p<0.0001). Of those with a colorectal interest, 97% of UK surgeons and 80% of Australian surgeons would opt for resection and anastomosis. In a haemodynamically stable patient with a good anaesthetic risk with a perforation of the sigmoid colon and purulent peritonitis, 46% of UK surgeons, 32% of Australian surgeons and 33% of US surgeons would opt for resection and anastomosis, and among colorectal surgeons, 68% of UK surgeons and 50% of Australian surgeons would opt for resection and anastomosis. CONCLUSIONS: The management of left-sided colonic emergencies varies depending on geographic location and degree of colorectal subspecialization. While the literature suggests that single-stage procedures are accepted and safe, the reasons for this variation are explored.

Monitored and modeled coral population dynamics and the refuge concept.

With large-scale impacts on coral reefs due to global climatic change projected to increase dramatically, and suitability of many areas for reef growth projected to decrease, the question arises whether particular settings might serve as refugia that can maintain higher coral populations than surrounding areas. We examine this hypothesis on a small, local scale in Honduras, western Caribbean. Dense coral thickets containing high numbers of the endangered coral Acropora cervicornis occur on offshore banks while being rare on the fringing reef on nearby Roatán. Geomorphological setting and community dynamics were evaluated and monitored from 1996 to 2005. A model of population dynamics was developed to test assumptions derived from monitoring. Coral cover on the fringing reef declined in 1998 from >30% to <20%, but the banks maintained areas of very dense coral cover (32% cover by A. cervicornis on the banks but <1% on the fringing reef). Bathymetry from satellite images showed the banks to be well-separated from the fringing reef, making asexual connectivity between banks and fringing reef impossible but protecting the banks from direct land-runoff during storms. Exposure to SE tradewinds also causes good flushing. Only four A. cervicornis recruits were recorded on the fringing reef over 6 years. Runoff associated with hurricanes caused greater mortality than did bleaching in 1998 and 2005 on the fringing reef, but not on the banks. Since 1870, our analysis suggests that corals on the banks may have been favored during 17 runoff events associated with tropical depressions and storms and potentially also during five bleaching events, but this is more uncertain. Our model suggests that under this disturbance regime, the banks will indeed maintain higher coral populations than the fringing reef and supports the assumption that offshore banks could serve as refugia with the capacity to subsidize depleted mainland populations.

Part III. Analysis of data gaps pertaining to enterotoxigenic Escherichia coli infections in low and medium human development index countries, 1984-2005.

Enterotoxigenic Escherichia coli (ETEC) is a common cause of profuse watery diarrhoea in the developing world, often leading to severe dehydration or death. We found only 15 population-based studies in low and medium human development index (HDI) countries from 1984 to 2005 that evaluate disease incidence. Reported incidence ranged from 39 to 4460 infections/1000 persons per year. The peak incidence of ETEC appeared to occur between ages 6 and 18 months. A median of 14% (range 2-36%) of diarrhoeal specimens were positive for ETEC in 19 facility- and population-based studies conducted in all age groups and 13% (range 3-39%) in 51 studies conducted in children only. Heat-labile toxin (LT)-ETEC is thought to be less likely to cause disease than heat-stable toxin (ST)-ETEC or LT/ST-ETEC. Because population-based studies involve enhanced clinical management of patients and facility-based studies include only the most severe illnesses, reliable data on complications and mortality from ETEC infections was unavailable. To reduce gaps in the current understanding of ETEC incidence, complications and mortality, large population-based studies combined with facility-based studies covering a majority of the corresponding population are needed, especially in low-HDI countries. Moreover, a standard molecular definition of ETEC infection is needed to be able to compare results across study sites.